Materiały źródłowe

• #1 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

• #2 Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16287204/

  Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control.

• #3 Chapter 11: Human Papillomavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html

  This chapter discusses pathogenesis, clinical features, epidemiology, vaccination, and surveillance of human papillomavirus, or HPV. […] Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. […] Persistent infections can develop into anogenital warts, precancers, and cervical, anogenital, or oropharyngeal cancers in women and men. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. […] High-risk HPV types are detected in 99% of cervical precancers. […] Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. […] The pathogenesis of other types of HPV-related cancers may follow a similar course, although less is known about their respective precursor lesions: anal HSIL has been identified as a precursor to anal cancer, vulvar HSIL has been identified as a precursor to vulvar cancer, and vaginal HSIL has been identified as a precursor to vaginal cancer. […] Persistent infection is the most important risk factor for the development of cervical cancer.

• #4 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11

  As the primary etiological agents of cervical cancer, human papillomaviruses (HPVs) must deliver their genetic material into the nucleus of the target cell. The viral capsid has evolved to fulfil various roles that are critical to establish viral infection. The entry of HPV in vitro is initiated by binding to a cell surface receptor in contrast to the in vivo situation where the basement membrane has recently been identified as the primary site of virus binding. Binding of HPV triggers conformational changes, which affect both capsid proteins L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. Most HPV types that have been examined, appear to enter the cell via a clathrin-dependent endocytic mechanism, although many data are inconclusive and inconsistent.

• #5 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11

  The HPV genome is surrounded by an icosahedral capsid (T = 7) of 55 nm in diameter composed by two structural proteins, the major protein L1 and the minor capsid protein L2. The L2 protein is an internally located multifunctional protein with roles in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions and nuclear transport of the HPV genome. […] The classical notion of a virus binding to a single receptor to enter cells through a single defined uptake mechanism is quickly being overtaken by a more complex picture. New findings, such as a specific co-receptor and virus attachment to multiple receptors, have raised the question that viruses known to bind to a non-specific receptor may turn out to also have a more specific co-receptor. […] Taken together, capsid interaction with HSPG induces conformational changes that result in the exposure of the L2 amino terminus. Exposure of this L2 N-terminus allows access to highly conserved consensus furin convertase recognition site and subsequent furin cleavage which is essential for successful infection.

• #6 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

• #7 Papillomaviridae – Wikipedia

  https://en.wikipedia.org/wiki/Papillomaviridae

  Papillomaviruses are usually considered as highly host- and tissue-tropic, and are thought to rarely be transmitted between species. […] Papillomaviruses replicate exclusively in the basal layer of the body surface tissues. […] The current understanding is that viral DNA replication likely occurs in the G2 phase of the cell cycle and rely on recombination-dependent replication supported by DNA damage response mechanisms (activated by the E7 protein) to produce progeny viral genomes. […] The expression of the viral late genes, L1 and L2, is exclusively restricted to differentiating keratinocytes in the outermost layers of the skin or mucosal surface. […] After successful infection of a keratinocyte, the virus expresses E1 and E2 proteins, which are for replicating and maintaining the viral DNA as a circular episome.

• #8 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

• #9 Ethiology and Pathophysiology of Whart Hpv Infection: A Review Article | Auctores

  https://www.auctoresonline.org/article/ethiology-and-pathophysiology-of-whart-hpv-infection-a-review-article

  The pathogenesis of HPV begins with infection of stem cells in the basal layer of the epithelium. Once inside the cell, the virus requires expression of the E1 and E2 genes to maintain a low genome copy number. These proteins bind to the origin of replication and the virus secretes cellular DNA polymerases and other proteins required for DNA replication. In the suprabasal layer, the expression of genes E1, E2, E5, E6 and E7 contributes to the maintenance of the viral genome and induces cell proliferation, increasing the number of HPV-infected cells in the epithelium, resulting in a higher number of cells that will eventually produce infectious virions. In more differentiated cells of the same epithelial layer, promoter activation is dependent on differentiation and maintenance of E1, E2, E6 and E7 gene expression. Furthermore, there will be an activation of the expression of the E4 gene, which will promote the amplification of viral genome replication, greatly increasing the number of virus copies per cell, at the same time the expression of L1 and L2 genes occurs.

• #10 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers.

• #11 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  The overexpression of E6 and E7 facilitates oncogenesis by disrupting the transcription of tumor suppressor genes and triggering flanking gene amplification. […] The specific oncogenic mechanisms of early proteins of hr-HPVs are discussed in the following part. […] E6 is well-known for binding with and degrading p53 in a ubiquitinproteasome way. Degradation of p53 promotes cell proliferation and inhibits apoptosis. […] E7 binds with pRb to release E2F, promoting cells entering the S-phase. E7 can increase the expression of cyclins to enable cells to alter from the G1-phase to S-phase unrestrictedly, resulting in uncontrolled cell proliferation. […] E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation. […] E6 promotes glycolysis and lipid synthesis to support cell growth.

• #12 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins, but no such functions are associated with the corresponding proteins from the low-risk types. High-risk E6 binds the p53 tumor suppressor protein as part of a trimeric complex with the cellular ubiquitin ligase, E6AP, leading to the rapid turnover of p53. E7 binds to the retinoblastoma (Rb) family of tumor suppressors, as well as other proteins involved in cell cycle regulation. […] The E1 protein is a DNA helicase/ATPase. E1 proteins function in origin recognition and exhibit both ATPase and 3-5 helicase activities. They recognize AT-rich sequences at the origins of HPV replication, which are located proximal to the start sites of early transcription. By itself, E1 weakly binds origin sequences, but this binding is facilitated by complex formation with E2 proteins. E2 binding sites are located adjacent to E1 recognition sequences, and E2 acts to load E1 onto the origin.

• #13 Human papillomavirus infection – Wikipedia

  https://en.wikipedia.org/wiki/Human_papillomavirus_infection

  The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7). The viral oncogenes E6 and E7 are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression.

• #14 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  The expression in and above the basal layer of E5, E6, and E7 creates the right conditions for HPV replication by, among other things, stimulating cell proliferation, inhibiting cell apoptosis, and evading the host immune response. […] The life cycle of HPV is shown in Figure 2. […] Early viral proteins such as E5, E6, and E7 play the most important role in the pathogenesis of neoplastic lesions arising from HPV infections. […] The E6 protein binds to the cellular anti-oncogene p53, leading to its inactivation. […] The integration appears in the course of persistent HPV infection, and causes the inhibition of the HPV replication cycle. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT).

• #15 Human papillomavirus pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Human_papillomavirus_pathophysiology

  P53 protein is a cellular check point at G0/G1 to S phase of cell cycle and is also responsible for cell apoptosis for unrepaired DNA mutations. E6 protein binds P53 which results in degradation of P53, leaving cell without any check for mutations and unregulated cell growth. […] Rb protein is negative regulator of cell growth. It binds E2F transcription factor which controls DNA replication and cyclin protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into S phase of cell cycle, resulting in increased replication rate of cells accumulating mutations.

• #16 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  The overexpression of E6 and E7 facilitates oncogenesis by disrupting the transcription of tumor suppressor genes and triggering flanking gene amplification. […] The specific oncogenic mechanisms of early proteins of hr-HPVs are discussed in the following part. […] E6 is well-known for binding with and degrading p53 in a ubiquitinproteasome way. Degradation of p53 promotes cell proliferation and inhibits apoptosis. […] E7 binds with pRb to release E2F, promoting cells entering the S-phase. E7 can increase the expression of cyclins to enable cells to alter from the G1-phase to S-phase unrestrictedly, resulting in uncontrolled cell proliferation. […] E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation. […] E6 promotes glycolysis and lipid synthesis to support cell growth.

• #17 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  E7 induces the expression of H3K27-specific demethylases KDM6A and KDM6B and promotes cell growth in HPV-16 positive cells. […] E7 can directly bind with E2F6, a member of the E2F family that can repress transcription, causing the extension of the S-phase. […] E7 promotes the invasion and migration of cancer cells, resulting in malignant phenotypes.

• #18 Human papillomavirus pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Human_papillomavirus_pathophysiology

  P53 protein is a cellular check point at G0/G1 to S phase of cell cycle and is also responsible for cell apoptosis for unrepaired DNA mutations. E6 protein binds P53 which results in degradation of P53, leaving cell without any check for mutations and unregulated cell growth. […] Rb protein is negative regulator of cell growth. It binds E2F transcription factor which controls DNA replication and cyclin protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into S phase of cell cycle, resulting in increased replication rate of cells accumulating mutations.

• #19 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation. […] The continuous activity of E6 and E7 proteins leads to aberrant cell proliferation, accumulation of oncogene mutations, and ultimately cervical cancer. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The interaction of E6 with various pathways is associated with cancer initiation, progression and metastasis.

• #20 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  The E5 protein is present in all high-risk mucosal HPV types; it promotes tumor progression as an early oncoprotein. […] E6 and E7 proteins may also activate the intracellular signal transduction pathways PI3K/AKT/mTOR and JAK/STAT. […] The metabolic pathways listed above play a role in the pathogenesis of many cancers.

• #21 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  The HPV E5 proteins are small hydrophobic proteins whose functions remain unresolved. These proteins are localized to endosomal membranes and the Golgi but on occasion are found in the cellular membranes. In bovine papillomaviruses (BPVs), the E5 protein encodes the primary transforming activity and acts by associating with the platelet-derived growth factor (PDGF) receptor. The HPV E5 proteins have little homology to their BPV counterparts and probably act through different cellular targets.

• #22 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  HPVs are among the most common pathogens affecting humans and genital HPV infection is considered the most common sexually transmitted disease. […] According to the WHO, HPV infections are responsible for approximately 5% of all cancers worldwide, and every year 625,600 women and 69,400 men develop cancer due to HPV infection. […] Almost all cases (99.7%) of cervical cancer are caused by HPV and 80% of all cancers caused by HPV are cervical. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The E6 protein (150–160 amino acids, about 18 kDal) is a major oncoprotein. […] The E7 protein binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation.

• #23 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  The E5 protein is present in all high-risk mucosal HPV types; it promotes tumor progression as an early oncoprotein. […] E6 and E7 proteins may also activate the intracellular signal transduction pathways PI3K/AKT/mTOR and JAK/STAT. […] The metabolic pathways listed above play a role in the pathogenesis of many cancers.

• #24 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins, but no such functions are associated with the corresponding proteins from the low-risk types. High-risk E6 binds the p53 tumor suppressor protein as part of a trimeric complex with the cellular ubiquitin ligase, E6AP, leading to the rapid turnover of p53. E7 binds to the retinoblastoma (Rb) family of tumor suppressors, as well as other proteins involved in cell cycle regulation. […] The E1 protein is a DNA helicase/ATPase. E1 proteins function in origin recognition and exhibit both ATPase and 3-5 helicase activities. They recognize AT-rich sequences at the origins of HPV replication, which are located proximal to the start sites of early transcription. By itself, E1 weakly binds origin sequences, but this binding is facilitated by complex formation with E2 proteins. E2 binding sites are located adjacent to E1 recognition sequences, and E2 acts to load E1 onto the origin.

• #25 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  E6 and E7 may also interact with other metabolic pathways involved in cell differentiation and proliferation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] Studies have shown that the site of integration, as well as the size and region of the viral DNA, can vary among individuals. […] The initiation of viral gene transcription is likely to be influenced by interactions with some PML NB-forming proteins, including Sp100. […] The E1 protein has helicase activity and forms a complex with E2, resulting in increased specificity to the target DNA sequence.

• #26 Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16287204/

  Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control.

• #27 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  Persistent infection with hr-HPVs can cause precancerous lesions, thus evolving into various cancers, including head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC), anal cancer, as well as vulvar, penile, and vaginal cancers that are less prevalent. […] The implications of this review extend beyond understanding the life cycle and oncogenic signaling pathways of hr-HPV infections. It also underscores the role of hr-HPV as a significant biomarker for cancer screening and early detection, as well as a therapeutic target for cancer treatment. […] hr-HPV integration has numerous ways to alter the state of host cells, thereby promoting the initiation and development of cancers. hr-HPV integration results in the formation of fusion transcripts, which have been found in hr-HPV-related CCs. Fusion transcripts elevate the mRNA expression levels of E6 and E7 and inhibit the E2 expression, which serves as a transcriptional inhibitor of E6 and E7.

• #28 The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response | Scientific Reports

  https://www.nature.com/articles/s41598-019-49886-4

  The Human Papillomavirus (HPV) E1 protein is the only viral protein with enzymatic activity. The main known function of this protein is the regulation of the viral DNA replication. […] Nevertheless, it has been demonstrated that the ablation of HPV18 E1 mRNA in HeLa cells promotes a deregulation of several genes, particularly those involved in host defense mechanisms against viral infections; however, the specific contribution of E1 protein in HPV-independent context has not been studied. […] We found that E1 proteins from HPV16 and 18 induced an overexpression of different set of genes associated with proliferation and differentiation processes, as well as downregulation of immune response genes, including IFN1 and Interferon-stimulated gene (ISG), which are important components involved in the antiviral immune response. Together, our results indicate that HR-(High-Risk) and LR-(Low-Risk) HPV E1 proteins play an important role in inhibiting the anti-viral immune response.

• #29 The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response | Scientific Reports

  https://www.nature.com/articles/s41598-019-49886-4

  Previous studies identified the presence of the HPV18 E1 protein in HeLa cells. […] It was demonstrated that knocking down the expression of E1 by siRNAs, de-regulates gene expression, particularly four sets of genes involved in host defense mechanisms against viral infections including TLR signaling, interferon signaling, antiviral interferon stimulated genes (ISG) and apoptosis signalling. […] Our results suggest that E1 proteins regulate immune response gene expression which is shared among high- and low-risk HPV types. […] HPV E1 proteins regulate cellular gene expression. […] These results indicate that the E1 protein from both, high and low risk HPVs have an effect on different cellular processes but mainly associated with immune response. […] Our results are in agreement with those of Castillo et al., (2014) who reported a change in the expression of genes associated with the innate immune response after the ablation of E1 expression in HeLa cells.

• #30 The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response | Scientific Reports

  https://www.nature.com/articles/s41598-019-49886-4

  Particularly, 4 genes were downregulated in common by the three HPV E1 proteins (IFN1, IFN1, Viperin and CCL5), which participate in the antiviral immune response. […] The E1 proteins from low- and high-risk HPVs regulate sets of genes in common. […] This suggests that the HPV E1 proteins might have a high impact on the expression of genes associated with the immune response. […] Taken together, these results demonstrate that HPV E1 proteins from low- and high-risk decrease the expression of IFN even after stimulating IFN gene transcription, showing that HPV16, 18 and 11 E1 proteins downregulate the expression of two key components of the antiviral immune response. […] Our results propose a novel mechanism in the modulation of the immune response induced by the HPV E1 protein, which could be associated to the replicative cycle and the viral persistence by evading the immune response.

• #31 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  E6 and E7 may also interact with other metabolic pathways involved in cell differentiation and proliferation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] Studies have shown that the site of integration, as well as the size and region of the viral DNA, can vary among individuals. […] The initiation of viral gene transcription is likely to be influenced by interactions with some PML NB-forming proteins, including Sp100. […] The E1 protein has helicase activity and forms a complex with E2, resulting in increased specificity to the target DNA sequence.

• #32 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  Persistent infection with hr-HPVs can cause precancerous lesions, thus evolving into various cancers, including head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC), anal cancer, as well as vulvar, penile, and vaginal cancers that are less prevalent. […] The implications of this review extend beyond understanding the life cycle and oncogenic signaling pathways of hr-HPV infections. It also underscores the role of hr-HPV as a significant biomarker for cancer screening and early detection, as well as a therapeutic target for cancer treatment. […] hr-HPV integration has numerous ways to alter the state of host cells, thereby promoting the initiation and development of cancers. hr-HPV integration results in the formation of fusion transcripts, which have been found in hr-HPV-related CCs. Fusion transcripts elevate the mRNA expression levels of E6 and E7 and inhibit the E2 expression, which serves as a transcriptional inhibitor of E6 and E7.

• #33 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation. […] The continuous activity of E6 and E7 proteins leads to aberrant cell proliferation, accumulation of oncogene mutations, and ultimately cervical cancer. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The interaction of E6 with various pathways is associated with cancer initiation, progression and metastasis.

• #34 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  Persistent infection with hr-HPVs can cause precancerous lesions, thus evolving into various cancers, including head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC), anal cancer, as well as vulvar, penile, and vaginal cancers that are less prevalent. […] The implications of this review extend beyond understanding the life cycle and oncogenic signaling pathways of hr-HPV infections. It also underscores the role of hr-HPV as a significant biomarker for cancer screening and early detection, as well as a therapeutic target for cancer treatment. […] hr-HPV integration has numerous ways to alter the state of host cells, thereby promoting the initiation and development of cancers. hr-HPV integration results in the formation of fusion transcripts, which have been found in hr-HPV-related CCs. Fusion transcripts elevate the mRNA expression levels of E6 and E7 and inhibit the E2 expression, which serves as a transcriptional inhibitor of E6 and E7.

• #35 Human Papillomavirus (HPV) – Structure,epidemiology an…

  https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en

  HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. […] Highly oncogenic HPV types: 16 and 18 induce precancerous lesions, increasing the risk of cancer development. The transition from dysplasia to invasive cancer appears to be associated with the integration of viral DNA into the genome of host cells. […] HPV prevalence in squamous cell carcinoma of the oral cavity and oropharynx is very diverse, ranging from 8% to 74%. […] HPV 16, which has a high oncogenic potential, is most frequently isolated in the squamous cell carcinoma of the head and neck. HPV 16 was found in 60–100% of the HPV positive squamous cell carcinomas. […] The HPV status of the tumor among patients diagnosed with oropharyngeal cancer is an independent and strong prognostic factor. HPV-positive cancer has been more frequent among non-smokers and those who have a shorter history of smoking than among heavy smokers.

• #36 HPV Infections—Classification, Pathogenesis, and Potential New Therapies

  https://www.mdpi.com/1422-0067/25/14/7616

  The expression in and above the basal layer of E5, E6, and E7 creates the right conditions for HPV replication by, among other things, stimulating cell proliferation, inhibiting cell apoptosis, and evading the host immune response. […] The life cycle of HPV is shown in Figure 2. […] Early viral proteins such as E5, E6, and E7 play the most important role in the pathogenesis of neoplastic lesions arising from HPV infections. […] The E6 protein binds to the cellular anti-oncogene p53, leading to its inactivation. […] The integration appears in the course of persistent HPV infection, and causes the inhibition of the HPV replication cycle. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT).

• #37 Human Papillomavirus (HPV) – Structure,epidemiology an…

  https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en

  HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. […] Highly oncogenic HPV types: 16 and 18 induce precancerous lesions, increasing the risk of cancer development. The transition from dysplasia to invasive cancer appears to be associated with the integration of viral DNA into the genome of host cells. […] HPV prevalence in squamous cell carcinoma of the oral cavity and oropharynx is very diverse, ranging from 8% to 74%. […] HPV 16, which has a high oncogenic potential, is most frequently isolated in the squamous cell carcinoma of the head and neck. HPV 16 was found in 60–100% of the HPV positive squamous cell carcinomas. […] The HPV status of the tumor among patients diagnosed with oropharyngeal cancer is an independent and strong prognostic factor. HPV-positive cancer has been more frequent among non-smokers and those who have a shorter history of smoking than among heavy smokers.

• #38 Pathogenesis of Human Papillomavirus – Immunological Responses to HPV Infection | IntechOpen

  https://www.intechopen.com/chapters/51256

  Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. […] Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. […] The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection.

• #39 Pathogenesis of Human Papillomavirus – Immunological Responses to HPV Infection | IntechOpen

  https://www.intechopen.com/chapters/51256

  HPV infections are normally cleared by the immune system; however, the persistence of HPV could trigger a progression to malignant lesion in the presence of other risk factors. […] Therefore, the establishment, persistence of HR-HPV infection and evasion of the host immune system are necessary for premalignant lesions to initiate and progress towards squamous carcinoma. […] The downregulation of MHC class I by E5 oncoprotein allows the infected cell to evade cell-mediated immune response and this potentially enables other HPV oncoproteins in the establishment and persistence of virus infection. […] The downregulation of MHC I is an imperative mechanism to evade CTL-mediated immune clearance, however, the lack of surface MHC I will activate NK cells to attack and destroy the infected cells.

• #40 Human Papillomavirus (HPV)- An Overview

  https://microbenotes.com/human-papillomavirus-hpv/

  Once the virus infects the target cells, it does not lyse the cell or cause viremia that reduces the exposure of viral antigen that aids to evade the host immune response. […] The HPV also has the ability to downregulate major histocompatibility complex class I (MHC 1) and disrupt the interferon (IFN) pathway facilitated by oncoproteins E5, E6, and E7. […] HR-HPV types are generally associated with many types of cancers like cervical cancer and hence the presence of certain genotypes indicates a risk factor for initiation and progression of 90% of cervical cancer cases.

• #41 Unlocking The Mechanisms of HPV Entry < Yale School of Medicine

  https://medicine.yale.edu/news-article/unlocking-the-mechanisms-of-hpv-entry/

  HPVs strategy is to stay inside these vesicles and never expose itself to the cellular immune system during entry. […] If a targeted drug could stop L2 from binding to retromer, the virus couldnt infect. […] Another possibility would be to stop L2 from protruding through the endosome membrane in the first place. […] We think these targeted approaches could be applicable to every single HPV type because all the papillomaviruses have L2 sequences that penetrate membranes and bind to retromer.

• #42 Human Papillomavirus (HPV)- An Overview

  https://microbenotes.com/human-papillomavirus-hpv/

  Once the virus infects the target cells, it does not lyse the cell or cause viremia that reduces the exposure of viral antigen that aids to evade the host immune response. […] The HPV also has the ability to downregulate major histocompatibility complex class I (MHC 1) and disrupt the interferon (IFN) pathway facilitated by oncoproteins E5, E6, and E7. […] HR-HPV types are generally associated with many types of cancers like cervical cancer and hence the presence of certain genotypes indicates a risk factor for initiation and progression of 90% of cervical cancer cases.

• #43 The Role of Human Papillomavirus in Cervical Cancer

  https://www.clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-6-125.php?jid=ijccr

  The early structural proteins of the virus play a key role in the infection. E5 oncoprotein induces the activity of an enzyme inducing the process of cellular apoptosis – COX-2. The E6 protein binds to the p53 protein, which in the host cell is one of the key elements regulating the cell cycle, and the resulting E6-p53 complex excludes p53-dependent regulation of cell division processes, resulting in a state of instability at the chromosomal level, thus increasing the degree of cellular mutation, having a direct impact on its proliferation and the development of cancerous transformation. […] Interestingly, HPV has also developed mechanisms that help avoid immune responses from the host. This is due to the activity of structural early proteins E6 and E7, which implicating the excitation of translocations of the IRF-2 and IRF-3 (Interferon Regulatory Factor) genes, reduce the production of IFRα and IFNβ, which are directly involved in the reduction of virus multiplication.

• #44 Frontiers | The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1407649/full

  HPV can interfere with the expression of TLR and immune signaling pathways. HPV can downregulate Th1 response by reducing pro-inflammatory cytokines. In addition, Th2 and Treg responses are stimulated by the virus. […] HPV has a certain interfering effect on CD4/CD8 lymphocyte response and NK cells, and affects tumor cell proliferation. […] HPV can infect primitive basal keratinocyte and may target stem cells, but viral assembly and high-level expression of viral proteins only occur in the upper layer of the spinous layer and in the granules of the squamous epithelium. […] The immune response plays a crucial role in clearing most infections, but some infections cannot be eliminated and can become additional risk factors after years of accumulation. […] HPV can suppress the phosphorylation of Tyk2 kinase STAT1 and STAT2 molecules participated in IFN signal transduction in cervical cancer cell lines.

• #45 Pathogenesis of Human Papillomavirus – Immunological Responses to HPV Infection | IntechOpen

  https://www.intechopen.com/chapters/51256

  Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. […] Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. […] The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection.

• #46 Pathogenesis of Human Papillomavirus – Immunological Responses to HPV Infection | IntechOpen

  https://www.intechopen.com/chapters/51256

  HPV infections are normally cleared by the immune system; however, the persistence of HPV could trigger a progression to malignant lesion in the presence of other risk factors. […] Therefore, the establishment, persistence of HR-HPV infection and evasion of the host immune system are necessary for premalignant lesions to initiate and progress towards squamous carcinoma. […] The downregulation of MHC class I by E5 oncoprotein allows the infected cell to evade cell-mediated immune response and this potentially enables other HPV oncoproteins in the establishment and persistence of virus infection. […] The downregulation of MHC I is an imperative mechanism to evade CTL-mediated immune clearance, however, the lack of surface MHC I will activate NK cells to attack and destroy the infected cells.

• #47 Frontiers | The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1407649/full

  HPV infection plays a crucial role in the developing process of cervical cancer, including the interference of keratinocyte reaction, the reduction of LC (Langerhans cell) number and the down-regulation of LC activation markers. […] HPV initially infects basal cells, but after several weeks, the virus replicates extensively in epithelial mucosa and continues to infect, ultimately leading to the development of cancer. […] HPV can alter the expression of TLR, which is beneficial for sustained viral infection and even carcinogenesis.

• #48 Frontiers | The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1407649/full

  HPV can interfere with the expression of TLR and immune signaling pathways. HPV can downregulate Th1 response by reducing pro-inflammatory cytokines. In addition, Th2 and Treg responses are stimulated by the virus. […] HPV has a certain interfering effect on CD4/CD8 lymphocyte response and NK cells, and affects tumor cell proliferation. […] HPV can infect primitive basal keratinocyte and may target stem cells, but viral assembly and high-level expression of viral proteins only occur in the upper layer of the spinous layer and in the granules of the squamous epithelium. […] The immune response plays a crucial role in clearing most infections, but some infections cannot be eliminated and can become additional risk factors after years of accumulation. […] HPV can suppress the phosphorylation of Tyk2 kinase STAT1 and STAT2 molecules participated in IFN signal transduction in cervical cancer cell lines.

• #49 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  HPV can use the evasion process to escape the immune response. […] Therefore, HPV can multiply in host cells during viral replication without causing cytolysis, which neither stimulates the inflammatory process nor presents viral antigenic representatives. […] In host cells, type-I IFNs levels are reduced by the E6 and E7 proteins of HPV16 and generate an immune tolerance stage in the absence of costimulatory factors through inflammatory cytokines. […] These immune escape phenomena may contribute to the existence and stability of HPV infection, which further addresses cancer progression. […] Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma.

• #50 Human papillomavirus infection – Wikipedia

  https://en.wikipedia.org/wiki/Human_papillomavirus_infection

  Human papillomavirus infection (HPV infection) is caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and results in either warts or precancerous lesions. All warts are caused by HPV. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat. Nearly all cervical cancer is due to HPV, and two strains HPV16 and HPV18 account for 70% of all cases. HPV16 is responsible for almost 90% of HPV-positive oropharyngeal cancers. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis. […] HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number.

• #51 Core Concepts – Human Papillomavirus Infection – Self-Study Lessons – National STD Curriculum

  https://www.std.uw.edu/go/comprehensive-study/hpv

  Transmission of genital HPV is predominantly associated with sexual activity that results in friction-induced microabrasions during skin-to-skin contact. The transmission rate of HPV between sex partners is high, and transmission often occurs from persons with HPV who are asymptomatic or have subclinical infection. Consistent and correct use of condoms reduces the risk of genital HPV acquisition or transmission, thereby reducing the risk for HPV-associated diseases. Condom use, however, does not entirely prevent transmission of HPV, since exposure to HPV can occur in areas that are not fully covered or protected by a condom. Treatment of warts or cervical cellular abnormalities will reduce, but not eliminate, the risk of transmission. […] Available data, primarily from cervical HPV natural history, suggest that more than 90% of individuals with genital HPV infections are asymptomatic and clear the infection within 3 years. The viral clearance can entail complete elimination of HPV from the tissues or cell-mediated immune suppression of the HPV to such a low level that HPV DNA levels are undetectable using sensitive HPV DNA tests (referred to as viral latency).

• #52 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. […] HPV infection is observed in >90% of cervical cancers. […] However, HPV is not the only virus participating in cervical cancer development; other hazardous situations such as coinfections (with herpes simplex virus type-2 and Chlamydia trachomatis), smoking, persistent use of oral contraceptives, multiparity, nutritional deficiencies, immunosuppression, and immune-associated diseases are also involved in cancer progression. […] Host immune responses fight against HPV infection and eliminate most of the viral part (nearly 90%) within 2–3 years or remain in the dormant phase, while the remaining 10% are converted into chronic infections; however, only 1% can cause cervical cancer.

• #53 Chapter 11: Human Papillomavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html

  This chapter discusses pathogenesis, clinical features, epidemiology, vaccination, and surveillance of human papillomavirus, or HPV. […] Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. […] Persistent infections can develop into anogenital warts, precancers, and cervical, anogenital, or oropharyngeal cancers in women and men. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. […] High-risk HPV types are detected in 99% of cervical precancers. […] Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. […] The pathogenesis of other types of HPV-related cancers may follow a similar course, although less is known about their respective precursor lesions: anal HSIL has been identified as a precursor to anal cancer, vulvar HSIL has been identified as a precursor to vulvar cancer, and vaginal HSIL has been identified as a precursor to vaginal cancer. […] Persistent infection is the most important risk factor for the development of cervical cancer.

• #54 Chapter 11: Human Papillomavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html?utm_source=chatgpt.com

  Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. […] Persistent infections can develop into anogenital warts, precancers, and cervical, anogenital, or oropharyngeal cancers in women and men. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. […] High-risk HPV types are detected in 99% of cervical precancers. […] Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. […] The pathogenesis of other types of HPV-related cancers may follow a similar course, although less is known about their respective precursor lesions: anal HSIL has been identified as a precursor to anal cancer, vulvar HSIL has been identified as a precursor to vulvar cancer, and vaginal HSIL has been identified as a precursor to vaginal cancer. […] Persistent infection is the most important risk factor for the development of cervical cancer.

• #55 Natural history and pathogenesis of hpv | PPT

  https://www.slideshare.net/slideshow/natural-history-and-pathogenesis-of-hpv/25975600

  Persistent infection with high-risk HPV types is required for progression from normal cervical epithelium to pre-cancerous lesions and eventually invasive cervical cancer, with the contribution of additional genetic mutations and external cofactors over long periods of time. […] HPV types primarily target infections of the basal cells in the stratified squamous epithelium and metaplastic cells within squamocolumnar junctions. […] HPV mediated oncogenesis requires accumulation of additional genetic mutations over time. This suggests a long precancerous state in most cases of invasive cancer that allows the accumulation of secondary genetic mutations along with other cofactors such as smoking, carcinogens and hormonal. […] HPV infection plays an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer.

• #56 Natural history and pathogenesis of hpv | PPT

  https://www.slideshare.net/slideshow/natural-history-and-pathogenesis-of-hpv/25975600

  HPV is stealthy and evades the immune system. Natural infection with HPV does not reliably protect against future infection or reactivation. […] Only persistent high-risk infection of the cervical epithelium appears to trigger neoplastic progression. […] HPV type is the strongest factor affecting the risk of viral persistence. […] HPV 16 is highly carcinogenic with an absolute risk of CIN 3 approaching 40% at 3-5 years. […] The average time from HPV infection to CIN 3 is 7-15 years, peaking at 25-30 years. […] HPV infection is very common and in most cases does not cause health problems, but some high-risk HPV types can cause cervical cancer over many years if left untreated. […] HPV works by integrating into the host cell’s genome and inactivating tumor suppressor proteins, leading to uncontrolled cell growth.

• #57 Chapter 11: Human Papillomavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html

  This chapter discusses pathogenesis, clinical features, epidemiology, vaccination, and surveillance of human papillomavirus, or HPV. […] Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. […] Persistent infections can develop into anogenital warts, precancers, and cervical, anogenital, or oropharyngeal cancers in women and men. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. […] High-risk HPV types are detected in 99% of cervical precancers. […] Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. […] The pathogenesis of other types of HPV-related cancers may follow a similar course, although less is known about their respective precursor lesions: anal HSIL has been identified as a precursor to anal cancer, vulvar HSIL has been identified as a precursor to vulvar cancer, and vaginal HSIL has been identified as a precursor to vaginal cancer. […] Persistent infection is the most important risk factor for the development of cervical cancer.

• #58 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and -18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. […] The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment.

• #59 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. […] HPV infection is observed in >90% of cervical cancers. […] However, HPV is not the only virus participating in cervical cancer development; other hazardous situations such as coinfections (with herpes simplex virus type-2 and Chlamydia trachomatis), smoking, persistent use of oral contraceptives, multiparity, nutritional deficiencies, immunosuppression, and immune-associated diseases are also involved in cancer progression. […] Host immune responses fight against HPV infection and eliminate most of the viral part (nearly 90%) within 2–3 years or remain in the dormant phase, while the remaining 10% are converted into chronic infections; however, only 1% can cause cervical cancer.

• #60 Non-sexual HPV transmission and role of vaccination for a better future (Review)

  https://www.spandidos-publications.com/10.3892/etm.2020.9316

  Human papilloma viruses (HPVs) belong to the Papillomaviridae family and are epitheliotropic infecting squamous epithelia (skin and mucosae). HPV is estimated to be the cause of 99% of cervical cancers, 90% of anal cancer, 65% vaginal cancers, 50% vulvar cancers, and 45-90% oropharyngeal cancers. The microabrasions of epithelia permit the HPV particles to penetrate the basal layer of cells (the early phase probably promotes HPV-related disease). The virus can remain latent or inactive for months or years (the mechanism may be immunological). Hormones are presumed to participate in the carcinogenic mechanism; thus, the malignancy prospect in the case of new or recurrent HPV infections in menopausal women is uncertain. The HPV-related disease is divided into malignant and benign tumors. The virus invades its host through the anogenital and/or oropharyngeal mucosae. The effects range from warts (low-risk types) to intraepithelial dysplastic lesions, which can advance to invasive carcinoma (high-risk types). The process of cancer development from HPV infection takes ~5-10 years minimum and 20-25 years on average. Cervical carcinogenesis is represented by 4 causal stages: HPV acquisition; HPV persistence (vs. clearance); Progression to precancerous lesions; Invasive cancer.

• #61

  https://www.who.int/news-room/fact-sheets/detail/human-papilloma-virus-and-cancer

  Human papillomavirus (HPV) is the name of a group of 200 known viruses. They do not cause concerns in most people, but infection with some high-risk types is common and can cause genital warts or cancer. […] Persistent HPV infection with high-risk HPV types is the cause of cervical cancer and is associated with cancers of the vulva, vagina, mouth/throat, penis and anus. […] HPV usually goes away on its own without treatment. Some HPV infections cause genital warts. Others can cause abnormal cells to develop, which go on to become cancer. […] Cervical cancer is the most common type of cancer caused by HPV, other less common cancers affecting men and women, including anal, vulvar, vaginal, mouth/throat and penile cancers. […] HPV infection that does not go away on its own can cause changes to cervical cells, which lead to precancers that may become cervical cancer if left untreated. It usually takes 15-20 years for cervical cancer to develop after HPV infection.

• #62 Non-sexual HPV transmission and role of vaccination for a better future (Review)

  https://www.spandidos-publications.com/10.3892/etm.2020.9316

  Human papilloma viruses (HPVs) belong to the Papillomaviridae family and are epitheliotropic infecting squamous epithelia (skin and mucosae). HPV is estimated to be the cause of 99% of cervical cancers, 90% of anal cancer, 65% vaginal cancers, 50% vulvar cancers, and 45-90% oropharyngeal cancers. The microabrasions of epithelia permit the HPV particles to penetrate the basal layer of cells (the early phase probably promotes HPV-related disease). The virus can remain latent or inactive for months or years (the mechanism may be immunological). Hormones are presumed to participate in the carcinogenic mechanism; thus, the malignancy prospect in the case of new or recurrent HPV infections in menopausal women is uncertain. The HPV-related disease is divided into malignant and benign tumors. The virus invades its host through the anogenital and/or oropharyngeal mucosae. The effects range from warts (low-risk types) to intraepithelial dysplastic lesions, which can advance to invasive carcinoma (high-risk types). The process of cancer development from HPV infection takes ~5-10 years minimum and 20-25 years on average. Cervical carcinogenesis is represented by 4 causal stages: HPV acquisition; HPV persistence (vs. clearance); Progression to precancerous lesions; Invasive cancer.

• #63 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  HPV can use the evasion process to escape the immune response. […] Therefore, HPV can multiply in host cells during viral replication without causing cytolysis, which neither stimulates the inflammatory process nor presents viral antigenic representatives. […] In host cells, type-I IFNs levels are reduced by the E6 and E7 proteins of HPV16 and generate an immune tolerance stage in the absence of costimulatory factors through inflammatory cytokines. […] These immune escape phenomena may contribute to the existence and stability of HPV infection, which further addresses cancer progression. […] Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma.

• #64 The Role of Human Papillomavirus in Cervical Cancer

  https://www.clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-6-125.php?jid=ijccr

  Cervical cancer is the fourth most common cancer among women in the world, causing annually about 275,000 deaths. However, the most important factor that has a huge impact on the development of cervical cancer is primarily persistent infection with hrHPV (mainly types 16 and 18), which can lead to uncontrolled course of infection. […] If the infection does not subside, within 10-30 years of viral replication will be accompanied by neoplastic changes, concerning the endothelium of the cervix, so-called CIN (Cervical Intraephitelial Neoplasia). […] In addition, cancer stages are also distinguished, which are classified depending on the stage of cancer disease, i.e. from I to IV. […] It is assumed that the vaccine will protect the patient from HPV infection until she is ready to begin routine cytological tests, preferably in conjunction with HPV molecular tests, proving at least the persistence of high HPV antibodies for 10 years after the injection of Cervarix. […] In the prevention of cervical cancer, it is not only important to detect changes early, but also to identify factors that have the most probable etiopathogenetic relationship to the carcinogenesis process within this organ.

• #65 Interconnectedness threat: unveiling the mechanisms behind human papillomavirus-induced cervical cancer

  https://www.explorationpub.com/Journals/em/Article/1001292

  Cervical cancer is the fourth leading cause of cancer-related deaths among women worldwide, causing over 660,000 new cases and 350,000 deaths in 2022, with a disproportionately high burden in low-resource countries where access to treatment is limited. Human papillomavirus (HPV) is a common sexually transmitted infection that accounts for approximately 95% of cervical cancer cases. Persistent HPV infection can progress to cervical dysplasia, categorized into varying severities (CIN1, CIN2, and CIN3), which significantly increases cancer risk. The mechanism of HPV-induced malignancy involves the disruption of cellular apoptosis by integrating viral genetic material into cervical cells, particularly within the transformation zone. The viral proteins E6 and E7 play pivotal roles in cervical carcinogenesis by inhibiting tumor suppressor proteins, promoting uncontrolled cell proliferation, and evading immune responses, ultimately driving progression toward malignancy.

• #66 Natural history and pathogenesis of hpv | PPT

  https://www.slideshare.net/slideshow/natural-history-and-pathogenesis-of-hpv/25975600

  Persistent infection with high-risk HPV types is required for progression from normal cervical epithelium to pre-cancerous lesions and eventually invasive cervical cancer, with the contribution of additional genetic mutations and external cofactors over long periods of time. […] HPV types primarily target infections of the basal cells in the stratified squamous epithelium and metaplastic cells within squamocolumnar junctions. […] HPV mediated oncogenesis requires accumulation of additional genetic mutations over time. This suggests a long precancerous state in most cases of invasive cancer that allows the accumulation of secondary genetic mutations along with other cofactors such as smoking, carcinogens and hormonal. […] HPV infection plays an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer.

• #67

  https://www.who.int/news-room/fact-sheets/detail/human-papilloma-virus-and-cancer

  Human papillomavirus (HPV) is the name of a group of 200 known viruses. They do not cause concerns in most people, but infection with some high-risk types is common and can cause genital warts or cancer. […] Persistent HPV infection with high-risk HPV types is the cause of cervical cancer and is associated with cancers of the vulva, vagina, mouth/throat, penis and anus. […] HPV usually goes away on its own without treatment. Some HPV infections cause genital warts. Others can cause abnormal cells to develop, which go on to become cancer. […] Cervical cancer is the most common type of cancer caused by HPV, other less common cancers affecting men and women, including anal, vulvar, vaginal, mouth/throat and penile cancers. […] HPV infection that does not go away on its own can cause changes to cervical cells, which lead to precancers that may become cervical cancer if left untreated. It usually takes 15-20 years for cervical cancer to develop after HPV infection.

• #68

  https://link.springer.com/article/10.1007/s10147-023-02337-7

  Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. […] For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. […] Cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). […] In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer. […] When HPV infects target cells, HPV-derived oncogenes E6 and E7 inactivate the tumor suppressor genes p53 and pRb, respectively, leading to apoptosis resistance and abnormal cell proliferation.

• #69 The Human Papillomavirus (HPV) in Human Pathology: Description, Pathogenesis, Oncogenic Role, Epidemiology and Detection Techniques

  https://opendermatologyjournal.com/VOLUME/3/PAGE/90/ABSTRACT/

  Persistent infection by human papilloma virus (HPV) is considered to be the main causative agent of cervical cancer and other anogenital cancers. Of more than 30 genotypes capable of infecting the anogenital tract it is estimated that, worldwide, HPV 16 and 18 cause 70 percent of the cervical cancers. […] According to their oncogenic risk, they are classified as low-risk HPV (LR-HPV) and high-risk HPV (HR-HPV). […] there is no doubt about the high prevalence or involvement of types 16 and 18 in high level pathologies and carcinomas in our population.

• #70 Human Papillomavirus Infection: Symptoms and Prevention

  https://www.healthline.com/health/human-papillomavirus-infection

  The easiest ways to prevent HPV are to use condoms and to practice safe sex. […] In addition, the Gardasil 9 vaccine is available for the prevention of genital warts and cancers caused by HPV. […] Contracting HPV doesnt decrease your chances of becoming pregnant. […] In rare cases, a woman with HPV can pass it on to her baby. […] Its estimated that 95 percent of anal cancers are caused by HPV infection. […] Two strains of HPV HPV 16 and 18 account for at least 70 percent of cervical cancer cases.

• #71 Non-sexual HPV transmission and role of vaccination for a better future (Review)

  https://www.spandidos-publications.com/10.3892/etm.2020.9316

  Human papilloma viruses (HPVs) belong to the Papillomaviridae family and are epitheliotropic infecting squamous epithelia (skin and mucosae). HPV is estimated to be the cause of 99% of cervical cancers, 90% of anal cancer, 65% vaginal cancers, 50% vulvar cancers, and 45-90% oropharyngeal cancers. The microabrasions of epithelia permit the HPV particles to penetrate the basal layer of cells (the early phase probably promotes HPV-related disease). The virus can remain latent or inactive for months or years (the mechanism may be immunological). Hormones are presumed to participate in the carcinogenic mechanism; thus, the malignancy prospect in the case of new or recurrent HPV infections in menopausal women is uncertain. The HPV-related disease is divided into malignant and benign tumors. The virus invades its host through the anogenital and/or oropharyngeal mucosae. The effects range from warts (low-risk types) to intraepithelial dysplastic lesions, which can advance to invasive carcinoma (high-risk types). The process of cancer development from HPV infection takes ~5-10 years minimum and 20-25 years on average. Cervical carcinogenesis is represented by 4 causal stages: HPV acquisition; HPV persistence (vs. clearance); Progression to precancerous lesions; Invasive cancer.

• #72 Human Papillomavirus Infection: Symptoms and Prevention

  https://www.healthline.com/health/human-papillomavirus-infection

  HPV can also cause cervical cancer and other cancers of the genitals, head, neck, and throat. […] The types of HPV that cause warts are different from the types that cause cancer. […] Some strains of HPV can cause penile, anal, and throat cancer in men. […] Some strains of HPV can cause cervical cancer or cancers of the vagina, anus, or throat. […] There are at least 14 strains of HPV that can lead to cancer. […] Cancers that develop from HPV may be treated by methods such as chemotherapy, radiation therapy, or surgery. […] Routine screening for HPV and cervical cancer is important for identifying, monitoring, and treating health problems that may result from HPV infection. […] If you contract a high-risk type of HPV, some factors can make it more likely that the infection will continue and may develop into cancer.

• #73 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.

• #74 Human Papillomavirus (HPV) – Structure,epidemiology an…

  https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en

  HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. […] Highly oncogenic HPV types: 16 and 18 induce precancerous lesions, increasing the risk of cancer development. The transition from dysplasia to invasive cancer appears to be associated with the integration of viral DNA into the genome of host cells. […] HPV prevalence in squamous cell carcinoma of the oral cavity and oropharynx is very diverse, ranging from 8% to 74%. […] HPV 16, which has a high oncogenic potential, is most frequently isolated in the squamous cell carcinoma of the head and neck. HPV 16 was found in 60–100% of the HPV positive squamous cell carcinomas. […] The HPV status of the tumor among patients diagnosed with oropharyngeal cancer is an independent and strong prognostic factor. HPV-positive cancer has been more frequent among non-smokers and those who have a shorter history of smoking than among heavy smokers.

• #75 Human Papillomavirus (HPV) – Structure,epidemiology an…

  https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en

  HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. […] Highly oncogenic HPV types: 16 and 18 induce precancerous lesions, increasing the risk of cancer development. The transition from dysplasia to invasive cancer appears to be associated with the integration of viral DNA into the genome of host cells. […] HPV prevalence in squamous cell carcinoma of the oral cavity and oropharynx is very diverse, ranging from 8% to 74%. […] HPV 16, which has a high oncogenic potential, is most frequently isolated in the squamous cell carcinoma of the head and neck. HPV 16 was found in 60–100% of the HPV positive squamous cell carcinomas. […] The HPV status of the tumor among patients diagnosed with oropharyngeal cancer is an independent and strong prognostic factor. HPV-positive cancer has been more frequent among non-smokers and those who have a shorter history of smoking than among heavy smokers.

• #76 Human Papillomavirus (HPV) – Structure,epidemiology an…

  https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en

  There is a strong congruency between the HPV status of the tumor, as specified by in situ hybridization, and p16 expression. HPV-16 in situ hybridization assessment is sensitive to single viral copies, and a positive outcome is highly correlated with the HPV E6 and E7 oncogene expression. […] The favorable prognosis for HPV-positive cancer in comparison to that for the HPV-negative squamous-cell carcinoma seems to be multifactorial. Recognized favorable factors connected with the HPV-positive subgroups account for approximately 10% of the observable difference in the outcome.

• #77 Core Concepts – Human Papillomavirus Infection – Self-Study Lessons – National STD Curriculum

  https://www.std.uw.edu/go/comprehensive-study/hpv/core-concept/all

  Transmission of genital HPV is predominantly associated with sexual activity that results in friction-induced microabrasions during skin-to-skin contact. The transmission rate of HPV between sex partners is high, and transmission often occurs from persons with HPV who are asymptomatic or have subclinical infection. Consistent and correct use of condoms reduces the risk of genital HPV acquisition or transmission, thereby reducing the risk for HPV-associated diseases. Condom use, however, does not entirely prevent transmission of HPV, since exposure to HPV can occur in areas that are not fully covered or protected by a condom. Treatment of warts or cervical cellular abnormalities will reduce, but not eliminate, the risk of transmission. […] The HPV vaccine is based on recombinant technology that produces L1 major proteins, which self-assemble into viral-like particles. In the United States, three HPV vaccines (2vHPV, 4vHPV, and 9vHPV) have been licensed for use, but the 9vHPV is now the only available HPV vaccine. The 9vHPV, which was FDA-approved in 2014, offers protection against 7 oncogenic HPV types (16, 18, 31, 33, 45, 52, and 58), which account for approximately 80% of cervical cancers, and 2 HPV types (6 and 11) that cause approximately 90% of genital warts. The 9vHPV vaccine has shown excellent safety in females and males.

• #78 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.

• #79 Core Concepts – Human Papillomavirus Infection – Self-Study Lessons – National STD Curriculum

  https://www.std.uw.edu/go/comprehensive-study/hpv/core-concept/all

  Transmission of genital HPV is predominantly associated with sexual activity that results in friction-induced microabrasions during skin-to-skin contact. The transmission rate of HPV between sex partners is high, and transmission often occurs from persons with HPV who are asymptomatic or have subclinical infection. Consistent and correct use of condoms reduces the risk of genital HPV acquisition or transmission, thereby reducing the risk for HPV-associated diseases. Condom use, however, does not entirely prevent transmission of HPV, since exposure to HPV can occur in areas that are not fully covered or protected by a condom. Treatment of warts or cervical cellular abnormalities will reduce, but not eliminate, the risk of transmission. […] The HPV vaccine is based on recombinant technology that produces L1 major proteins, which self-assemble into viral-like particles. In the United States, three HPV vaccines (2vHPV, 4vHPV, and 9vHPV) have been licensed for use, but the 9vHPV is now the only available HPV vaccine. The 9vHPV, which was FDA-approved in 2014, offers protection against 7 oncogenic HPV types (16, 18, 31, 33, 45, 52, and 58), which account for approximately 80% of cervical cancers, and 2 HPV types (6 and 11) that cause approximately 90% of genital warts. The 9vHPV vaccine has shown excellent safety in females and males.

• #80 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.

• #81 How a single HPV vaccine dose can prevent cervical cancer | PATH

  https://www.path.org/our-impact/articles/how-a-single-hpv-vaccine-dose-can-prevent-cervical-cancer/

  HPV vaccine is a subunit vaccine, which is a class of vaccines that uses a piece of the virus to generate an immune response. Researchers used an HPV protein called L1, an important region for the immune systems interaction with the virus. When the vaccines teach the immune system to recognize L1, were able to fight the real virus in the future. […] Protection from just one dose of a subunit vaccine was unprecedented. To understand what set HPV vaccines apart, researchers took a close look at the immune response. […] In HPV vaccines, the L1 protein is delivered using a virus-like particle (VLP) mechanism, which retains the proteins original shape. […] This simultaneous response to multiple L1 proteins (as opposed to one or two L1 proteins) results in potent B cell activation signals, and these strong signals stimulate the development of long-lasting plasma cells (LLPCs).

• #82 How a single HPV vaccine dose can prevent cervical cancer | PATH

  https://www.path.org/our-impact/articles/how-a-single-hpv-vaccine-dose-can-prevent-cervical-cancer/

  Critically, LLPCs dont depend on additional vaccine doses or virus exposures to continue production. True to their name, these cells provide long-lasting protection. […] Evidence of this type of immune response has borne out in clinical observation: after an approximately one-year decline following a single dose of HPV vaccine, the antibody level stabilizes at a steady plateau and is sufficient to provide solid long-term protection from infection. […] While monitoring will continue, given what we know about this type of immune response, the levels are unlikely to dramatically change in subsequent years, and are expected to maintain protection against the HPV infections that are at highest risk of becoming cervical cancer.

• #83 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  The combination of HPV vaccination and cervical screening can provide the greatest protection against cervical cancer. Also, HPV vaccination reduces the risk of developing cancers caused by HPV at sites other than the cervix. […] Widespread HPV vaccination has the potential to reduce cervical cancer incidence around the world by as much as 90%. In addition, the vaccines may reduce the need for screening and subsequent medical care, biopsies, and invasive procedures associated with follow-up from abnormal cervical screening, thus helping to reduce health care costs and anxieties related to follow-up procedures. […] Although HPV vaccines have been found to be safe when given to people who are already infected with HPV, the vaccines provide maximum benefit if a person receives them before he or she is sexually active. […] It is likely that someone previously infected with HPV will still get some residual benefit from vaccination, even if he or she has already been infected with one or more of the HPV types included in the vaccines.

• #84

  https://link.springer.com/article/10.1007/s10147-023-02337-7

  HPV-infected cells have mechanisms to evade the human immune response. […] HPV-derived E5 and E7 suppress the ability of host cells to present HPV antigens by downregulating the expression of Human leukocyte antigen (HLA) class I, which is necessary for antigen presentation. […] HPV-derived products not only suppress immune responses but are also attenuated antigen-presenting capacity of HPV-infected cells. […] Treatment strategies based on the characteristics of carcinogenic mechanisms have been investigated in HPV-associated cervical tumors. […] Therapeutic approaches that focus on the immune response against the HPV protein have been drawing attention.

• #85

  https://link.springer.com/article/10.1007/s13337-023-00824-z

  Over 98% of cervical cancers (CC) are caused by regular infections with „high risk” genotype of the human papilloma virus (HPV). […] Therefore, production of HPV vaccinations represents a significant chance to minimize the risk of CC. […] Phase III studies for a number of preventative HPV vaccines based on L1-virus-like particle (VLPs) have just been completed and the preliminary results are very convincing. […] Although these vaccines were 90% effective at preventing HPV infection as these offered only modest advantages for the removal of pre-existing infections. […] New advancements in the creation of therapeutic vaccinations have been explored for further improvement and post-vaccination surveillance. […] Therapeutic vaccines attempted to boost cell-mediated immunities and these are detrimental to the infected cell as opposed to neutralizing antibodies (different from prophylactic vaccines).

• #86 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. […] HPV infection is observed in >90% of cervical cancers. […] However, HPV is not the only virus participating in cervical cancer development; other hazardous situations such as coinfections (with herpes simplex virus type-2 and Chlamydia trachomatis), smoking, persistent use of oral contraceptives, multiparity, nutritional deficiencies, immunosuppression, and immune-associated diseases are also involved in cancer progression. […] Host immune responses fight against HPV infection and eliminate most of the viral part (nearly 90%) within 2–3 years or remain in the dormant phase, while the remaining 10% are converted into chronic infections; however, only 1% can cause cervical cancer.

• #87 The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006039

  The productive human papillomavirus (HPV) life cycle is tightly linked to the differentiation and cycling of keratinocytes. Deregulation of these processes and stimulation of cell proliferation by the action of viral oncoproteins and host cell factors underlies HPV-mediated carcinogenesis. […] Thus, CXCR4 and its potential activation by genetic alterations in the course of the carcinogenic process can be considered as an important host factor for HPV carcinogenesis. […] Here, we thought to investigate this issue by providing mechanistic insights into the selective susceptibility to HPV pathogenesis displayed by patients who are immunosuppressed as a consequence of mutations in the CXCR4 gene encoding for the receptor of the CXCL12 chemokine (WHIM syndrome). […] Our results, which identify CXCR4 as an important gatekeeper of keratinocyte proliferation and as a new susceptibility factor in HPV pathogenesis, may be translated into anti-viral and anti-cancer strategies.

• #88 The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006039

  Our study is providing the rational for future mechanistic investigations of the productive life cycle of cutaneous low-risk HPV, which remains underappreciated due to the lack of robust in vitro models. […] Increased production of E6 and E7 proteins in the context of CXCR41013 expression makes rafts prone to drive the viral lifecycle toward carcinogenesis as demonstrated by the altered levels of keratinocyte proliferation and apoptosis and by a disturbance in the ordered expression of viral gene products that normally leads to virus replication and production. […] The CXCL12/CXCR4 signaling pathway appears to be an important host factor in HPV-induced pathogenesis.

• #89 Unlocking The Mechanisms of HPV Entry < Yale School of Medicine

  https://medicine.yale.edu/news-article/unlocking-the-mechanisms-of-hpv-entry/

  Human papillomavirus (HPV) causes almost all cancers of the cervix and anus, and a large percentage of cancers of the vagina, vulva, penis, and the back of the throat. […] Several years ago, he and other researchers discovered that HPV follows an unusual path to the cell nucleus. […] Dr. DiMaio and his colleagues also showed that for HPV to successfully complete the entry process, a viral protein named L2 must bind to a protein called retromer inside the cell cytoplasm. […] We found that L2 has a short sequence of only six amino acids that can actually poke through the endosome membrane into the cytoplasm, so it can bind to retromer, said Dr. DiMaio. […] In another first, they also discovered that L2 contains a cell-penetrating peptide (CPP). […] After the probing end of L2 pierces the membrane, it functions as a pipeline into the cell for the HPV particle.

• #90 Unlocking The Mechanisms of HPV Entry < Yale School of Medicine

  https://medicine.yale.edu/news-article/unlocking-the-mechanisms-of-hpv-entry/

  HPVs strategy is to stay inside these vesicles and never expose itself to the cellular immune system during entry. […] If a targeted drug could stop L2 from binding to retromer, the virus couldnt infect. […] Another possibility would be to stop L2 from protruding through the endosome membrane in the first place. […] We think these targeted approaches could be applicable to every single HPV type because all the papillomaviruses have L2 sequences that penetrate membranes and bind to retromer.

• #91 The Role of Human Papillomavirus in Cervical Cancer

  https://www.clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-6-125.php?jid=ijccr

  Long-term infection with human papillomavirus (HPV) is the cause of cervical cancer and its precursor – cervical intraepithelial neoplasia (CIN). The presence of HPV infection can be presumed in more than 99% of cases of cervical cancer worldwide. […] It was also underlined the importance of performing molecular tests for the presence of HPV DNA as a more sensitive and the most accurate method of detecting the threat posed by infection with this oncovirus. The review also highlights the most beneficial prophylactic algorithm, which should be guided by gynecologists during the diagnosis, individual clinical cases. […] The gateway to HPV infection is the formation of a minute of the basal layer of squamous epithelial cells and mucous membranes into which the virus is tropism. After binding to the appropriate receptor on the epithelial cell surface (some data suggest that the receptors may be heparin sulfate or α6β4 integrins), for which the L1 structural protein corresponds, the virus performs a productive replication cycle. Its course is conditioned by the efficiency of the epithelial maturation process, specific systemic and cellular factors as well as viral proteins.

• #92 The Role of Human Papillomavirus in Cervical Cancer

  https://www.clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-6-125.php?jid=ijccr

  Cervical cancer is the fourth most common cancer among women in the world, causing annually about 275,000 deaths. However, the most important factor that has a huge impact on the development of cervical cancer is primarily persistent infection with hrHPV (mainly types 16 and 18), which can lead to uncontrolled course of infection. […] If the infection does not subside, within 10-30 years of viral replication will be accompanied by neoplastic changes, concerning the endothelium of the cervix, so-called CIN (Cervical Intraephitelial Neoplasia). […] In addition, cancer stages are also distinguished, which are classified depending on the stage of cancer disease, i.e. from I to IV. […] It is assumed that the vaccine will protect the patient from HPV infection until she is ready to begin routine cytological tests, preferably in conjunction with HPV molecular tests, proving at least the persistence of high HPV antibodies for 10 years after the injection of Cervarix. […] In the prevention of cervical cancer, it is not only important to detect changes early, but also to identify factors that have the most probable etiopathogenetic relationship to the carcinogenesis process within this organ.

• #93 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/

  Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

• #94 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers.

• #95 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-02083-w

  The overexpression of E6 and E7 facilitates oncogenesis by disrupting the transcription of tumor suppressor genes and triggering flanking gene amplification. […] The specific oncogenic mechanisms of early proteins of hr-HPVs are discussed in the following part. […] E6 is well-known for binding with and degrading p53 in a ubiquitinproteasome way. Degradation of p53 promotes cell proliferation and inhibits apoptosis. […] E7 binds with pRb to release E2F, promoting cells entering the S-phase. E7 can increase the expression of cyclins to enable cells to alter from the G1-phase to S-phase unrestrictedly, resulting in uncontrolled cell proliferation. […] E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation. […] E6 promotes glycolysis and lipid synthesis to support cell growth.

• #96 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  HPV can use the evasion process to escape the immune response. […] Therefore, HPV can multiply in host cells during viral replication without causing cytolysis, which neither stimulates the inflammatory process nor presents viral antigenic representatives. […] In host cells, type-I IFNs levels are reduced by the E6 and E7 proteins of HPV16 and generate an immune tolerance stage in the absence of costimulatory factors through inflammatory cytokines. […] These immune escape phenomena may contribute to the existence and stability of HPV infection, which further addresses cancer progression. […] Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma.

• #97 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  The involvement of HPV in cancer induction and progression can take many years for conversion into a carcinoma with the help of different tumor-stimulating steps, such as E6/E7 proteins that interact with cellular proteins. […] Additionally, a few reports have suggested that imbalanced immunity and chronic inflammation in the tumor microenvironment (TME) may provoke precancerous cervical lesions that turn into invasive cancer. […] In this article, we reviewed the prevalence status of HPV infection, its mechanistic role in carcinogenesis, its molecular and immunopathogenesis process, host immune response activated by HPV, its immune escape mechanism, its vaccination scheme, and preventive measures and strategies that could protect against HPV infection and associated cancers.

• #98 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.

• #99 Human Papillomavirus (HPV) Vaccines – NCI

  https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

  The combination of HPV vaccination and cervical screening can provide the greatest protection against cervical cancer. Also, HPV vaccination reduces the risk of developing cancers caused by HPV at sites other than the cervix. […] Widespread HPV vaccination has the potential to reduce cervical cancer incidence around the world by as much as 90%. In addition, the vaccines may reduce the need for screening and subsequent medical care, biopsies, and invasive procedures associated with follow-up from abnormal cervical screening, thus helping to reduce health care costs and anxieties related to follow-up procedures. […] Although HPV vaccines have been found to be safe when given to people who are already infected with HPV, the vaccines provide maximum benefit if a person receives them before he or she is sexually active. […] It is likely that someone previously infected with HPV will still get some residual benefit from vaccination, even if he or she has already been infected with one or more of the HPV types included in the vaccines.

• #100 Molecular Pathogenesis of Human Papillomavirus: Insights into Viral Oncoproteins and Host Integration – International Journal of Health & Medical Research

  https://ijhmr.com/molecular-pathogenesis-of-human-papillomavirus-insights-into-viral-oncoproteins-and-host-integration/

  Human Papillomavirus (HPV) is a major cause of death from cervical cancer and other anogenital cancers throughout the world. Pathogenicity of HPV is governed by intricate interplay of HPV and host cells mediated primarily by its oncoproteins E6 and E7. […] These oncoproteins disrupt critical pathways, including those involving tumor suppressors p53 and retinoblastoma (Rb) to induce unregulated cell proliferation and evasion of apoptosis. […] New diagnostic and therapeutic approaches to HPV research encompassing an expanding clinical landscape hold promise to reduce incidence of HPV associated malignancies and improve patient outcomes. […] This review summarizes the molecular pathogenesis of HPV with respect to host cells and discusses its implications for diagnostics and therapeutics, including the need for further development in this area.

Zobacz więcej