Oncogenic Human Papillomavirus Research Articles

Prevalence of anal HPV infection and anal HSIL among MSM 50 years and older living with or without HIV

Background: Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSIL). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years of age, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH). Setting: We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, California. Methods: 129 MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with biopsy of visible lesions. Results: Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (OR:45.1, 95% CI:15.8-129), other oncogenic HPV types (OR:5.95, 95% CI:2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status. Conclusion: The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remain very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening.

Immunological Response against Breast Lineage Cells Transfected with Human Papillomavirus (HPV)

Breast cancer is the most common neoplasm worldwide. Viral infections are involved with carcinogenesis, especially those caused by oncogenic Human Papillomavirus (HPV) genotypes. Despite the detection of HPV in breast carcinomas, the virus’s activity against this type of cancer remains controversial. HPV infection promotes remodeling of the host’s immune response, resulting in an immunosuppressive profile. This study assessed the individual role of HPV oncogenes in the cell line MDA-MB-231 transfected with the E5, E6, and E7 oncogenes and co-cultured with peripheral blood mononuclear cells. Immunophenotyping was conducted to evaluate immune system modulation. There was an increase in CD4+ T cell numbers when compared with non-transfected and transfected MDA-MB-231, especially in the Treg profile. Pro-inflammatory intracellular cytokines, such as IFN-γ, TNF-α, and IL-17, were impaired by transfected cells, and a decrease in the cytolytic activity of the CD8+ and CD56+ lymphocytes was observed in the presence of HPV oncogenes, mainly with E6 and E7. The E6 and E7 oncogenes decrease monocyte expression, activating the expected M1 profile. In the monocytes found, a pro-inflammatory role was observed according to the cytokines released in the supernatant. In conclusion, the MDA-MB-231 cell lineage transfected with HPV oncogenes can downregulate the number and function of lymphocytes and monocytes.

Human malignancies associated with persistent HPV infection.

Human papillomavirus (HPV)-associated malignancies account for ~5% of human cancers worldwide. Thirteen, or more, HPV types are oncogenic, but infection with these viruses is common and usually cleared within 2 years. Only infections that become persistent are associated with the development of cancer, often occurring several decades later. These cancers mostly arise in 6 different anatomical regions: 5 are anogenital (anus, cervix, penis, vagina, and vulva) and the sixth is the oropharynx. Oncogenic HPVs promote cellular proliferation and genomic instability, but the anatomical niche of the target tissue also plays an important role in the development of cancer. Cells that reside in transitional regions between different types of epithelia, such as in the anus, cervix, and oropharynx, are particularly vulnerable to oncogenesis.

P16 overexpression identifies oncogenic high-risk HPV infection in non-oropharyngeal squamous cell carcinoma of the head and neck.

Human papillomavirus (HPV) is an increasing risk factor for cancer. HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable outcome. Blockstaining for p16 is a surrogate marker for HPV+ OPSCC. In oral and laryngeal squamous cell carcinoma (OSCC/LSCC), the relevance of p16 immunohistochemistry, alone or in combination with other cell cycle-related proteins, to identify HPV-driven non-OPSCC is less well understood. We stained for p16, pRb, cyclin D1, and p53 in 327 HNSCC. In 310 OPSCC, HPV-status was assessed by HPV DNA PCR. In 119 non-OPSCC, RNA in situ hybridization was additionally performed. HPV-status was correlated with staining patterns, p53 and clinical data. The OPSCC showed blockstaining for p16 in 36%, 8% were equivocal. Of these, HPV-testing was performed in 57%, and 53% were positive for HPV DNA. HPV-association correlated with absence of pRb and cyclin D1 and favorable outcome. In non-OPSCC, 18% showed p16-blockstaining, and 13% showed E6/E7 RNA. Six of seven HPV+ OSCC and 8/8 LSCC lost pRb and cyclin D1. Compared to HPV-negative counterparts, patients with HPV+ cancers had lower rates of alcohol consumption and keratinizing morphology. HPV-positive OSCC had a longer overall survival (p < 0.05). HPV subtype 16 was the most common. We conclude that HPV-positive non-OPSCC are associated with p16 overexpression and low levels of pRb and cyclin D1. High expression of pRb and cyclin D1 indicates HPV-negativity.

Cervical Squamous Intraepithelial Lesions: A Comparison of Diagnostic Approaches

Aim. To compare the effectiveness of Papanicolaou test, screening for oncogenic human papillomavirus (HPV) strains, and colposcopy in diagnosis of cervical squamous intraepithelial lesions and cervical cancer.Materials and Methods. We conducted a retrospective study which included 101 patients aged 21-65 years (mean age 36.9 ± 8.2 years). All patients underwent cytological examination, screening for 14 high-risk HPV types, and colposcopy. The prognostic value of the methods was calculated using standard formulas for determining the sensitivity, specificity, and prognostic value of positive and negative results. Cervical biopsy was accepted as the gold standard.Results. Among the examined women (n = 101), high-risk HPV types were detected in 78 women (77.2%). According to the results of cytological examination, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and cancer were detected in 24 (23.8%), 24 (23.8%), 22 (21.7%), and 2 (2%) cases, respectively. Abnormal colposcopy results of the 1st and 2nd degree were found in 33 (32.7%) and 51 (50.5%) women, respectively. The highest sensitivity in the diagnosis of low-grade squamous intraepithelial lesion was demonstrated by colposcopy (81.3%), whilst HPV testing and cytological examination had lower sensitivity values (75.0% and 58.3%, respectively). However, HPV testing had the highest sensitivity (85.7%) in diagnosis of high-grade squamous intraepithelial lesion and cervical cancer, whereas colposcopy and Papanicolaou test were behind (82.9% and 63.6%, respectively).Conclusion. Detection of high-risk HPV types has a high sensitivity in detecting both low- and highgrade squamous intraepithelial lesions and cervical cancer.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden.

Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

Designing of a novel and potent HPV66 L1 major capsid protein-epitope based therapeutic vaccine against Human Papillomavirus (HPV): A bioinformatics approach

Aim: Oncogenic human papillomaviruses (HPV) cause various types of cancer, including cervical cancer. The main protein of HPV is capsid, targeted in many vaccine attempts. However, these vaccines do not cover enough high-risk HPV serotypes. Therefore, a low-cost potential HPV vaccine to protect against all serovars of the α-papillomaviruses family would be promising in the future. Our study aimed to develop a therapeutic epitope vaccine for HPV using bioinformatics methods. Methodology: Bioinformatics approach was followed to analyze and identify potential T-cell and B-cell dominant epitopes of HPV-66 L1 major capsid protein. Additionally, various aspects of this protein were examined, including its physico-chemical properties, and secondary and tertiary structures. These analyses helped us to design an effective HPV infection therapeutic vaccine. Results: The findings revealed that the L1 major capsid protein was unstable and hydrophilic. The secondary structure of this protein composed 39% α- helices, 17.97% β sheets and 31.80% loops. Our study demonstrated 19 dominant epitopes of HPV-66 L1 major capsid protein including 5 B-cell epitopes and 14 T-cell epitopes (10 HTL epitopes, and 4 CTL epitopes) for a novel vaccine candidate. Interpretation: This study provides a comprehensive biological information about the HPV-66 L1 major capsid protein, which will serve as a theoretical foundation for developing a multi-epitope vaccine against HPV infection. Key words: B-cell epitope, Cervical Cancer, Human papillomavirus, HPV66 L1 major capsid protein, T-cell epitope

Prognostic role of p16 overexpression in sinonasal squamous cell carcinoma: A retrospective analysis of Alberta patients

AbstractObjectiveSinonasal squamous cell carcinoma (SNSCC) is rare in the general population. No clear and consistent etiologic correlation between human papillomavirus (HPV) and SNSCC has yet been delineated in the literature. p16 is a tumor suppressor protein used as a surrogate marker for HPV. This study aims to evaluate the relationship between p16 overexpression in SNSCC and its role in prognosis and survival.MethodsA population‐based retrospective analysis was performed using prospectively collected data from the Northern Alberta Head and Neck Tumour Board, the Alberta Cancer Registry, and the Alberta Cancer Research Biobank. p16 overexpression was analyzed from pathologic samples of patients meeting study criteria, and participants were dichotomized by status. Subsequently, nonparametric analysis of demographics, initial staging, and initial treatment were performed, and a Kapan–Meier curve was developed to assess differences in survival.ResultsSixteen patients were included in the analysis. p16 overexpression was seen in 68.8% of patients. p16 positive and negative groups were comparable for age, gender, smoking status, stage, and treatment. A statistically significant 5‐year survival advantage was observed in patients with p16 positive SNSCC (P = 0.013).ConclusionsThis is the first Canadian study to demonstrate a high prevalence of p16 positivity in SNSCC and its presence denoting a statistically significant survival advantage. Results demonstrate a previously unconfirmed role of oncogenic HPV in SNSCC.

Moving from conventional to adaptive risk stratification for oropharyngeal cancer.

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.

Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.

Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.

The Epidemiology of Anal Human Papillomavirus (HPV) in HIV-Positive and HIV-Negative Women and Men: A Ten-Year Retrospective Observational Study in Rome (Italy).

Human papillomaviruses (HPVs) commonly infect the anogenital mucosa; most infections are transient, but a fraction of those caused by high-risk (HR) types persist and may lead to anogenital cancer. The epidemiology of HPV genotypes in anal infections in groups at different risk for anal cancer has not been well described in Italy. This retrospective study reports the results of HPV DNA testing and complete genotyping performed on anal swabs from 691 female and male patients attending proctology clinics in Rome during 2012-2021; one-third had repeated testing. Cumulative HPV positivity in 1212 anal swabs was approximately 60%, was not age related, and showed an increasing trend over the study period. HPV rates differed significantly by sex and HIV status: HIV-negative women had the lowest (43.6%) and HIV-positive men the highest (83.5%) HPV prevalence. HIV-positive men had more oncogenic HPV genotypes detected, more multiple infections, and the highest frequency of persistent infections. Two-thirds of all infections were vaccine-preventable. This study found that anal HPV infection rates are still elevated and even increasing in groups at low and high risk of developing anal cancer. Prevention programs need to be improved to reduce rates of anal infection in young women and men.

696 - Human papillomavirus oncogenes may promote cervical dysplasia progression through dysregulation of miR-4488 and Wnt signaling

696 - Human papillomavirus oncogenes may promote cervical dysplasia progression through dysregulation of miR-4488 and Wnt signaling

Chitosan-Functionalized Poly(β-Amino Ester) Hybrid System for Gene Delivery in Vaginal Mucosal Epithelial Cells.

Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful application of the gene therapy method depends on effective gene delivery into the vagina. To improve mucosal penetration and adhesion ability, quaternized chitosan was introduced into the poly(β-amino ester) (PBAE) gene-delivery system in the form of quaternized chitosan-g-PBAE (QCP). At a mass ratio of PBAE:QCP of 2:1, the polymers exhibited the highest green fluorescent protein (GFP) transfection efficiency in HEK293T and ME180 cells, which was 1.1 and 5.4 times higher than that of PEI 25 kD. At this mass ratio, PBAE-QCP effectively compressed the GFP into spherical polyplex nanoparticles (PQ-GFP NPs) with a diameter of 255.5 nm. In vivo results indicated that owing to the mucopenetration and adhesion capability of quaternized CS, the GFP transfection efficiency of the PBAE-QCP hybrid system was considerably higher than those of PBAE and PEI 25 kD in the vaginal epithelial cells of Sprague-Dawley rats. Furthermore, the new system demonstrated low toxicity and good safety, laying an effective foundation for its further application in gene therapy.

Immunohistochemical characterization of integrin alfa 6 in uterus and cervix of the cynomolgus monkeys (Macaca fascicularis) with MfPV3 infection.

Cervical cancer is an abnormal growth of cervical tissue epithelial cells due to persistent human papilloma virus (HPV) infection. Cynomolgus monkeys (Macaca fascicularis) can be naturally and spontaneously infected with M. fascicularis Papillomavirus Type 3 (MfPV3), a virus that is phylogenetically closely related to human oncogenic HPV (HPV-16 and HPV-34), and therefore a potentially beneficial for modeling HPV disease. This study aims to evaluate the expression of the integrin alpha 6 (ITGα6) receptor in cynomolgus monkeys spontaneously infected with MfPV3, which this receptor also found in human infected with HPV. The study was done on archived Formalin-fixed Paraffin-Embedded (FFPE) samples of uterine and cervix tissue of cynomolgus monkeys. Immunohistochemistry was also performed to quantify the expression levels of ITGα6. The results showed 80% of the samples positive Cervical Intraepithelial Neoplasia (CIN) and increased expression of ITGα6 significantly in Positive-MfPV3 group than negative-MfPV3 group. This indicated the potential of cynomolgus monkeys as a spontaneous oncogenesis model of PV infection type.

The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

Serum oxidative biomarkers associated with genital HPV infection and cervical lesions in women.

Human papillomavirus (HPV) infection is a major cause of cervical cancer. Studies showed HPV carcinogenesis may be induced by oxidative stress affecting the host immune system. The objective of this study is to evaluate levels of four circulating oxidative stress biomarkers associated with the HPV infection, persistence, and cervical lesion status in women. The three serum biomarkers measuring oxidative damage to biomolecules (8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] for DNA, 4-hydroxy-2-nonenal [4-HNE] for lipid, and protein carbonyl [PC] for protein) and one antioxidant (glutathione, GSH) collected from 38 women were evaluated. The PC levels were significantly higher for women with oncogenic HPV infection (p = 0.047) and persistence (p = 0.053) based on the unadjusted linear model. In particular, women with ≥3 oncogenic HPV types had a higher PC level than those without HPV infection (p = 0.041). Women with low-grade squamous intraepithelial lesions showed an elevated PC (p = 0.058). These trends remained similar after adjusting for age. The GSH levels were lower for women infected with ≥3 oncogenic HPV types based on age-adjusted results (p = 0.061). This study supported that serum PC was associated with HPV infection, persistence, and cervical lesions, so it can potentially be used to monitor HPV carcinogenesis. Further large-scale studies will be needed to confirm these findings.

Expression of Aberrant MicroRNAs and p16INK4a Associated with HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, and 56) in Oral Dysplasia and Squamous Cell Carcinoma: A Retrospective Study.

A few studies indicate that human papillomavirus (HPV) induces aberrant expression of microRNAs (miRNAs) and correlate this with p16INK4a in oral dysplasia (OD) and oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the expression of miRNA-21, miRNA-22, and miRNA-224 by q-PCR and the p16 INK4a by immunohistochemical (IHC) as markers for HPV-positive OSCC and OD in comparison to controls as miRNA expression can be altered by the HPV oncogenes and hence can be used as a biomarker for HPV positive cases. Fifty-two specimens were collected from archived paraffin blocks for patients aged between 19 and 88 (31 males and 21 females) from various oral sites. They were examined by IHC using p16 INK4a, by RT-PCR for the detection of HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, 56), and by q-PCR for the expression of miRNA-21, miRNA-22, and miRNA-224 in positive specimens. Out of the 15 OD, three were positive by both techniques. Meanwhile, 17 out of all OSCC specimens showed intense nuclear and cytoplasmic staining by p16 INK4a, and only 16 were also positive by RT-PCR. However, all control specimens were negative. MiRNA-21, miRNA-22, and miRNA-224 were overexpressed in 3 specimens of OD and 16 of OSCC. MiRNA-21, miRNA-22, and miRNA-224, besides p16 INK4a, could be used as indicators for HPV-associated OD and OSCC as their expression is attributed to the HPV oncoprotein. Further studies using follow-up data should be done to correlate it with miRNA overexpression.

High prevalence of high-risk HPV genotypes in individuals attending an infectious diseases clinic from 2018 to 2022 in Milan, Italy.

Human papillomavirus (HPV) is the most common sexually transmitted infection, linked to several types of lesions. HPV, specifically HPV 16, accounts for most of anal cancer cases. In this study, we evaluated the proportion of samples tested positive for HPV and characterized genotypes distribution in anal specimens collected from individuals at risk of anal HPV infection attending from 2018 to 2022 a large Infectious Diseases Department in Italy. The presence of HPV DNA was investigated through a commercial kit detecting 12 HR-HPV, 8 probable/possible HR-HPV, and 8 LR-HPV genotypes. Among 1514 samples, 84% (1266/1514) resulted positive for any type of HPV. The prevalence of high-risk HPV types remained high during all the years of the study period, from 2018 to 2022, ranging from 65% to 73%. Most of HR-HPV, LR-HPV and HPV 16 positive samples were collected from men >45 years. HPV 16 was also the most frequent type in men and women. We did not observe significant variations between years in detection of HR-HPV, instead of LR-HPV, that significantly decreased. In conclusion, the high prevalence of oncogenic HPV genotypes underlines the necessity of clear anal HPV screening guidelines and, along with frequent HR-HPV coinfections, reinforces the urge to intensify the anti-HPV vaccination campaign.

Risk factors of oncogenic HPV infection in HIV-positive men with anal condyloma acuminata in Shenzhen, Southeast China: a retrospective cohort study.

Human immunodeficiency virus (HIV)-positive patients with anal condyloma acuminata (CA) present an increased risk of anal cancer progression associated with oncogenic human papillomavirus (HPV) infection. It is essential to explore determinants of anal infection by oncogenic HPV among HIV-positive patients with CA. A retrospective cohort study was performed in HIV-positive patients with CA between January 2019 to October 2021 in Shenzhen, Southeast China. Exfoliated cells were collected from CA lesions and the anal canal of HPV genotypes detected by fluorescence PCR. Unconditional logistic regression analysis was used to probe associations of independent variables with oncogenic HPV infection. Among HIV-positive patients with CA, the most prevalent oncogenic genotypes were HPV52 (29.43%), HPV16 (28.93%), HPV59 (19.20%), and HPV18 (15.96%). Risk of oncogenic HPV infection increased with age at enrollment (COR: 1.04, 95% CI: 1.01-1.07, p = 0.022). In the multivariable analysis, age ≥ 35 years (AOR: 2.56, 95% CI: 1.20-5.70, p = 0.02) and history of syphilis (AOR: 3.46, 95% CI: 1.90-6.79, p < 0.01) were independent risk factors statistically associated with oncogenic HPV infection. History of syphilis (AOR: 1.72, 95% CI: 1.08-2.73, p < 0.02) was also an independent risk factor statistically associated with HPV16 or HPV18 infection. In clinical practice, HIV-positive CA patients aged ≥35 years or with a history of syphilis should carry out HR-HPV testing and even anal cancer-related examinations to prevent the occurrence of anal cancer.

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes

There are over 220 identified genotypes of Human papillomavirus (HPV), and the HPV genome encodes 3 major oncogenes, E5, E6, and E7. Conservation and divergence in protein sequence and function between low-risk versus high-risk oncogenic HPV genotypes has not been fully characterized. Here, we used modern computational and structural folding algorithms to perform a comparative analysis of HPV E5, E6, and E7 between multiple low risk and high risk genotypes. We first identified significantly greater sequence divergence in E5 between low- and high-risk genotypes compared to E6 and E7. Next, we used AlphaFold to model the structure of papillomavirus proteins and complexes with high confidence, including some with no established consensus structure. We observed that HPV E5, but not E6 or E7, had a dramatically different 3D structure between low-risk and high-risk genotypes. To our knowledge, this is the first comparative analysis of HPV proteins using Alphafold artificial intelligence (AI) system. The marked differences in E5 sequence and structure in high-risk HPVs may contribute in important and underappreciated ways to the development of HPV-associated cancers.