Distinct anal microbiome is correlated with anal cancer precursors in men who have sex with men living with HIV.

OBJECTIVES: Anal cancer risk is elevated in men who have sex with men living with HIV (MSMLWH). Anal high-risk human papillomavirus (hr-HPV) infection is necessary but insufficient to develop high-grade squamous intraepithelial lesion (HSIL), the anal cancer precursor, suggesting additional factors. We sought to determine whether the microbiome of the anal canal is distinct by comparing it with the microbiome of stool. We also sought to determine whether changes in the anal microbiome are associated with HSIL among MSMLWH. DESIGN: Cross-sectional comparison of the microbiome of the anal canal with the microbiome of stool in MSMLWH and cross-sectional comparison of the anal microbiome of MSMLWH with anal HSIL with the anal microbiome of MSMLWH without anal HSIL. METHODS: Sterile swabs were used to sample the anus of MSMLWH for microbiome and HPV testing, followed by high-resolution anoscopy. Stool samples were mailed from home. 16S sequencing was used for bacterial identification. Measures of alpha diversity, beta diversity and differential abundance analysis were used to compare samples. RESULTS: 166 anal samples and 103 matching stool samples were sequenced. Beta diversity showed clustering of stool and anal samples. Of hr-HPV-positive MSMLWH, 31 had HSIL and 13 had no SIL. Comparison of the microbiome between these revealed 28 different species. The highest-fold enrichment among MSMLWH/hr-HPV/HSIL included pro-inflammatory and carcinogenic Prevotella, Parasuterella, Hungatella, Sneathia and Fusobacterium species. The anti-inflammatory Anaerostipes caccae showed the greatest reduction among MSMLWH/hr-HPV/HSIL. CONCLUSIONS: The anal microbiome is distinct from stool. A pro-inflammatory and carcinogenic environment may be associated with anal HSIL.

AIDS Malignancy Consortium 054: Safety and Immunogenicity of the Quadrivalent Vaccine in Indian Women Living With HIV.

BACKGROUND: Human papillomavirus (HPV)-associated cervical cancer is a leading cause of death among Indian women. Indian women living with HIV (WLWH) may be at especially high risk. The quadrivalent HPV (qHPV) vaccine is effective in prevention of initial infection with HPV-6/11/16/18 in HIV-negative women. Little is known about previous exposure to HPV-6/11/16/18, safety, and immunogenicity of qHPV in Indian WLWH. METHODOLOGY: One hundred fifty WLWH with different CD4 levels and HIV viral load (VL) were vaccinated at 0/2/6 months at CART-CRS-IDMC, Chennai, India. Serology was performed at weeks 0, 28, and 52 for HPV-6/11/16/18 using a competitive Luminex immunoassay and for HPV-16/18 using a pseudovirion-based neutralization assay. RESULTS: Mean age was 30.8 years (range, 19-44 years). 71/87/73/81% of women were naive (sero-negative and DNA-negative) to HPV-6/11/16/18 at baseline, respectively. Among per-protocol women naive to HPV-6/11/16/18 at baseline, 100/99/99/90%, respectively, seroconverted at week 28 and 95/96/98/71% were sero-positive at week 52, respectively. Pseudovirion-based neutralization assay identified more seroconversion to HPV-18 than competitive Luminex immunoassay. There were no significant differences in the proportion seroconverting by baseline or nadir CD4 or HIV VL; however, there was a trend for increased proportion seroconverting to HPV-18 among women with higher baseline CD4 level (P = 0.052). There were no qHPV-related serious adverse events and no change in CD4 level or HIV VL among women on ART. CONCLUSIONS: qHPV vaccine was safe and immunogenic in Indian WLWH. A high proportion were naive to HPV-6/11/16/18 and may benefit from vaccination although many were married and several years post-initiation of sexual activity.

Prevalence and risk factors for neutralizing antibodies to human papillomavirus types 16 and 18 in HIV-positive men who have sex with men.

OBJECTIVE: Human papillomavirus (HPV) vaccination is routinely recommended in HIV-positive men who have sex with men (MSM) aged ≤ 26 years. Levels of previous HPV exposure in older HIV-positive MSM are assumed to be too high to warrant routine HPV vaccination. However, little is known about the prevalence of and risk factors for neutralizing antibody seropositivity to HPV-16 or HPV-18, a key measure of previous exposure to these types. METHODS: Cross-sectional analysis of baseline visit for 296 HIV-positive MSM participating in a prospective cohort study of anal squamous intraepithelial lesions at a university-based research clinic. Participants completed a questionnaire detailing behaviors and medical history. Phlebotomy, anal cytology, HPV DNA testing with quantitation, and high-resolution anoscopy with biopsy were performed. A pseudovirion-based neutralizing antibody assay was used to measure HPV-16 and HPV-18 neutralizing antibodies. RESULTS: One hundred thirty-two of 296 (45%) men were HPV-16 seropositive and 141 of 296 (48%) were HPV-18 seropositive. One hundred seventy-five of 296 (59%) of the men were positive for HPV-16 antibodies or DNA and 167 of 296 (56%) were positive for HPV-18 antibodies or DNA. In multivariable analysis, HPV-16 seropositivity did not correlate with age, years of HIV positivity, CD4 level, or HIV viral load. Significant risk factors included HPV-16 DNA positivity with higher DNA levels (ptrend < 0.001) and higher number of receptive sexual partners in the last year (ptrend = 0.012). CONCLUSIONS: A high proportion of HIV-positive MSM aged >26 years are DNA negative and seronegative to HPV-16 and HPV-18 even when using a sensitive pseudovirion-based neutralizing antibody assay. Prospective studies are needed to determine the clinical- and cost-effectiveness of HPV vaccination in HIV-positive MSM aged >26 years.

HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus.

The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.