Local and systemic immune correlates of anal high-risk HPV infection and clearance in men living with HIV and men at high risk for HIV.

INTRODUCTION

Human papillomavirus (HPV) prevalence is high among men who have sex with men (MSM), increasing the risk of anal cancer. Key risk factors include HIV co-infection and persistent HPV infection, although the underlying mechanisms remain unclear.

METHODS

We characterized HPV burden in 75 men (median age 53 years [IQR 41-60]) presenting to LMU University Hospital or the medical practice prinzmed between 2022 and 2024. 64/75 defined themselves as MSM, 49 MSM were living HIV and 15 without HIV. 11/75 non-MSM were living with HIV. To identify systemic immunological correlates of HPV clearance or persistence, we performed IFN-γ ELISpot and peripheral blood T cells were analyzed by flow cytometry. Further, in a subgroup ano-mucosal CD8+ T cells were profiled via low-input RNA sequencing to determine immune signatures associated with persistent HPV infection.

RESULTS

Anal HPV infection was highly prevalent at baseline (67/75) in this largely unvaccinated cohort (73/75), particularly among MSM (59/64), and was independent of HIV status. At baseline, simultaneous infection with multiple HPV types was detected in 50/64 MSM versus 4/11 non-MSM, and most infections persisted over 1 year. Type-specific systemic T-cell responses were detected in 3/4 individuals who cleared a given HR HPV type, compared with 0/14 with persistent HR HPV (p = 0.049). Among men living with HIV, HR HPV clearance was lower compared to men without HIV. Peripheral T cells in men living with HIV and infected with at least one HR HPV strain exhibited markers of exhaustion (TIM-3+ CD4+ and CD8+ T cells [p-value = 0.01 for CD4+ and p-value = 0.04 for CD8+]; Tcf1-PD-1+TIM-3+ CD4+ T cells [p-value = 0.02]), and senescence (CD57+ CD4+ T cells, p-value = 0.02). Ano-mucosal CD8+ T cells of HR HPV infected men living with HIV showed upregulation of genes associated with exhaustion (CTLA4, CD101), activation and effector function (GZMK, CTSW) compared to non-HR HPV infected men.

DISCUSSION: Our findings show a high anal HPV burden and low clearance among MSM, regardless of HIV status. Clearance was associated with type-specific systemic T-cell responses, while T-cell exhaustion and senescence may contribute to reduced clearance in men living with HIV.