Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review

Background: Anal squamous cell carcinoma (SCC) is a rare gastrointestinal malignancy with rising incidence, both in the United States and internationally. The primary risk factor for anal SCC is human papillomavirus (HPV) infection. However, there is a growing burden of disease in patients with human immunodeficiency virus (HIV) and HPV coinfection, with the incidence of anal SCC significantly increasing in this population. This is particularly true in HIV-infected men. The epidemiologic correlation between HIV-HPV coinfection and anal SCC is established; however, the immunologic mechanisms underlying this relationship are not well understood. Summary: HIV-related immunosuppression due to low circulating CD4+ T cells is one component of increased risk, but other mechanisms, such as the effect of HIV on CD8+ T lymphocyte tumor infiltration and the PD-1/PD-L1 axis in antitumor and antiviral response, is emerging as significant contributors. The goal of this article is to review existing research on HIV-HPV coinfected anal SCC and precancerous lesions, propose explanations for the detrimental synergy of HIV and HPV on the pathogenesis and immunologic response to HPV-associated cancers, and discuss implications for future treatments and immunotherapies in HIV-positive patients with HPV-mediated anal SCC. Key Messages: The incidence of anal squamous cell carcinoma is increased in human immunodeficiency virus (HIV)-infected patients, even in patients on highly active antiretroviral therapy. Locoregional HIV infection may enhance human papillomavirus oncogenicity. Chronic inflammation due to HIV infection may contribute to CD8+ T lymphocyte exhaustion by upregulating PD-1 expression, thereby blunting cytotoxic antitumor response.