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

Abstract

<b><i>Background:</i></b> 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. <b><i>Summary:</i></b> 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. <b><i>Key Messages:</i></b> 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.

The Role of Inflammation in Anal Cancer

“…According to a recent systematic review, 72% of patients diagnosed with anal cancer were HPV DNA positive [ 5 ]. In addition, several studies have reported a presence of HPV infection in 80% to 97% of patients with diagnosed anal cancer [ 4 , 11 , 12 , 13 , 14 , 15 ].…”

“…There are over 200 known HPV strains. Among them, types 6, 11, 16, and 18 are associated with anal infection [ 4 , 14 ]. Besides these types, some researchers discovered a connection between types 31, 33, and 45 and anal cancer [ 17 ].…”

“…Besides these types, some researchers discovered a connection between types 31, 33, and 45 and anal cancer [ 17 ]. Types 6 and 11 are considered “low risk” strains, as they mainly cause the development of papillomas, whose progression to invasive anal cancer in immunocompetent individuals is uncommon [ 14 , 18 , 19 ]. However, types 16 and 18 are related to a higher risk of AIN and cancer development [ 20 ].…”

“…HPV infects basal epithelial cells and stimulates transcription of a few “early” and “late” viral proteins [ 22 ]. E1–E8 are known as “early” viral genes, and they promote viral replication and viral protein translation [ 14 ]. Oncoproteins E6 and E7 reduce tumor suppressor protein p53 and the retinoblastoma protein (Rb) activity in epithelial cells, which causes viral genome replication and epithelial cell proliferation.…”

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance anti-HIV activity in vitro

“…24,25,26 On the other hand, there has been increasing evidence that PD ligand 1 (PD-L1) expression was induced on a variety of cell types by chronic HIV infection. 27,28,29,30 Previous studies have demonstrated that the blockade of PD-1 by using monoclonal antibodies enhanced T cell cycling and differentiation and resulted in rapid expansion of virus-specific CD8 T cells with improved functional quality in simian immunodeficiency virus (SIV)-infected rhesus macaques. 31,32 Those improved immune responses by PD-1 blockade induced significant reductions in plasma viral load and prolonged the survival of SIV-infected macaques.…”