Project 2: Novel investigation of Epstein-Barr virus as a potential cause of conjunctival squamous cell carcinoma among people living with HIV in Zimbabwe

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PROJECT SUMMARY – PROJECT 2 Conjunctival squamous cell carcinoma (cSCC) is an eye cancer with unknown etiology. cSCC disproportionately impacts Sub-Saharan Africa (SSA), a setting where presentation with advanced disease is common. This translates into a high morbidity burden, as treatment of advanced cSCC includes destructive eye surgery leading to vision loss. This can result in severe impact on household economic productivity given an average age of cSCC diagnosis of only ~40 years. It is crucial to understand the underlying cause of this cancer to guide development of effective early detection and management strategies to avoid this public health burden. One of the only identified risk factors for cSCC is HIV infection. People living with HIV (PLWH) are at least 10 times more likely to be diagnosed with cSCC. Because HIV-associated immunosuppression impairs host ability to control infections, PLWH are susceptible to cancers caused by viruses (e.g., Kaposi Sarcoma, cervical cancer). The pronounced elevation in cSCC among PLWH suggests an infectious etiology. Existing studies have primarily investigated cutaneous human papillomavirus (HPV) types as potential contributors to cSCC; however, IARC considers cutaneous HPV as non-causal for cancer. Emerging data, including our preliminary findings, suggest a potential role for Epstein-Barr virus (EBV) in cSCC. Our overall goal is to determine if EBV contributes to cSCC in PLWH. We propose to test the EBV hypothesis among 800 participants from Parirenyatwa Hospital- Sekuru Kaguvi Eye Unit (SKEU) in Harare, Zimbabwe. These 800 patients will be leveraged to accomplish the following study aims: Aim 1: Compare EBV DNA detection and RNA expression in malignant versus benign conjunctival tissue in PLWH. This aim will test the hypothesis that PLWH with invasive cSCC will have 1) higher prevalence of EBV detection and 2) higher EBV expression compared to PLWH with benign eye lesions. Aim 2: Estimate the prevalence of an altered immune response, as measured using an EBV antibody panel, in PLWH with cSCC compared to cancer-free controls. This aim will test the hypothesis that PLWH with invasive cSCC (cases) will have a higher EBV antibody score than PLWH without eye lesions (controls). Aim 3: Estimate the association between HIV status and cSCC clinical outcome. This aim will test the hypothesis that PLWH and cSCC will have poorer survival after cSCC diagnosis compared to cases without HIV. Exploratory Aim. We will characterize tumors from ~100 cSCC cases (50 with and 50 without HIV) as immune infiltrated or immune excluded based on presence of T-cells and assess quantity and spatial pattern of T-cells, immune checkpoint expression, and markers of immune exhaustion by HIV status.