Immunogenomic profiles of HIV-associated classic Hodgkin lymphoma from Malawi

Classic Hodgkin lymphoma (cHL) is a hematolymphoid neoplasm highly associated with Epstein-Barr virus (EBV), and molecular differences by tumor EBV status have been well characterized. Additionally, people with HIV (PWH) are 5 times as likely to develop cHL, and cHL in PWH is nearly exclusively EBV associated. However, there are limited published molecular characterizations of cHL arising in PWH (HIV⁺ cHL). This gap is particularly impactful in the Global South where cancer mortality and HIV prevalence are high. In this study, we evaluated the whole exome, transcriptome, and T-cell receptor (TCR) repertoire of an HIV-inclusive cohort of patients with cHL from Malawi. HIV⁺ cHL had increased tumor mutational burden compared with cHL in people without HIV (HIV^- cHL). EBV positive (EBV⁺)/HIV^- tumors exhibited a distinct transcriptional profile compared with EBV^-/HIV^- and EBV⁺/HIV⁺. Additionally, both EBV and HIV were associated with cellular composition changes within the tumor microenvironment, including increases in memory B cells and CD8⁺ T cells compared with EBV^- and HIV^- cHL. TCR clonality was increased in EBV⁺ cHL, with trend towards further increase in clonality in HIV⁺. Through a multiomic approach of a well-characterized, HIV-inclusive cHL cohort from one of the most resource-limited countries in the world, we were able to recapitulate known, and identify novel molecular differences by HIV and EBV status.