Utilising heterogeneities in the African HIV epidemic to address the HIV reservoir and immune dysfunction challenges to facilitate HIV cure (360G-Wellcome-306962_Z_23_Z)

HIV reservoirs, consisting of replication-competent proviral DNA in immune cells are the major barrier to HIV cure, necessitating lifelong antiretroviral treatment. Cure has been achieved in non-human primate models via early treatment followed by treatment interruption, combined with immunotherapy. Immune mechanisms can control the HIV reservoir, but the underlying mechanisms are poorly understood. Critically, cure research has not focused on the distinct African populations or the specific viral subtypes that are central to the HIV epidemic. Furthermore, even under effective treatment, immune dysfunction persists, resulting in higher comorbidities for all people living with HIV (PLWH). Adjunctive immunotherapies are needed to improve health outcomes for PLWH. Our goal here is to utilise the heterogeneity of the HIV African epidemic, represented by unique, well-pedigreed observational and interventional cohorts comprised of diverse HIV subtypes, host genetic and immune backgrounds, to understand how reservoirs are maintained, and controlled through immune mechanisms. We will focus here on humoral immunity, type I interferon responses and natural killer and CD8+ T cells as the most probable mediators of reservoir control. This work led in Africa will identify virus and immune therapeutic targets to facilitate HIV cure and/or adjunctive therapies that will benefit PLWH across the world.