Abstract
The development of a sterilizing cure for HIV remains a major global health priority. HIV/AIDS continues to threaten human health worldwide, with 1.5 million new infections diagnosed and nearly 700,000 AIDS-related deaths reported each year. While antiretroviral therapy (ART) is highly effective in preventing disease progression, it is not a cure and requires taking lifelong daily medication. Furthermore, ART simply inhibits viral replication, leaving the reservoir of HIV-infected cells with integrated proviral genomes intact; a sterilizing cure will require elimination of this infected cell reservoir. CD8+ cytotoxic T lymphocytes (CTL) possess tremendous potential to kill HIV-infected cells. CTLs are the predominant force suppressing viremia from peak to setpoint levels during acute infection and allowing rare elite controllers (ECs) to spontaneously control chronic-phase viremia in the absence of ART. However, in most individuals, CTL efficacy will markedly decline during HIV infection due to viral escape and CTL exhaustion. In contrast, CTLs specific for the chronic and ubiquitous herpesvirus cytomegalovirus (CMV) remain highly functional and do not become exhausted, even after decades of antigen exposure. To restore CTL efficacy in HIV infection and facilitate depletion of the infected cell reservoir, we propose retargeting CMV-specific CTLs using peptide-major histocompatibility complex I-monoclonal antibody (pMHCI-mAb) fusion proteins. In this dissertation, we examine the feasibility of this novel HIV cure strategy using the SIVmac239 model of HIV infection in Indian rhesus macaques (RMs).