HIV cure has emerged as an important research priority. A key challenge in HIV eradication strategies is the "HIV reservoir," i.e., the cells in which HIV persists despite antiretroviral therapy (ART). Studies are now underway to understand how the HIV reservoir is established and how cells harboring HIV may be eradicated. The experiments of this K23 proposal will use state-of-the-art genetic sequencing techniques to discover potential host genetic mutations that determine (1) the HIV reservoir size and (2) the response to a novel drug aimed at "flushing out" HIV from reservoir sites. The determinants of HIV reservoir size include stage of disease at ART initiation (lower reservoir sizes with acute versus chronic infection) and host factors such as the level of T cell activation and T cell function. However, these factors onl explain a fraction of the person-to- person variability in HIV reservoir size. Since host genetics (e.g., polymorphisms in HLA and CCR5 genes) influence the degree to which HIV replicates in the absence of therapy, we hypothesize that a unique set of host genetic polymorphisms will play a role in shaping the size and distribution of the HIV reservoir during ART-mediated viral suppression. Experiments addressing this hypothesis will be the focus of Aim 1. The experiments of Aim 2 will evaluate host genetic predictors of drug response to an anti-programmed cell death-1 (PD-1) antibody, lambrolizumab. Despite viral suppression with life-long ART, chronically HIV-infected patients exhibit persistent immune dysfunction and inflammation. The host immune system attempts to dampen harmful systemic inflammation by upregulating anti-inflammatory processes. One such inhibitory process is the PD-1 signaling pathway. PD-1 expressing T cells are less functional and do not clear pathogens effectively. In HIV disease, PD-1 expressing cells also appear to be enriched for virus. Our collaborators have shown that blocking PD-1 in rhesus macaques with lambrolizumab, leads to a transient increase in virus released from reservoir sites as well as improved immune function. Given the putative role of PD-1 as a cause of HIV persistence, a Phase I clinical trial of lambrolizumab has been developed and is planned to begin in 2014. This drug has also been studied in early cancer trials, demonstrating good tumor response rates and few adverse effects. A consistent and perplexing finding from cancer and hepatitis C trials of PD-1 pathway inhibitors is the dichotomous host responses; patients either respond very well or minimally to the drug. The experiments of Aim 2 will evaluate the role of host genetics in the dichotomous response to lambrolizumab while those of Aim 3 will more completely evaluate the role of any genes implicated in the host responses identified in Aim 2. The work associated with the experiments of this proposal will provide me with important training in HIV immunology and genetics with the goal of contributing to future HIV cure research.