Mentored Scientist Award

Clonal expansion is a major driver of HIV persistence in antiretroviral therapy (ART)-suppressed people with HIV (PWH). This clonal expansion is facilitated by homeostatic proliferation, primarily orchestrated by cytokines like IL7 within tissue reservoirs, the main site of HIV persistence. Recent studies have identified CD127, the alpha chain of the IL7 receptor crucial for IL7 signaling, as a defining marker of long-lived CD4+ T memory (Tm) cells from human tonsils that preferentially undergo latent HIV infection. These transcriptionally active reservoir cells, notably the CD127+ Tm subset, represent pivotal targets for HIV cure strategies, given their capacity to sustain inflammation despite ART and may also act as a source of rebound-competent virus in PWH. In this study, we aim to utilize an in vitro tissue-based primary cell model of HIV persistence to investigate the effects of inhibiting IL7 signaling (Aim 1) and directly depleting CD127+ Tm reservoir cells through effector cell-mediated cytotoxicity and phagocytosis (Aim 2). Both aim to leverage the unique properties of the monoclonal antibody 4A10, which selectively binds to CD127, inhibits IL7 signaling and activates Fcmediated innate immune functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Our preliminary data demonstrates the effectiveness of 4A10 in mediating ADCC against HIV-infected tonsillar CD127+ Tm reservoir cells in vitro, resulting in a substantial reduction in the overall burden of HIV infected cells. We propose to follow up on this finding and to interrogate the possibility of implementing 4A10 as a strategy to achieve HIV remission, particularly by targeting tissue-based CD127+ HIV reservoir cells. Furthermore, we will assess the effects of 4A10 (vs. control isotype) on virological (HIV DNA/RNA) and host (scRNAseq/CITEseq/VDJ) parameters. Together, these studies will provide an in-depth assessment of 4A10 impact on latently infected CD127+ cells that are targeted by, or resistant to, 4A10 therapy.