Identification and targeting of metabolic profiles in cytotoxic T-lymphocyte (CTL)-resistant, HIV-infected CD4+ T-cells

/ABSTRACT HIV infection remains an unmet global health and socioeconomic burden lacking a safe and scalable cure or a vaccine for prevention. While in the last decades the development of highly effective antiretroviral therapy (ART) has revolutionized infection outcome drastically decreasing transmission and AIDS-related mortality/morbidity among infected individuals, treatment remains a lifelong burden. This is due to the inability of ART and the immune system to clear rare intact, transcriptionally competent and persistent proviruses already integrated into the genome of infected cells – the HIV reservoir. Viral latency is a crucial barrier towards eliminating the HIV reservoir, enabling viral immune escape through transcriptional silence during ART. However, recent lines of evidence have demonstrated that low level HIV production persists over years of ART and correlates with HIV- specific cytotoxic T-lymphocyte (CTL) responses that shape the HIV reservoir. This suggests that rare cells with transcriptionally active proviruses are actively surveilled by HIV-specific CTL responses but are unable to be eliminated. Profiling of the HIV reservoir has also demonstrated that persistent HIV-harboring cells become preferentially clonal and express molecules that can inhibit CTL cytolytic interactions with infected target cells (BCL-2, SERPINB9 and PVR), further implicating CTL resistance as a mechanism of infected cell persistence. Our preliminary work using an in vitro infection model designed to evaluate CTL resistance in infected cells has demonstrated that a rare subset of HIV-expressing cells is preferentially resistant to CTL elimination. Multiomic analysis of these rare cells has confirmed the presence of previously suggested features of CTL resistance, and further revealed a vastly shared transcriptional and surface protein signature denoting dampened levels of metabolic flux and oxidative stress. Here, we aim to demonstrate the presence of a metabolic profile skewed towards quiescence in CTL resistant, HIV expressing infected cells. We hypothesize that lower levels of metabolic flux puts CTL resistant infected cells at a lower threshold of oxidative stress than the general population of infected cells, making them harder targets to push over the edge of irreversible and lethal damage. The experiments of this proposal will evaluate the therapeutic value of pharmacologically inducing oxidative stress in HIV-infected cells to improve CTL mediated elimination of infected cells and HIV reservoirs. Project Number: 1F31AI191953-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Alberto Herrera | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F17A-G (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19195301