Leveraging Jak 1/2 Inhibition with Baricitinib Towards HIV Cure in the Veteran Population

Veterans Health Administration, Decatur PA

Investigators

Abstract

A major barrier to HIV eradication is maintenance of latently infected cells in people living with HIV (PWH). The Veteran population of PWH is nearly 2.5-fold greater versus non-Veteran individuals living in the United States, underscoring a major unmet need within the United States Veteran's population for safe, specific agents that can cure HIV and prevent or reverse associated co-morbidities. Chronic inflammation despite suppressive ART drives HIV persistence and co-morbidities, including cardiovascular disease, frailty, diabetes, and HIV- associated neurocognitive dysfunction (HAND). The Janus Kinase Signal Transducer and Activator of Signal Transduction (Jak-STAT) pathway is a major mechanism of elevated immune dysregulation, even during viral suppression. In viremic individuals, elevated pSTATs including pSTAT5 are associated with increased reservoir size, viral loads, and decreased CD4+ T cell counts, underscoring the direct link between the Jak-STAT pathway and the HIV-1 reservoir. Our team (Vincent Marconi (VAMC) William Tyor (VAMC) and Christina Gavegnano) has extensively studied the class of Jak 1/2 inhibitors (indication HIV-1), including a first-generation Jak 1/2 inhibitor ruxolitinib, and demonstrated in a recently completed multi-site Phase 2a ACTG-sponsored study (A5336;n=60) that ruxolitinib is safe, well-tolerated, and reduces key markers of immune activation associated with HIV-1 persistence (HLA-DR/CD38, sCD14, and cellular lifespan marker bcl-2). We also showed a reduction in the HIV-1 reservoir in individuals with higher baseline frequency of integrated HIV-1 DNA, demonstrating proof- of-concept that Jak 1/2 inhibition can reduce the reservoir in a clinical setting. Furthermore, we observed that ruxolitinib, in an in vitro model of HIV-1-infection in total memory CD4+ T cells, pushes differentiation of central memory cells (TCM) to a shorter lived phenotype (effector memory T cells-TEM), which could also induce HIV- 1 reservoir decay. Baricitinib is a second-generation Jak 1/2 inhibitor (FDA approved for rheumatoid arthritis and COVID-19), presenting a markedly improved safety profile versus ruxolitinib including approval for chronic long- term use (including children), once daily dosing and renal clearance (making drug-drug interactions with hepatically cleared agents unlikely; critical for add-on to ART). We have shown that baricitinib significantly reduces the HIV-1 reservoir in primary T cells and reverses HIV-1 persistence markers and inflammation (murine model). We also demonstrated that baricitinib confers substantial improvement of CD4/CD8 HIV-specific effector function, boosting natural immune function that may i) enhance reservoir decline and ii) block or prevent inflammatory driven co-morbidities in PWH. However, how baricitinib can confer reservoir reduction in ex vivo patient samples, and in a dynamic in vivo (murine) model of systemic infection, remains unclear. We will define the multi-functional action of baricitinib, a Jak ½ inhibitor developed by our team for treatment of viral infections including HIV and COVID-19, towards control HIV reservoirs and persistence. This will be done by leveraging our now-enrolling Phase2a study for baricitinib towards reduction of HIV-1 reservoir in the CNS (NCT05452564) across peripheral blood and cerebral spinal fluid samples from the study, and existing VA cohorts from Dr. Vincent Marconi (VA, Emory). Additional mechanisms will be bolstered by collaboration with Dr. William Tyor (VA and Emory) using the humanized murine model of HIV-1 infection. Data will streamline translation to additional human studies in the Veteran PWH population, for comorbidities and eventual HIV cure.