JAK-STAT inhibition to reduce inflammation during ART-treated SIV infection

About This Grant

People with HIV (PWH) on antiretroviral therapy (ART) experience persistent immune activation and inflammation despite effective viral suppression. Over time, this results in chronic inflammatory conditions across multiple organ systems, including neurocognitive decline and liver disease. The high risk for these conditions in PWH necessitates the identification of therapies to suppress inflammation that would be an adjunct to ART. One promising approach is through inhibition of the JAK-STAT signaling pathway. Small molecule JAK inhibitors (JAKi) have been highly successful in treating chronic inflammatory diseases and a second-generation orally available JAKi, baricitinib, is FDA approved for rheumatoid arthritis, alopecia areata, and systemic inflammation associated with COVID19. Recently, two Phase 2 clinical trials were initiated to evaluate the ability ofbaricitinib to control HIV replication and associated inflammation in PWH. like all clinical trials, these are limited in the types of samples that can be collected, resulting in a restriction to the mechanistic understanding of any viral or immune benefits that are observed. This proposal will bridge this gap by testing baricitinib in SN-infected macaques on ART (SIV +ARn, a system that is recognized as the gold standard for mechanistically evaluating HIV treatments. Our studies will test the hypothesis that JAK inhibition will reduce levels ofinflammatory biomarkers in tissues ofSN+ARTmacagues better than ART alone and that this benefit will be present even in a heightened inflammation model of/ow-dose lipopolysaccharide (LPS). We further hypothesize that reduced inflammation will result in lower SN levels and a smaller SN reservoir due to a reduction in activation and homeostatic proliferation of SN target cells. We will test the hypothesis in two specific aims, the first will assess peripheral tissues (blood and lymph nodes), while the second will assesses deep tissue sites within the macaques (CNS, lungs, liver and GI tract). Inflammatory mediators, immune cells and viral reservoirs will be assessed at each of these tissue sites. This proposal is timely as it investigates JAKi as potential anti-inflammatory and anti-viral therapy in the context of SIV +ART macaques, assessing key tissue sites that cannot be easily accessed during human clinical trials. In addition, baricitinib will be evaluated in the context of heightened inflammation associated with low-dose LPS exposure, with the potential to uncover strengths or weaknesses regarding JAK inhibition that might not be observed in a clinical trial. The long-term goal of the proposed studies is to obtain mechanistic insights into the effectiveness of JAK inhibition during SIV+ART. If proven efficacious, it is possible that baricitinib will be utilized as a therapy to suppress inflammation, reduce HIV replication, reduce HIV reservoir size, and increase life expectancy for PWH. We hope that the repurposing ofbaricitinib to address a persistent problem for PWH will represent a paradigm shift in the treatment of chronic HIV infection in the United States and globally.