Project Summary/Abstract Although HIV infection is controllable with antiretroviral therapy (ART), HIV cure continues to be extremely elusive. Cure of HIV is desperately needed for many reasons. People with HIV (PWH) have persistent increases in morbidity and mortality despite ART, and while newer ART agents have become better tolerated, they are still associated with multiple side effects. Having to attend HIV clinics and take ART over the long term still carries significant stigma for PWH. Additionally, many PWH have a preference for cure rather than a lifetime of ART, and some would take significant risks to achieve a cure. For all of these reasons, finding a cure for HIV is one of the ultimate goals of the field. There is a large and growing body of evidence that the central nervous system (CNS) is an HIV reservoir site that represents another barrier to HIV eradication. HIV DNA is commonly found in brain tissue from PWH on suppressive ART, and there are multiple published reports of CNS virologic escape. Multiple studies, including from our group, have demonstrated that HIV RNA can be detected at very low levels in CSF during suppressive ART and that anti-HIV antibodies are also present in the CSF among individuals on ART. New members of our group recently presented findings with an innovative assay (Double-R) to reliably quantitate HIV RNA and DNA from CSF. Our group has performed extensive pre-clinical and clinical work on the Janus Kinase (Jak 1/2) inhibitor drug class to target HIV. This includes work on baricitinib, an FDA approved orally bioavailable Jak 1/2 inhibitor for rheumatoid arthritis. We have demonstrated that baricitinb blocks HIV replication, HIV-induced activation and infection in key CNS cells, and reservoir reseeding. In vivo, we have shown in our murine model that baricitinib decreases CNS HIV and reverses behavioral abnormalities conferred by HIV. We have also demonstrated that baricitinib achieves therapeutic CNS concentrations in the rhesus macaque model. We now propose to study baricitinib as a therapy to decrease the HIV CNS reservoir in a study of PWH with durable virologic suppression on ART. This will be a phase IIa randomized placebo controlled study. Our primary hypothesis is that individuals randomized to baricitinib will be more likely to achieve a decrease in CSF cell associated HIV RNA and DNA by Double-R assay. We also hypothesize that baricitinib treatment will be associated with a significant decrease in other markers of HIV CNS persistence, including HIV-specific CSF antibodies, CSF cell associated DNA including by Integrated Proviral DNA (IPDA), CSF RNA by single copy assay, CSF HIV Tat levels, and markers of inflammation that have been linked to CNS HIV persistence, as well as magnetic resonance imaging and spectroscopy markers. Additionally, we hypothesize that baricitinib treatment will be safe for the CNS as defined by neuropsychological performance, depression symptoms, and neuronal damage. We ...