Therapeutic Interventions during Acute Infection to Address the CNS Reservoir for

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Central nervous system (CNS) infection of HIV is established early in the course of infection and intervention during the phase of acute HIV infection (prior to antibody seroconversion) provides the best opportunity to prevent the establishment of HIV reservoirs in the CNS. Here we capitalize on an established infrastructure for intensive CNS studies in a unique cohort of acute HIV infection subjects in Bangkok enrolled as part of the ongoing US Military-funded RV254 study. We propose two distinct randomized intervention strategies given in addition to antiretroviral therapy (ART) instituted during the earliest stages of acute HIV infection. The first study will employ immediate adjunctive telmisartan therapy (an antifibrotic/anti-inflammatory angiotensin II receptor blocker) to reduce HIV-associated inflammation and reservoir establishment in the CNS. We hypothesize that telmisartan therapy with ART versus ART alone during acute infection will reduce systemic immune activation and trafficking of activated and HIV-infected cells to the CNS, limiting establishment and persistence of the CNS reservoir of HIV. The second study will assess the CNS effect of delayed adjunctive romidepsin (a histone deacetylase inhibitor) therapy given to activate and kill systemic latently HIV-infected cells. We hypothesize that while romidepsin has a postulated effect of activating latent HIV and purging systemic reservoirs, due to low CNS penetration of romidepsin, romidepsin with ART versus placebo with ART will have limited effect on the CNS reservoir. Finally, we will assess early CNS compartmentalization of HIV species as well as the source of rebound HIV detected in the CNS after interruption of ART in the romidepsin study using ultra-deep sequencing to compare blood and cerebrospinal fluid (CSF) variants prior to ART and after ART interruption. Twenty-one subjects in each study will be randomized 2:1 to intervention versus no intervention and followed for 1.5 years. Careful neuropsychological testing will be performed, and blood, CSF samples and magnetic resonance imaging and spectroscopy will be collected to interrogate brain function and inflammation. These data will significantly advance our understanding of HIV persistence and inflammation in the CNS. The knowledge gained will be critically relevant to the 40 million people worldwide living with HIV, informing novel strategies aimed at viral eradication of HIV and prevention of inflammation in the CNS.