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.

Public Health Relevance

HIV enters the central nervous system (CNS) early in infection and can lead to inflammation and infection in the brain associated with a compartmentalized neurologic reservoir for HIV. This work will investigate the neurologic effects of two therapies, telmisartan and romidepsin, given in addition to early antiretroviral therapy to reduce systemic and CNS reservoirs for HIV. Such therapies may have significant public health impact in contributing to our understanding of potential HIV eradication and cure CNS HIV infection, potentially reducing CNS morbidity in the 40 million people worldwide infected with HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS084911-01
Application #
8544692
Study Section
Special Emphasis Panel (ZMH1-ERB-M (03))
Program Officer
Wong, May
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$500,000
Indirect Cost
$145,362
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520