Joshua Cyktor, PhD, has been awarded funding in the amount of $940,424 for a five-year grant by the National Institutes of Health/National Institute of Mental Health (NIH/NIMH) entitled, “CNS Viral Persistence and Neuropsychiatric Perturbations in HIV: Single cell and Molecular Interrogation.” This proposal was submitted in response to the competitive funding opportunity entitled Eradication of HIV-1 from Central Nervous system Reservoirs (R01) under funding opportunity number PA-20-151 in conjunction with Dr. Serena Spudich at Yale University.
Despite prolonged suppression of HIV on antiretroviral therapy (ART), eradication or sustained remission of the infection has not been achieved. Low levels of HIV DNA are still detectable in peripheral blood mononuclear cells (PBMC) from people living with HIV (PWH) taking ART. Cells containing rebound-competent virus can reside in sanctuary tissue sites, including lymph nodes, gut, genital tract, and the central nervous system (CNS). Recently highly sensitive virologic assays in livingdonors have been utilized to detect HIV DNA in cerebrospinal fluid (CSF) cells in up to 50% of individuals on long-term ART. Importantly, those with detectable CSF HIV DNA had poorer global cognitive function that those in whom CSF HIV DNA was not detected. Critical gaps in understanding CNS HIV persistence include what the characteristics and function of infected immune cells are in CSF; whether HIV proviruses in CSF are intact and genetically compartmentalized compared to proviruses in blood; and, how these features relate to neuropsychiatric function of long-term HIV. Dr. Cyktor will use single cell technology to measure the transcriptional and cytokine profile of CNS cells combined with novel quantification of intact HIV DNA and single genome sequencing. This work could lead to the discovery of new correlations within the CNS reservoir.
This study proposes to rigorously examine the cognitive function and mental health of people living with HIV utilizing sophisticated implementation of the new NIMH Research Domain Criteria (RDoC) framework and analyzing how differences in neuropsychiatric outcomes relate to specific immunological and virological characteristics of the CNS in a diverse cohort of participants with a range of neuropsychiatric comorbidity.