HIV-associated neurocognitive disorders (HANDs) and substance abuse comorbidity remain prevalent
despite combination antiretroviral therapy (cART). A major challenge in the AIDS therapeutic development field
is the identification of targetable mechanisms that underlie persistent neuronal dysfunction in HIV-infected
individuals despite ART.
While internal RNA modifications have been known for decades, their roles in RNA metabolism and
function are only beginning to be elucidated. In particular, dynamic RNA modifications are believed to
represent a new layer of control of gene expression. The present proposal will test the overarching hypothesis
that understanding the role of RNA modifications in the implementation of gene expression programs that are
dysregulated by the interaction of HIV, cART and substance abuse in neurons, astrocytes and microglia, can
indicate transformative new mechanistic hypotheses on neuroAIDS pathogenesis that will have the potential to
lead to the identification of novel therapeutic targets to improve neuropsychological functioning in people with
HIV. The impact of RNA modifications on HIV transcripts and splicing and HIV protein levels in HIV Tg rats will
also be investigated.
To test the present hypothesis we assembled a collaborative team involving expertise in behavioral and
molecular neurobiology, gene expression and advanced systems biology methods to study transcriptional,
post-transcriptional and post-translational regulatory mechanisms.
In particular, we will explore RNA modifications in well-established behavioral paradigms of moderate or
compulsive (dependent) cocaine self-administration in HIV transgenic (Tg) rats in the setting of combination
antiretroviral therapy (cART). We will use a systems biology approach in conjunction with RNA profiling in
identified brain cell types to investigate the role of RNA modifications in neuronal injury and glia dysfunction in
neuroAIDS. We will focus primarily on the most abundant mRNA modification, N6-methyladenosine (m6A) and
the proteins that compose its regulatory machinery. The effects of histories of cocaine intake and cART on m6A
modification of HIV transcripts in HIV Tg rats will also be investigated. The mechanisms identified will also be
investigated in follow-up studies in models of moderate and compulsive self-administration of other drugs of
abuse as well as available human gene expression datasets.
Ultimately this proposal - at the interface of computational analysis of gene network regulation and
advanced behavioral pharmacology - is aimed at identifying new testable mechanistic hypotheses that may
lead to transformative new therapeutic concepts to improve neuropsychological functioning in people with HIV.