Thursday, November 21, 2024
11/21/2024
Methamphetamine, HIV integration and latency in the brain Methamphetamine (Meth), a stimulant drug used by people with HIV (PWH pathways in addiction, aggravating effects of HIV in the brain, where reservoir cells bearing HIV integrated provirus challenge cure strategies and contribute to perpetuating neurological consequences, despite ), influences inflammation and antiretroviral treatments (ART). Neurotransmitters involved in addiction such as dopamine (DA) modulate HIV targets that express DA receptors, including the microglia diverse population. Chromatin organization in HIV-1 integration represents an important prerequisite for understanding infection and latency. However, there is a critical gap in understanding relationships between chromatin organization and proviral integration associated with HIV-1 persistence in microglia cellular reservoirs, and particularly in the best experimental model, the SIV- rhesus macaque. Moreover, it is unknown how Meth modifies these relationships. We hypothesize that Meth impacts chromatin enhancing viral integration susceptibilities in HIV/SIV brain target cells, and that effects vary by brain region that differ in dopaminergic projections. Critical to this goal is the progression of models reflected in phases, first in vitro using human microglia cell lines and iPSC-derived, where the characteristics of HIV integration have been defined, and effects of Meth, or DA, can be controlled. This is followed by models ex vivo and in vivo in the SIV-rhesus macaques, to replicate HIV, chronic Meth and ART-suppression. In the R61 phase, we will concentrate on whether chromatin accessibility and the architectural protein CTCF, which interacts with LEDGF/p75 to tether the HIV-1 Integrase, mediate insertions into genomic boundaries of topologically associated domains (TADs), modified by Meth, or DA. We will assess the impact of integration patterns on the integrity of proviral genomes to gain insights about the real size of the functional viral reservoir. Aim 1) delineates relationships between epigenomic changes in microglia upon Meth and proviral genomes inserted into the pre- established regions with marked presence of CTCF and H3K36me3 (TAD boundaries), Aim 2) connects epigenetic profiles and HIV-1 insertion patterns with the cellular and viral transcription profiles, while confirming these rules in the SIV system, and Aim 3) determines the contribution of DA. Go-No-Go: If epigenomic changes caused by Meth or DA are linked to integration sites, with similar rules in all models, the R33 phase will move to the in vivo SIV model, to test effects of Meth chronic use on epigenomic vulnerabilities to SIV integration in microglia, in relation to subset heterogeneity in mesolimbic areas where DA projections are abundant compared to control regions of the brain. Aim 4) tests whether SIV integration site availability follows rules dictated by chromatin states, accessibility and CTCF binding that can be used to predict susceptibilities in the context of Meth. Aim 5) tests whether integration susceptibilities and patterns vary in brain areas that differ in dopaminergic projections, and heterogeneous microglia populations. This project enables novel studies on microglia chromatin and SIV integration dynamics in brain areas that differ by function, cellular density, and neurotransmitters.
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