Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain

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HIV-associated neurocognitive disorders persist in the era of combination antiretroviral therapy (cART) while HIV latency, and cell-specific expression of HIV transcript in human CNS remains incompletely understood. There is high prevalence of HIV-associated neurologic disease and increasing recognition of CNS viral escape in people stably suppressed with cART, often further complicated by the co-registered epidemic of substance use disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have profound impact on CNS function. Ongoing work in our laboratory is providing first assessments of cell-type specific HIV 'molecular signatures', including genome integration patterns and alterations on the level of the transcriptome and epigenome in reward- and addiction circuitry of the human postmortem brain. As described in detail in the Preliminary Data section, we found dramatically high levels of HIV expression in a subset of microglia from postmortem specimens, with HIV transcript levels ranking among the top 5 highest expressed RNAs in microglia, or the 99.9% percentile of all microglial transcript. Correspondingly, HIV genome integration sites in addiction circuitry are dominated by microglia-specific genes, with strong preference for active chromatin compartments. However, lingering effects of latent infection that persist during cART have not been well characterized—in part because of fundamental challenges in identifying the extent to which microglial cells contribute to the latent reservoir. Our preliminary studies also provide a model system whereby we can track and isolate persistently infected cells which can be applied to the microglial compartment and will allow us to define the genomic perturbations that persist during cART. By studying HIV genomics in human microglia residing in the mouse brain and linking this with technology to track persistently infected microglia, we will be able to model, for the first time, experimental therapies and interventions to complement our descriptive work in human postmortem brain. Specifically, our Cre-reporter based HIV-induced lineage tracing (HILT) marking system will allow us to quantify and isolate the rare latently infected microglia that persist during cART, and map transcriptomic and epigenomic alterations separately both for infected, and non-infected microglia, both collected from the same mouse brain. With focus on addition circuitry, we will study neuroinflammation, cognition and reward behavior in mice treated with standard cART regimens and an experimental therapy involving Cannabinoid receptor 2 agonist drugs that, according to our preliminary data, are linked to anti-inflammatory activity limiting the extent of HIV infection in tissues.