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

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.

Grant Number: 5R01DA054526-05
NIH Institute/Center: NIH
Principal Investigator: Schahram Akbarian