Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders

Abstract

The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

Disrupted Decision-Making: EcoHIV Inoculation Following a History of Cocaine Use

“…No statistically significant sex differences in the number of EcoHIV-EGFP signals were observed (p>0.05). Second, EcoHIV-EGFP and Iba1, a microglial marker, were highly co-localized in the mPFC supporting microglia as the predominant cell type for EcoHIV expression; observations which are consistent with previous reports in HIV-1 seropositive individuals (Ko et al, 2016) and the EcoHIV rat (Li et al, 2021a(Li et al, , 2021b.…”

“…Notably, the inferences drawn from the measurement of dendritic spines are consistent with profound alterations observed in electrophysiological recordings (Cirino et al, 2020), as well as measurements of dopaminergic neurotransmission (for review, McLaurin et al, 2021a; e.g., Kumar et al, 2009;Denton et al, 2019) The harboring of EcoHIV infection in microglia may partly underlie the profound synaptodendritic alterations observed in the EcoHIV rat. During early HIV-1 infection, the transmigration of infected monocytes and CD4+ cells across the blood-brain barrier leads to the infection of cells, including microglia, in the central nervous system (Cosenza et al, 2002); microglia are also a long-term viral reservoir for productive HIV-1 infection (Ko et al, 2019;Li et al, 2021a). Under homeostatic conditions, microglia are involved in the environmental surveillance of synaptic structures, including dendritic spines (Wake et al, 2009;Tremblay et al, 2010).…”

“…Host's cells are infected with ecotropic MLV via the cationic amino acid transporter (CAT-1; Kim et al, 1991, Wang et al, 1991. Critically, EcoHIV infection recapitulates many of the clinical features of HIV-1, including lymphocyte, macrophage, and microglia infection, neurocognitive impairments, and synaptodendritic alterations (e.g., Geraghty et al, 2017;Gu et al, 2018;Kelschenbach et al, 2019;Li et al, 2021a). The recent extension of the EcoHIV model of HIV-1 infection to rats (Li et al, 2021a;, which are more commonly used in studies of substance use disorders and neurocognitive impairments, may afford a biological system to investigate comorbid cocaine use and HIV-1.…”

Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure

“…Specifically, early in the course of infection, HIV-1-infected monocytes migrate across the blood-brain barrier infiltrating the brain and infecting microglia [53,54]. Following chronic HIV-1 viral protein exposure, microglia serve as a viral reservoir for HIV-1 in the brain [36,54,55] supporting a cell type that may underlie aberrant neurite and synaptic pruning. In the PFC, neurite [13] and synaptic [11,52] pruning are a hallmark of adolescent neurodevelopment [51].…”

“…Specifically, the HIV-1 viral proteins Tat , gp120 , nef, and vif are expressed in multiple brain regions, including the prefrontal cortex, striatum, and hippocampus [ 35 ]. Furthermore, HIV-1 mRNA expression exhibits a restricted and region-specific distribution, whereby abundant expression was observed in the mPFC [ 36 ]. The HIV-1 Tg rat, therefore, affords a biological system to examine synaptodendritic alterations following chronic HIV-1 viral protein exposure.…”