HIV infects astrocytes in vivo and egresses from the brain to the periphery

Abstract

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. This understanding has significant implication for the brain as a reservoir for HIV and most importantly HIV interplay between the brain and peripheral organs. Given the sheer number of astrocytes in the human brain and their controversial role in HIV infection, we evaluated their infection in vivo and whether HIV infected astrocytes can support HIV egress to peripheral organs. We developed two novel models of chimeric human astrocyte/ human peripheral blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/ HuPBMCs) whereby we transplanted HIV (non-pseudotyped or VSVg-pseudotyped) infected or uninfected primary human fetal astrocytes (NHAs) or an astrocytoma cell line (U138MG) into the brain of neonate or adult NSG mice and reconstituted the animals with human peripheral blood mononuclear cells (PBMCs). We also transplanted uninfected astrocytes into the brain of NSG mice and reconstituted with infected PBMCs to mimic a biological infection course. As expected, the xenotransplanted astrocytes did not escape/ migrate out of the brain and the blood brain barrier (BBB) was intact in this model. We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4-5.2% integrated HIV gag DNA and 2-7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

“…Thus, to the best of our knowledge, this is the first report directly comparing two different HIV-1 Tat induction methods to evaluate changes in behavior and gene expression in a rodent model. We showed that Tat induction in iTat mice led to mild behavioral deficits when compared to WT controls including one or more of the following trends [1] higher anxiety levels depicted by reduced time spent in the open arms of EPM [2] altered ambulation during LMA [3] higher swim speeds in MWM [4] altered learning in T-maze. Simultaneously, we also depicted that gene expressions of [1] select inflammatory cytokines were unchanged, [2] MMPs were elevated, [3] TIMPs were altered depending on the duration of Tat exposure, subsequently impacting the brain MMP/TIMP balance.…”

“…During the antiretroviral therapy (ART) era, the brain remains a viral reservoir for HIV (1)(2)(3), and milder forms of HIV-associated neurocognitive disorders (HAND) affect nearly 18 million HIVinfected individuals lowering the quality of life (4)(5)(6)(7). Patients suffering from these milder forms of HAND exhibit difficulty with working memory, executive functioning, and speed of information processing (6).…”

Novel role of mortalin in attenuating HIV-1 Tat-mediated astrogliosis

“…HIV-1 Tat is a regulatory protein that is released and efficiently taken up by many cell types including astrocytes [ 5 ]. Astrocytes are extensively infected with HIV-1, and these cells also act as a “safe heaven” for the latent form of the virus [ 6 , 7 ]. In addition, the clinical reports also reveal the presence of HIV-1 Tat protein in the cerebrospinal fluid (CSF) from the infected patients successfully treated with cART [ 8 ].…”

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

“…Taken together, most data support that astrocytes can be infected by HIV, release high levels of inflammatory factors and produce several viral proteins including Tat, Nef, and Rev, which promote inflammation and damage to surrounding cells (Ferrell and Giunta, 2014 ; Hong and Banks, 2015 ). In fact, recent studies propose that astrocytes infected with HIV in addition to releasing viral proteins, may also release infectious virions that can infect T-cells in the brain that can then be trafficked to the periphery (Lutgen et al, 2020 ).…”