HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate

Document Type

Journal Article

Publication Date

2-15-2019

Journal

Journal of NeuroVirology

Volume

25

Issue

1

DOI

10.1007/s13365-018-0693-6

Keywords

Astrocytes; Central memory T cells; DNA damage response; Glutamate; HIV latency; Pericytes

Abstract

Reduced pericytes’ coverage of endothelium in the brain is one of the structural changes leading to breach of the blood-brain barrier during HIV infection. We previously showed in central memory T (T ) cells that HIV latency increases cellular susceptibility to DNA damage. In this study, we investigated susceptibility of primary brain pericytes infected with HIV-1 to DNA damage in response to glutamate and TNF-α, both known to induce neuronal death during chronic inflammatory conditions. To infect pericytes, we used a single-cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein and maintained the cultures until latency was established. Our data indicate that pericytes silence HIV-1 expression at similar rate compared to primary T cells. TNF-α and IL-1β caused partial reactivation of the virus suggesting that progression of disease and neuroinflammation might facilitate virus reactivation from latency. Significant increases in the level of γH2AX, which reflect DNA damage, were observed in infected cultures exposed to TNF-α and glutamate at day 2 post-infection. Glutamate, an excitatory neurologic stimuli, also caused increases in the γH2AX level in latently infected pericytes, whereas PARP and DNA-PK inhibitors caused reductions in cell population suggesting that HIV-1 latency affects repairs of single- and double-strand DNA breaks. For comparison, we also analyzed latently infected astrocytes and determined that DNA damage response in astrocytes is less affected by HIV-1. In conclusion, our results indicate that productive infection and HIV-1 latency in pericytes interfere with DNA damage response, rendering them vulnerable to the agents that are characteristic of chronic neuroinflammatory disease conditions. CM CM

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