Short‐term exposure to HIV Tat induces glial activation and changes in perineuronal nets

• Published in: The European journal of neuroscience Vol. 60; no. 3; pp. 4303 - 4316
• Main Authors: Carey, Sean D., Conant, Katherine, Maguire‐Zeiss, Kathleen A.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.08.2024
• Subjects: Animals; Antiretroviral therapy; Cells, Cultured; Cognition; Complement system; Excitability; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Gene expression; glia; Glial cells; Gliosis; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; HIV; HIV‐associated neurocognitive disorder; Human immunodeficiency virus; Humans; Inflammation; Interneurons; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; matrix metalloproteinases; Mice; Mice, Inbred C57BL; Microglia; Nerve Net - drug effects; Nerve Net - metabolism; Nets; Neuroglia - drug effects; Neuroglia - metabolism; neuroinflammation; Neuronal-glial interactions; Neurons - drug effects; Neurons - metabolism; Neurons - virology; Neurotoxicity; Oxidants; Parvalbumin; Parvalbumins - metabolism; Perineuronal nets; tat Gene Products, Human Immunodeficiency Virus - metabolism; Tat protein; neuroinflammation; glia; matrix metalloproteinases; parvalbumin; HIV‐associated neurocognitive disorder
• ISSN: 0953-816X; 1460-9568; 1460-9568
• DOI: 10.1111/ejn.16427

Despite widespread use of combination antiretroviral therapy (cART), there remains a subset of individuals who display cognitive impairment broadly known as HIV‐associated neurocognitive disorder (HAND). Interestingly, HIV‐infected cells continuously release the HIV‐1 protein Tat even in the presence of cART. Persistent exposure to Tat is proposed to increase both neuroinflammation and neurotoxicity. In vitro evidence shows that matrix metalloproteinases (MMPs) are among the neuroinflammatory molecules induced by Tat, which are known to disrupt specialized neuronal extracellular matrix structures called perineuronal nets (PNNs). PNNs predominantly surround parvalbumin interneurons and help to buffer these cells from oxidant stress and to independently increase their excitability. In order to better understand the link between short‐term exposure to Tat, neuroinflammation, and PNNs, we explored the direct effects of Tat on glial cells and neurons. Herein, we report that in mixed glial cultures, Tat directly increases the expression of proinflammatory molecules, including MMP‐9. Moreover, direct injection of Tat protein into mouse hippocampus increases the expression of astrocyte and microglia markers as well as MMP‐9. The number of PNNs is decreased following Tat exposure, followed later by decreased numbers of hippocampal parvalbumin‐expressing neurons. In older mice, Tat induced significant increases in the gene expression of proinflammatory molecules including markers of gliosis, MMPs and complement system proteins. Taken together, these data support a direct effect of Tat on glial‐derived MMP expression subsequently affecting PNNs and neuronal health, with older mice more susceptible to Tat‐induced inflammation.