HIV-induced redox changes and inflammation in the central nervous system and modulatory factors

Abstract

Currently 34 million people live with human immunodeficiency virus (HIV) infection. Although the lifespan of HIV patients has been prolonged by highly active antiretroviral treatment, the prevalence of HIV-associated neurocognitive disorders (HANDs) is increasing. Oxidative stress and inflammation in the central nervous system (CNS) are major causes of HANDs, and concurrent drug abuse may accelerate the progression of symptoms. This dissertation aims to study HIV-induced changes in antioxidants, oxidative stress, and inflammation in the CNS, assess the effects of concurrent methamphetamine (Meth) exposure, and evaluate the protective effect of dietary supplementation of bamboo Phyllostachys edulis extract (BEX). This study centered on the most abundant antioxidant in the brain-glutathione (GSH). The changes of GSH metabolism and GSH-dependent antioxidant enzymes were measured in cerebrospinal fluid (CSF) of human cohorts with HIV infection and/or uses of Meth, and in the brain tissues of HIV-1 model transgenic rats (HIV-1Tg expressing 7 HIV viral proteins) with or without Meth exposure. HIV infection resulted in elevated gamma-glutamyl transpeptidase (GGT) activity, GSH depletion and a several-fold increase in lipid peroxidation in human CSF. Compared to HIV infection, use of Meth resulted in less severe oxidative stress, which may be partially explained by the upregulation of glutathione peroxidase (GPx) and GSH in the CSF. Meth did not interact with HIV in modulating the redox changes in the CSF. In HIV-1Tg rats, redox and inflammatory changes were observed in the brain in a region-specific manner, with little synergy from Meth exposure. The thalamus was highlighted by its high GSH content and systematic upregulation of GSH biosynthesis and GSH-dependent antioxidant enzymes in the HIV-1Tg rats. On the other hand, neuroinflammation markers, such as glial fibrillary acidic protein (GFAP) and p65, were increased in the hippocampus of the transgenic rats, and such changes were effectively normalized by dietary supplementation of BEX. In summary, this dissertation documents the significance of GSH and GSH-dependent antioxidant enzymes in regulating the redox status of CNS, and the potential anti-neuroinflammatory effects of BEX in the context of HIV infection.