Analysis of glutathione levels in the brain tissue samples from HIV-1-positive individuals and subject with Alzheimer's disease and its implication in the pathophysiology of the disease process

Abstract

HIV-1 positive individuals are at high risk for susceptibility to both pulmonary tuberculosis (TB) and extra-pulmonary TB, including TB meningitis (TBM) which is an extreme form of TB. The goals of this study are to determine the mechanisms responsible for compromised levels of glutathione (GSH) in the brain tissue samples derived from HIV-1-infected individuals and individuals with Alzheimer's disease (AD), investigate the possible underlying mechanisms responsible for GSH deficiency in these pathological conditions, and establish a link between GSH levels and pathophysiology of the disease processes. We demonstrated in the autopsied human brain tissues that the levels of total and reduced forms of GSH were significantly compromised in HIV-1 infected individuals compared to in healthy subjects and individuals with AD. Brain tissue samples derived from HIV-1-positive individuals had substantially higher levels of free radicals than that derived from healthy and AD individuals. Enzymes that are responsible for the de novo synthesis of GSH such as γ-glutamate cysteine-ligase catalytic subunit (GCLC-rate limiting step enzyme) and glutathione synthetase (GSS-enzyme involved in the second step reaction) were significantly decreased in the brain tissue samples derived from HIV-1-positive individuals with low CD4 + T-cells (< 200 cells/mm3) compared to healthy and AD individuals. Levels of glutathione reductase (GSR) were also decreased in the brain tissue samples derived from HIV-1 infected individuals. Overall, our findings demonstrate causes for GSH deficiency in the brain tissue from HIV-1 infected individuals explaining the possible reasons for increased susceptibility to the most severe form of extra-pulmonary TB, TBM.

Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress

“…Antioxidant treatment for HIV was proposed more than two decades ago when it was discovered that plasma levels of cysteine and the cysteine dimer cystine, both precursors for intracellular GSH, as well as GSH itself, are depleted in HIV (121). Consistent with this early work, a recent postmortem study reported low frontal cortex GSH levels in HIV+ subjects (122). As oxidative stress increases and antioxidants can suppress HIV virus replication (123–126), antioxidants not only might reduce depression-like behavior but also could help maintain HIV latency.…”

Effects of viral proteins on the nuclear organization of human peripheral blood B-cells

“…En addition la carence d'autres antioxydants chez les patients infectés, a été détectée, comme la vitamine A (Chiu et al, 2008) et la vitamine E (Mehta et al, 2010;Pacht et al, 1997). A signaler que l'expression de certains enzymes antioxydants a été réprimée, citant par exemple le GSTP1 (Strange et al, 2001) et ainsi que le -GCS (Morris et al, 2014;Saing et al, 2016).…”

Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis

“…GSH, a tripeptide comprised of glutamate, cysteine and glycine, functions to protect the cells and tissues from oxidative damage thereby restoring redox homeostasis within the body [20]. Further studies have demonstrated that the biological antioxidant GSH has both antimycobacterial effects and immune-modulating properties [21-23].…”

“…Our laboratory has previously reported that the levels of GSH were significantly decreased in the red blood cells, NK cells, macrophages and T cells derived from the peripheral blood of individuals with HIV infection [24-26]. Furthermore, we have also demonstrated that the levels of GSH were significantly compromised in brain tissue samples derived from the frontal cortex of individuals with HIV infection [21]. The decreased levels of GSH among the HIV infected individuals correlated with the diminished control of M. tb infection [21-23].…”

“…Furthermore, we have also demonstrated that the levels of GSH were significantly compromised in brain tissue samples derived from the frontal cortex of individuals with HIV infection [21]. The decreased levels of GSH among the HIV infected individuals correlated with the diminished control of M. tb infection [21-23]. Additional studies have shown that the levels of GSH were significantly compromised in individuals with type 2 diabetes (T2DM) due to diminished levels of enzymes involved in the GSH synthesis [27].…”