Genetic and Metabolic Control of the Mitochondrial Transmembrane Potential and Reactive Oxygen Intermediate Production in HIV Disease

Abstract

Redox mechanims play important roles in replication of human immunodeficiency virus type 1 (HIV-1) and cellular susceptibility to apoptosis signals. Viral replication and accelerated turnover of CD4+ T cells occur throughout a prolonged asymptomatic phase in patients infected by HIV-1. Disease development is associated with steady loss of CD4+ T cells by apoptosis, increased rate of opportunistic infections and lymphoproliferative diseases, disruption of energy metabolism, and generalized wasting. Such pathological states are preceded by: (i) depletion of intracellular antioxidants, glutathione (GSH) and thioredoxin (TRX), (ii) increased reactive oxygen species (ROS) production, and (iii) changes in mitochondrial transmembrane potential (deltapsi(m)). Disruption of deltapsi(m) appears to be the point of no return in the effector phase of apoptosis. Viral proteins Tat, Nef, Vpr, protease, and gp120, have been implicated in initiation and/or intensification of oxidative stress and disruption of deltapsi(m). Redox-sensitive transcription factors, NF-kappaB, AP-1, and p53, support expression of viral genes and proinflammatory lymphokines. ROS regulate apoptosis signaling through Fas, tumor necrosis factor (TNF), and related cell death receptors, as well as the T-cell receptor. Oxidative stress in HIV-infected donors is accompanied by increased glucose utilization both on the cellular and organismal levels. Generation of GSH and TRX from their corresponding oxidized forms is dependent on NADPH provided through the pentose phosphate pathway of glucose metabolism. This article seeks to delineate the genetic and metabolic bases of HIV-induced oxidative stress. Such understanding should lead to development of effective antioxidant therapies in HIV disease.

Using an advanced intercross line to identify quantitative trait loci controlling immune response during collagen-induced arthritis

“…22 Previous studies showed that ROS production was partially controlled by genetic factors. 23 We also observed a difference in ROS production between inbred mouse strains with the FVB/N producing higher ROS than the DBA/1 strain (data not shown). In this study, we identified the first QTL controlling ROS production in mice.…”

Investigation of the levels of oxidative stress parameters in HIV and HIV-TB co-infected patients

“…antioxidants present in human serum become insufficient to circumvent HIV-1 replication secondary to cellular ROS production (superoxide anion, hydroxyl radical, hydrogen peroxide etc.) by a pro-oxidant effect of inflammatory cytokines and/or a polymorphonuclear leukocyte activation [13].…”

The pathogenesis of transaldolase deficiency

“…Disruption of the mitochondrial membrane potential has been proposed as the point of no return in apoptotic signaling (19 -21). Metabolic fluxes between glycolysis and the PPP are particularly relevant for maintaining the mitochondrial transmembrane potential (Dc m ) and balancing cellular requirements for energy and ROI production (18,22).…”