Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers [see comments]

Abstract

In several models of lymphocyte apoptosis, two alterations of mitochondrial function precede advanced DNA fragmentation: (1) a reduction of mitochondrial transmembrane potential (delta psi m) and (2) an increase in mitochondrial generation of superoxide anion. Here we show that two fluorochromes allow for the identification of analogous mitochondrial perturbations in circulating T lymphocytes from human immunodeficiency virus (HIV)-1+ donors. The first among these fluorochromes, the cationic lipophilic dye DiOC6(3), measures delta psi m; the second marker, hydroethidine (HE), is nonfluorescent, unless it is oxidized by superoxide anions to the product ethidium (Eth). CD4+ or CD8+ cells from clinically asymptomatic HIV-1 carriers contain a significantly elevated percentage of cells endowed with enhanced HE --> Eth conversion and/or reduced DiOC6(3) uptake as compared with normal controls. Phenotypic characterization of (HE --> Eth)high cells from HIV+ donors shows that these cells possess a low delta psi m, thus demonstrating a functional alteration of mitochondria. In addition, (HE --> Eth)high cells display a reduced incorporation of the cardiolipin-specific dye nonyl-acridine orange (NAO), showing a structural defect of the cardiolipin-containing inner mitochondrial membrane. Control experiments involving rotenone, an inhibitor of the respiratory chain complex I, indicate that the reactive oxygen species responsible for HE --> Eth conversion is generated during mitochondrial electron transport. In synthesis, it appears that mitochondrial alterations occur in a significant percentage of circulating T lymphocytes from HIV-1 carriers. The extent of delta psi m reduction, as determined ex vivo, correlates with the frequency of cells undergoing DNA fragmentation after overnight in vitro culture. These observations may be important for the understanding and for the direct ex vivo quantitation of HIV-triggered lymphocyte destruction.

HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir

“…We have extended these findings by looking at various intracellular events leading to HIV Env-induced apoptosis. We observe that the apoptosis in our model was mediated via a mitochondrial pathway, as has been seen by others in Env cocultures [49] and virus infection [18]. We also find that the cells undergoing apoptosis show signs of high ROS, a marker of oxidative stress, and a phenomenon reported in HIV-infected cultures [16] or in lymphocytes from infected patients ex vivo [20].…”

“…Apoptosis mediated via various stimuli involves mitochondrial depolarization and ROS production as early events in the apoptotic pathway. In HIV infection, mitochondrial dysfunction has been associated with T cell loss in vivo [18]. To determine the signaling mechanism involved in HIV Envinduced apoptosis, we first determined whether apoptosis was mediated via the mitochondrial pathway.…”

“…Although the interaction of HIV gp120 with receptor and coreceptor is required for the induction of apoptosis, signaling via either of these receptors seems dispensable for this process [14,15]. Hence, the signaling mechanism via which HIV Env mediates apoptosis in bystander cells is not clear, although several reports indicate that caspase activation [16,17], mitochondrial dysfunction [18,19], and reactive oxygen species (ROS) may be involved [20]. Nevertheless, the sequence of these events in HIV Env-mediated apoptosis remains unclear.…”

Frequent reversible membrane damage in peripheral blood B cells in human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

“…These findings did not give further clues to the mechanism of increased annexin V staining of B cells, but suggested that this increased staining was not a result of apoptosis. Although we cannot conclude that this abnormal PS exposure on B cells is specific to HAM/TSP, it has been reported that in HIV infection there is not a high level of annexin V positivity, although there are significant levels of mitochondrial depolarization in fresh PBMC [14].…”

Glutathione and HIV infection: reduced reduced, or increased oxidized?

“…NADPH is formed in cytosol and mitochondria via the hexose monophosphate shunt. Interestingly, seropositive subjects have been shown to have mitochondrial dysfunctions [8], which could contribute to low NADPH levels and GSH reductase activity and lowered GSH/ increased GSSG levels.…”