Oxidative Stress in HIV Infection and Alcohol Use: Role of Redox Signals in Modulation of Lipid Rafts and ATP-Binding Cassette Transporters.

AIMS: Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. RESULTS: In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE2) in plasma when compared with either HIV or alcohol alone. INNOVATION: This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. CONCLUSION: These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337.

Synthesis of chiral phosphoantigens and their activity in gamma delta T cell stimulation.

Gammadelta T cells expressing Vgamma2Vdelta2 T cell receptors are activated by a broad range of phosphorus-containing small molecules, termed phosphoantigens, and are of interest in the context of the chemotherapy of B cell malignancies. Here, we report the synthesis of four pairs of chiral phosphoantigens: the bromohydrins of isopentenyl diphosphate (Phosphostim), the epoxides of isopentenyl diphosphate (EIPP); and the corresponding bromohydrin and epoxide analogs of but-3-enyl diphosphate. The ability of each compound to stimulate human Vgamma2Vdelta2 T cells was determined by TNF-alpha release and cell proliferation. In these assays, the (R)-bromohydrin diphosphates were, on average, about twice as active as the (S)-bromohydrin diphosphates. In contrast, the (S)-form of EIPP was about twice as active as (R)-EIPP. The activities of the epoxy but-3-enyl diphosphates were both very low. These results suggest that chiral phosphoantigens, as opposed to racemic mixtures, may have utility in immunotherapy.

International conference on byssinosis. Mechanisms of disease induction.

From this work and other published data there are at least three distinct compounds that have been shown to be capable of inducing symptoms of byssinosis. There is an aminopolysaccharide-protein complex in cotton plant bracts that acts by causing histamine release in the human lung and also causes necrosis of bronchiolar epithelium. There is endotoxin or endotoxin-like material present in cotton plant bracts that acts by a mechanism other than by causing histamine release. This can induce histologic features of chronic bronchitis over a period of time. There is a polyphenol compound whose action is unlikely to be via complement activation, even though higher titers of antibody to it are present in byssinotic compared with nonbyssinotic subjects. It is postulated that such a compound is held in the lungs by antibody and exerts its effect on the pulmonary vasculature, altering capillary resistance. It also produces pathologic change as might be expected from its ability to precipitate proteins and activate complement.

Induction of human skin sensitization to ethanol.

In predictive skin sensitization tests, 50% aqueous ethanol induced delayed allergic skin reactivity in 6 of 93 human volunteers. This was confirmed 2 months after the primary challenge by producing an allergic response in each of the 6 with a single 24-hr application of 50% aqueous ethanol. Three of these reactive subjects also responded to lower concentrations of ethanol in water, and 2 of them still showed allergic reactivity 18 months later. Possible allergens other than the ethanol itself (i.e., an impurity or an ethanol-soluble component of the patch) were eliminated. Responses of 1 subject to ethanol that had been purified by gas chromatography confirmed that ethanol alone was the sensitizer. This subject also reacted to other short-chain primary alcohols, a secondary alcohol, and acetaldehyde, suggesting an antigenic relationship among all of these compounds in the skin. One of the authors, who had become sensitized to acetaldehyde, showed a similar pattern of cross-reactivity. Previous infrequent reports of ethanol sensitivity have been limited to case studies and diagnostic patch testing. This work provides evidence that a test designed to predict skin-sensitizing potential will identify even a weak sensitizer such as ethanol. Aqueous ethanol solutions approaching 50% concentrations should be avoided as vehicles in human predictive sensitization testing.