Chronic alcohol abuse and HIV infection frequently coexist in the same host. Alcohol abuse, the most common form of drug abuse in America, affects about 7 percent of the adult population and has been reported to have greater prevalence in the HIV-infected population. Estimates from the Centers for Disease Control (CDC) indicate that over 320,000 individuals in America are now living with AIDS. Muscle wasting is a common feature of both chronic alcohol consumption and AIDS. Involuntary weight loss greater than 10 percent in an HIV- infected individual is a hallmark of AIDS according to the CDC. The AIDS wasting syndrome and the resulting decline in body cell mass remains a major cause of morbidity and mortality, despite the significant improvement in control of HIV-infection with the use of highly active anti-retroviral therapy. Excess alcohol consumption is associated with a 50 percent incidence of skeletal muscle myopathy resulting from decreased muscle protein synthesis as well as accelerated muscle proteolysis. In addition, chronic alcohol abuse impairs the nutritional state of the individual affecting micronutrients, which in turn, modulate circulating and tissue levels of growth factors. Thus, the effects of alcohol consumption on muscle metabolism appear to be multifactorial. The hypothesis to be tested by the specific aims described in this proposal is that chronic alcohol administration accelerates the progression and exacerbates the severity of muscle wasting associated with simian immunodeficiency virus (SIV) infection by altering the balance between protein anabolic and catabolic mechanisms. The experimental SIV infection of macaque monkeys results in a disease that is remarkably similar to human AIDS and is the best animal model for studying the pathogenesis of HIV- like infection. The general aim of the studies proposed is to determine the impact of chronic alcohol administration on the temporal progression of whole body, tissue and molecular alterations in body composition, muscle mass and muscle protein synthesis and breakdown, in SIV-infected rhesus monkeys. We will accomplish this by (a) determining body composition throughout the course of SIV infection in chronically alcohol-administered monkeys and measuring, in parallel, the in vivo rates of muscle protein synthesis and breakdown, as well as (b) the rate- controlling molecular mechanisms involved in both synthetic (eukaryotic initiation factors, and myostatin) and degradation (ubiquitin-proteasome) pathways and (c) the recognized endocrine (IGF-I, GH, insulin and testosterone) nutritional (amino acids) and immune (pro-inflammatory cytokines) modulators of muscle mass. The results from these studies will provide detailed knowledge of how alcohol and SIV independently as well as in concert thereby impair the host's cellular metabolic and synthetic mechanisms involved in the regulation of muscle mass.
|Siggins, Robert W; Bagby, Gregory J; Molina, Patricia et al. (2009) Alcohol exposure impairs myeloid dendritic cell function in rhesus macaques. Alcohol Clin Exp Res 33:1524-31|