Alcohol use disorders frequently coexist with human immunodeficiency (HIV) infection. Both chronic alcohol consumption and HIV infection produce marked alterations in metabolic regulation that lead to muscle wasting, loss of bone mineral mass, and lipodystrophy. Highly active antiretroviral therapy (HAART) causes metabolic toxicity that may significantly increase comorbidity in this patient population. We have demonstrated that chronic alcohol consumption results in decreased total caloric intake, altered nutrient selection, and decreased nitrogen intake, which together led to a greater decrease in lean body mass and increased the incidence of AIDS wasting in a non-human primate model of simian immunodeficiency virus (SIV) infection. Moreover, a strong association between development of simian acquired immunodeficiency syndrome (SAIDS) wasting and decreased time to end-stage was observed. We hypothesize that chronic alcohol prevents the neuroendocrine anabolic response to feeding in SIV-infected macaques and that chronic alcohol consumption favors tissue proinflammatory and pro-oxidative milieus that disrupt the balance between the synthetic and catabolic mechanisms leading to erosion of muscle, bone, and adipose tissue mass. We predict that chronic alcohol consumption during SIV infection will result in decreased functional metabolic mass and thereby augment ART-induced metabolic burden and toxicity.
The specific aims of this proposal are: to quantify the combined impact of chronic alcohol feeding, SIV infection, and ART on skeletal muscle, bone, and adipose tissue mass and functional metabolic phenotype;to elucidate the co-morbid effects of chronic alcohol administration, SIV infection and ART on the neuroendocrine and skeletal muscle anabolic response to controlled calorie/nutrient feeding;and to determine the tissue mechanisms by which ART and alcohol increase loss of functional metabolic tissue mass in SIV-infected macaques. Results from these studies will provide critical information about the mechanisms by which alcohol, SIV, and ART cause loss of fat and lean body mass by interfering with normal neuroendocrine, cellular catabolic and anabolic processes. The proposed studies will investigate whole body, tissue, cellular, and molecular mechanisms that are altered by alcohol and disrupted by ART, accentuating metabolic toxicity.
HIV infedion is now a chronic disease that frequently coexists with other conditions, including alcohol abuse disorders. The chronic alcohol consumption may aggravate not only the course of the infection, but may exacerbate the toxicity resulting from antiretroviral therapy. No previous studies have investigated the mechanisms affected by chronic alcohol consumption that may lead to greater toxicity when patients are treated with antiretrovirals.
|Choi, Sun-Mi; McAleer, Jeremy P; Trevejo-Nunez, Giraldina et al. (2014) Acute alcohol intoxication impairs methicillin-resistant Staphylococcus aureus clearance in the lung by impeding epithelial production of Reg3?. Infect Immun 82:1402-7|
|Siggins, Robert W; Molina, Patricia; Zhang, Ping et al. (2014) Dysregulation of myelopoiesis by chronic alcohol administration during early SIV infection of rhesus macaques. Alcohol Clin Exp Res 38:1993-2000|
|Brown, Armand O; Mann, Beth; Gao, Geli et al. (2014) Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 10:e1004383|
|Dodd, Tracy; Simon, Liz; LeCapitaine, Nicole J et al. (2014) Chronic binge alcohol administration accentuates expression of pro-fibrotic and inflammatory genes in the skeletal muscle of simian immunodeficiency virus-infected macaques. Alcohol Clin Exp Res 38:2697-706|
|Loganantharaj, Nisha; Nichols, Whitney A; Bagby, Gregory J et al. (2014) The effects of chronic binge alcohol on the genital microenvironment of simian immunodeficiency virus-infected female rhesus macaques. AIDS Res Hum Retroviruses 30:783-91|
|Ghare, Smita S; Joshi-Barve, Swati; Moghe, Akshata et al. (2014) Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells. J Immunol 193:412-21|
|Molina, Patricia E (2014) Alcohol binging exacerbates adipose tissue inflammation following burn injury. Alcohol Clin Exp Res 38:33-5|
|Deshmukh, Hitesh S; Liu, Yuhong; Menkiti, Ogechukwu R et al. (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20:524-30|
|Simon, Liz; LeCapitaine, Nicole; Berner, Paul et al. (2014) Chronic binge alcohol consumption alters myogenic gene expression and reduces in vitro myogenic differentiation potential of myoblasts from rhesus macaques. Am J Physiol Regul Integr Comp Physiol 306:R837-44|
|El Hajj, Elia C; El Hajj, Milad C; Voloshenyuk, Tetyana G et al. (2014) Alcohol modulation of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs favors collagen accumulation. Alcohol Clin Exp Res 38:448-56|
Showing the most recent 10 out of 37 publications