Alcohol abuse is prevalent in HIV infected patients and is associated with suboptimal responses to antiretroviral therapy (ART). Both HIV and alcohol abuse predispose to infections at mucosal sites of which bacterial pneumonia is a common complication. During the last funding period, we found that experimental pneumonia using Streptococcus pneumoniae in alcohol fed, SIV-infected macaques resulted in statistically significant higher viral loads in the lung. This may be due to increased virus production by prolonged activation of cells (either CD4+ macrophages or CD4+ T-cells) and/or due to reduced SIV-specific cytotoxic CD8+ T-cells. Our lab has also demonstrated that IL-17 and IL-22, products of a subset of CD4+ T-cells, Th17 cells, play critical roles in mucosal immunity against extracellular bacterial infections in the lung. SIV infection leads to a loss of mucosal IL-17 producing T-cells and reduces expression of mucosal IL-17 and IL-22 resulting in Impaired local bacterial control in the intestine. Whether a similar depletion of Th17 cells occurs in the lung is unknown. Furthermore, preliminary studies show that alcohol suppresses IL-17 production by murine and non-human primate T-cells in vitro. These data suggest that alcohol and HIV/SIV may have additive or synergistic effects on mucosal T-cell populations and immunity in the lung. Additionally alcohol may impair T-cell reconstitution during ART. These data lead us to hypothesize that chronic alcohol ingestion is additive or synergistic with SIV to impair CD4+ Th-cell immune responses to extracellular pathogens. Utilizing our well-characterized model of intragastric ethanol feeding in the SIV rhesus macaque model, our Specific Aims are to: 1) Test the prediction that alcohol consumption will impair recovery of peripheral CD4+ T cells during ART treatment for SIV infection;2) Test the prediction that chronic alcohol consumption will impair the mucosal IL-17 and IL-22 responses to experimental pneumonia with S. pneumoniae as well as the generation of memory CD4+ T-cells after bacterial challenge. These experiments will improve our understanding on the respective roles of SIV, alcohol and the response to ART in terms of pulmonary mucosal immunity.
Alcohol and HIV are significant co-factors that predispose to infection. This project will investigate if alcohol and SIV (a model of HIV) depletes specific types of T helper cells which may explain in part the increased risk of opportunistic infections. This knowledge will not only advance our understanding of disease pathogenesis but also identify immune effector arms that can be the subject of future vaccine strategies to prevent infectious complications of HIV/AIDS.
|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|
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