Alcohol abuse enhances neuroinflammation and impairs immune responses in an animal model of human immunodeficiency virus-1 encephalitis.
Neuroinflammatory disorders (including human immunodeficiency virus-1 encephalitis, HIVE) are associated with oxidative stress and inflammatory brain injury, and excessive alcohol use can exacerbate tissue damage. Using a murine model of HIVE, we investigated the effects of alcohol abuse on the clearance of virus-infected macrophages and neuroinflammation. Severe combined immunodeficient mice were reconstituted with human lymphocytes, and encephalitis was induced by intracranial injection of HIV-1-infected monocyte-derived macrophages (HIV-1(+) MDM). Animals were fed an ethanol-containing diet beginning 2 weeks before lymphocyte engraftment and for the entire duration of the experiment. Lymphocyte engraftment was not altered by ethanol exposure. Alcohol-mediated immunosuppression in ethanol-fed mice was manifested by a significant decrease in CD8(+)/interferon-gamma(+) T lymphocytes, a fivefold increase in viremia, and diminished expression of immunoproteasomes in the spleen. Although both groups showed similar amounts of CD8(+) T-lymphocyte infiltration in brain areas containing HIV-1(+) MDMs, ethanol-fed mice featured double the amounts of HIV-1(+) MDMs in the brain compared to controls. Ethanol-exposed mice demonstrated higher microglial reaction and enhanced oxidative stress. Alcohol exposure impaired immune responses (increased viremia, decreased immunoproteasome levels, and prevented efficient elimination of HIV-1(+) MDMs) and enhanced neuroinflammation in HIVE mice. Thus, alcohol abuse could be a co-factor in progression of HIV-1 infection of the brain.
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, 985215 Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Raghava
R
Potula
James
J
Haorah
Bryan
B
Knipe
Jessica
J
Leibhart
Jesse
J
Chrastil
David
D
Heilman
Huanyu
H
Dou
Rindha
R
Reddy
Anuja
A
Ghorpade
Yuri
Y
Persidsky
D000437:Alcoholism / Q000150:complications / Q000276:immunology* / Q000821:virology; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000150:complications / Q000276:immunology / Q000473:pathology*; D000431:Ethanol / Q000633:toxicity; D015658:HIV Infections / Q000150:complications / Q000276:immunology / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D008264:Macrophages / Q000637:transplantation / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017628:Microglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D018384:Oxidative Stress; D014766:Viremia / Q000276:immunology
D000431:Ethanol