Alcohol abuse and its related consequences together with HIV/AIDS are the major health problems in many parts of the world. Chronic alcohol use has been found to impair various immune functions, thereby making the body more susceptible to invading pathogens. Based on the several studies in the literature that alcohol consumption leads to immunological deterioration, we hypothesize that alcohol use may exacerbate HIV infection and also accelerate the onset of clinical disease. This is a complex research issue and, to date, there are no clear answers in this regard. The prospect of testing proof-of-concept studies regarding correlation between alcohol consumption and disease in HIV-positive humans is untenable because of variable incubation periods and long length time that are required to address this important issue. Furthermore it is not known whether alcohol abuse will adversely affect the vaccine-induced immune response and it will confer inferior protection after natural infection. The latter issue becomes more important because several HIV candidate vaccine are in various phase of clinical trial. The present application is designed to address these vital questions in SHIVKU/macaque model of AIDS. This model of HIV/AIDS has been successfully used in our laboratory to study the pathogenesis of the virus, effect of anti retroviral drugs and evaluation of different candidate vaccines. In this proposal we will test the hypotheses in four specific aims. The experiments in Aim-1 will examine the effect of alcohol on co-receptor expression and replication of SIV and SHIV(s). We will also examine the effect of alcohol on NFkb activation, and whether suppressing NFkb activation can modulate virus replication. The proposed experiments in Aim-2 deal with establishment of a SHIV/macaque model of alcohol dependence and examine whether alcohol consumption accelerates the onset of SHIV-induced AIDS in macaques.
In Aim 3 and 4, we will examine the effect of chronic alcohol consumption on development and persistence of a live attenuated vaccine-induced immune responses and whether challenge with a pathogenic SHIV confers inferior protection in alcohol-dependent macaques. These studies will help us not only to understand pathogenesis of the SHIVKU in alcohol abuse set-up, but also whether chronic alcohol abuse compromises vaccine-induced development and persistence of virus-specific immune responses and vaccine mediated protection after pathogenic challenge. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015045-05
Application #
7480340
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wang, Joe
Project Start
2004-07-05
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$329,567
Indirect Cost
Name
University of Missouri Kansas City
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Jin, Mengyao; Kumar, Anil; Kumar, Santosh (2012) Ethanol-mediated regulation of cytochrome P450 2A6 expression in monocytes: role of oxidative stress-mediated PKC/MEK/Nrf2 pathway. PLoS One 7:e35505
Silverstein, Peter S; Shah, Ankit; Weemhoff, James et al. (2012) HIV-1 gp120 and drugs of abuse: interactions in the central nervous system. Curr HIV Res 10:369-83
Kumar, Santosh; Kumar, Anil (2011) Differential effects of ethanol on spectral binding and inhibition of cytochrome P450 3A4 with eight protease inhibitors antiretroviral drugs. Alcohol Clin Exp Res 35:2121-7
Jin, Mengyao; Arya, Priyanka; Patel, Kalpeshkumar et al. (2011) Effect of alcohol on drug efflux protein and drug metabolic enzymes in U937 macrophages. Alcohol Clin Exp Res 35:132-9
Perez-Casanova, Antonio; Husain, Kazim; Noel Jr, Richard J et al. (2008) Interaction of SIV/SHIV infection and morphine on plasma oxidant/antioxidant balance in macaque. Mol Cell Biochem 308:169-75
Noel Jr, Richard J; Kumar, Anil (2007) SIV Vpr evolution is inversely related to disease progression in a morphine-dependent rhesus macaque model of AIDS. Virology 359:397-404
Rivera-Amill, Vanessa; Noel Jr, Richard J; Orsini, Suheydi et al. (2007) Variable region 4 of SIV envelope correlates with rapid disease progression in morphine-exposed macaques infected with SIV/SHIV. Virology 358:373-83
Perez-Casanova, Antonio; Noel Jr, Richard J; Rivera-Amill, Vanessa et al. (2007) Morphine-mediated deterioration of oxidative stress leads to rapid disease progression in SIV/SHIV-infected macaques. AIDS Res Hum Retroviruses 23:1004-7
Persidsky, Yuri; Fox, Howard (2007) Battle of animal models. J Neuroimmune Pharmacol 2:171-7
Kumar, Rakesh; Orsoni, Suheydi; Norman, Lisa et al. (2006) Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques. Virology 354:192-206

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