Alcohol and AIDS: Pathogenesis and Immunity in Macaque

描述（由申请人提供）：酗酒及其相关后果与艾滋病毒/艾滋病是世界许多地区的主要健康问题。研究发现，长期饮酒会损害各种免疫功能，从而使身体更容易受到入侵病原体的影响。基于文献中关于饮酒导致免疫功能恶化的几项研究，我们假设饮酒可能会加剧HIV感染，并加速临床疾病的发作。这是一个复杂的研究问题，迄今为止，在这方面没有明确的答案。由于潜伏期不同，解决这一重要问题所需的时间也很长，因此，对艾滋病毒阳性者饮酒与疾病之间的相关性进行概念验证研究的测试前景是不可行的。此外，目前尚不清楚酗酒是否会对疫苗诱导的免疫反应产生不利影响，以及在自然感染后是否会产生较差的保护作用。后一个问题变得更加重要，因为几种HIV候选疫苗处于临床试验的不同阶段。本申请旨在解决艾滋病的SHIVKU/猕猴模型中的这些重要问题。本实验室已成功地利用该模型研究了HIV/AIDS的发病机制、抗逆转录病毒药物的作用以及不同候选疫苗的评价。在本提案中，我们将在四个具体目标中检验假设。Aim-1中的实验将检查酒精对SIV和SHIV的共受体表达和复制的影响。我们还将研究酒精对NF κ B活化的影响，以及抑制NF κ B活化是否可以调节病毒复制。Aim-2中提出的实验涉及建立酒精依赖的SHIV/猕猴模型，并检查酒精消耗是否加速猕猴中SHIV诱导的AIDS的发作。在目标3和4中，我们将研究长期饮酒对减毒活疫苗诱导的免疫应答的发展和持续性的影响，以及致病性SHIV的攻击是否会在酒精依赖性猕猴中产生较差的保护作用。这些研究将帮助我们不仅了解酒精滥用中SHIVKU的发病机制，而且还了解慢性酒精滥用是否会损害疫苗诱导的病毒特异性免疫应答的发展和持续性以及病原体攻击后疫苗介导的保护。

DESCRIPTION (provided by applicant): 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.