Alcohol and AIDS: Pathogenesis and Immunity in Macaque

说明（由申请人提供）：酗酒及其相关后果以及艾滋病毒/艾滋病是世界许多地区的主要健康问题。人们发现，长期饮酒会损害各种免疫功能，从而使身体更容易受到病原体入侵的影响。基于文献中关于饮酒导致免疫功能恶化的几项研究，我们假设饮酒可能加剧HIV感染并加速临床疾病的发生。这是一个复杂的研究问题，到目前为止，在这方面还没有明确的答案。在艾滋病毒阳性人群中测试关于饮酒与疾病之间相关性的概念验证研究的前景是站不下去的，因为解决这一重要问题需要不同的潜伏期和较长的时间。此外，目前尚不清楚酒精滥用是否会对疫苗诱导的免疫反应产生不利影响，并且在自然感染后它会使保护作用降低。由于几种HIV候选疫苗正处于不同的临床试验阶段，后一个问题变得更加重要。本应用程序旨在解决这些至关重要的问题，在SHIVKU/猕猴艾滋病模型。这个HIV/AIDS模型已经成功地在我们的实验室中用于研究病毒的发病机制、抗逆转录病毒药物的效果和评价不同的候选疫苗。在本提案中，我们将在四个具体目标中测试这些假设。Aim-1的实验将检验酒精对SIV和SHIV共受体表达和复制的影响。我们还将研究酒精对NFkb激活的影响，以及抑制NFkb激活是否可以调节病毒复制。在Aim-2中提出的实验涉及建立SHIV/猕猴酒精依赖模型，并研究饮酒是否加速了猕猴SHIV诱导的艾滋病的发病。在Aim 3和Aim 4中，我们将研究慢性饮酒对减毒活疫苗诱导的免疫反应的发展和持续的影响，以及致病性SHIV攻击是否会在酒精依赖的猕猴中产生较差的保护作用。这些研究不仅将帮助我们了解酒精滥用中SHIVKU的发病机制，而且还将帮助我们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反应的发展和持续，以及疫苗在致病性攻击后介导的保护。

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.