ALCOHOL, SIV INFECTION AND HOST DEFENSE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 酗酒和人类免疫缺陷病毒（HIV）感染是常见的，并经常在同一个人共存。 长期以来，人们都知道饮酒会抑制先天免疫和特异性免疫的关键方面，从而增加宿主对感染的易感性。 HIV感染主要对表达CD 4膜受体的免疫细胞发挥其致病作用，这导致CD 4+细胞的进行性耗竭、免疫监视受损、机会性感染和死亡。 目前，关于这两种免疫抑制状态如何相互作用以改变针对原发性病毒感染和/或继发性机会性感染的宿主防御机制的信息很少。该项目的重点是确定酒精对恒河猴SIV感染的进展和后遗症的影响，因为它与原发感染本身和继发感染的发展有关。 我们的假设是，酒精作为辅助因子加速SIV感染的进展，以及增加宿主对机会性感染的易感性，这反过来又会进一步加速SIV感染的进展。本研究通过解决以下具体目的来检验这一假设：1）检验酒精通过损害病毒特异性T淋巴细胞应答而增加SIV感染的猕猴中的血浆病毒设定点的假设; 2）检验在实验性肺炎球菌肺炎期间SIV复制在肺泡巨噬细胞（AM）中上调并且这种上调通过饮酒而增强的假设; 3）检验由机会性肺部感染诱导的SIV复制增加和酒精增强与AM中NF-κ B活化的机制相关的假设;和4）检验由机会性感染诱导的SIV增殖和由酒精促进的SIV增殖导致巨噬细胞选择性复制的假设，嗜性SIV基因型，并有助于新的表型和抗原变体的进化。在一个明确定义和公认的非人灵长类HIV感染模型的背景下解决这些具体目标，将提供关于酒精对改变宿主对HIV原发感染及其进展的防御作用的新的和重要的信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alcohol abuse and human immunodeficiency virus (HIV) infection are common and frequently coexist in the same individual. Alcohol consumption has long been known to suppress critical aspects of both innate and specific immunity thereby increasing host susceptibility to infections. HIV infection primarily exerts its pathogenic effects on immune cells expressing CD4 membrane receptor which leads to progressive depletion of the CD4+cells, compromised immunosurveillance, opportunistic infections, and death. Currently, there is little information on how these two immunosuppressive states interact to alter host defense mechanisms directed against both the primary viral infection and/or secondary opportunistic infections. The focus of this project is to determine the impact of alcohol on the progression and sequelae of SIV infection in rhesus monkeys as it relates to the primary infection itself and the development of secondary infections. It is our hypothesis that alcohol functions as a cofactor to accelerate the progression of SIV infection as well as to increase host susceptibility to opportunistic infections which, in turn, will further accelerate progression of SIV infection. This research tests this hypothesis by addressing the following Specific Aims: 1) to test the hypothesis that alcohol increases the plasma viral set point in SIV infected macaques by compromising viral specific T lymphocyte responses; 2) to test the hypothesis that SIV replication is upregulated in alveolar macrophages (AM) during experimental pneumococcal pneumonia and this upregulation is enhanced by alcohol consumption; 3) to test the hypothesis that the increase in SIV replication induced by an opportunistic pulmonary infection and enhanced by alcohol is mechanistically associated with activation of NF-kB in AM; and 4) to test the hypothesis that the proliferation of SIV induced by an opportunistic infection and enhanced by alcohol results in the selective replication of macrophage-tropic SIV genotypes and contributes to the evolution of novel phenotypic and antigenic variants. Addressing these specific aims in the context of a well-defined and accepted nonhuman primate model of HIV infection will provide novel and important information on the effects of alcohol on altering host defenses to both primary infection with HIV and its progression.