ALCOHOL, SIV INFECTION AND HOST DEFENSE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景：酒精滥用和人类免疫缺陷病毒(HIV)感染是常见的，并且经常在同一个体中共存。长期以来，人们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，而HIV主要通过感染和耗尽CD4T淋巴细胞来发挥其致病作用。然而，酒精如何影响艾滋病毒疾病的传播、发病机制、进展和治疗，目前还知之甚少。该项目测试了酒精作为辅助因素加速SIV感染进展以及增加宿主对机会性感染的易感性的假设，这反过来将通过解决以下具体目标进一步加速SIV感染的进展：1)测试酒精通过损害病毒特异性T淋巴细胞反应而增加SIV感染猕猴的血浆病毒设定点的假设；2)测试酒精促进肺炎期间SIV复制上调的假设；3)测试肺中SIV复制的增加是由肺泡巨噬细胞中的NF-kB激活所诱导的假设；以及4)验证这样一种假设，即这种SIV在肺部的增殖增加会导致新的SIV基因的产生，而这些新的SIV基因与疾病进展的加速有关。方法：目前，25只恒河猴在感染SIV后，通过外科手术植入了用于注射乙醇或蔗糖溶液的导管(对照组)。所有动物在麻醉下每周检查一次，并在那时收集样本。结果：初步数据显示，酒精不会改变SIV感染时CD8+的特异性。然而，正在进行的研究表明，酒精可能会增加4个月内支气管肺泡灌洗液(BALF)中SIV的存在，并通过部分增加核转录因子-kB而增加肺炎球菌攻击肺中SIV的产生。结论：在明确定义和被接受的非人类灵长类动物HIV感染模型的背景下完成这些特定的目标，将为酒精在改变宿主对HIV初次感染及其进展的防御能力方面的影响提供新的和重要的信息。

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. Background: 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, and HIV primarily exerts its pathogenic effects by infecting and depleting CD4 T lymphocytes. However, how alcohol impacts HIV disease transmission, pathogenesis, progression and treatment are poorly understood. This projects tests the 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 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 upregulation of SIV replication during pneumococcal pneumonia is enhanced by alcohol consumption; 3) to test the hypothesis that this increase in SIV replication in the lung is induced by activation of NF-kB in alveolar macrophages; and 4) to test the hypothesis that this increased of SIV proliferation in the lung results in the generation of new SIV genotypes that are associated with increased disease progression. Methods: Currently, 25 rhesus macaques have surgically implanted catheters used to administer either ethanol or sucrose (control subjects) solution after infection with SIV. All animals are examined under anesthesia once weekly and samples are collected at that time. Results: Preliminary data reveals that alcohol does not alter the CD8+ specific in response to SIV infection. However, ongoing studies show that alcohol may increase SIV presence in bronchoalveolar lavage fluid (BALF) 4 months PI, and increases SIV production in lungs challenge with pneumococcus by in part increasing nuclear NF-kB. Conclusion: Completing 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.