Alcohol, SIV infection, and Host Defense

酗酒和人类免疫缺陷病毒(HIV)感染是美国的主要公共卫生问题，经常在同一个人身上共存。虽然一些研究已经表明饮酒和感染艾滋病毒的风险之间存在显著的关联，但这种关联是否源于行为和/或生物医学机制仍有待确定。此外，现有数据既没有证实也没有反驳酒精可以作为辅助因素加速艾滋病毒感染进展的假设。对HIV感染者的研究天生就限制了他们控制变量的能力 例如接触艾滋病毒的时间和剂量、营养、同时使用其他滥用药物、使用高效抗逆转录病毒疗法，以及饮酒的频率和数量。对酒精对艾滋病毒感染性和疾病进展的影响缺乏了解，这是了解艾滋病毒相关发病率和死亡率的主要障碍。为了研究饮酒对HIV感染的影响，我们建立了恒河猴感染猴免疫缺陷病毒(SIV)的慢性饮酒模型。我们的研究表明，酒精增加了SIV感染的饮酒猕猴的病毒设定点，这是生存的预测，并增强了病毒的作用 病毒复制上的机会性感染。我们现在计划确定其中涉及的免疫学机制，并提出以下具体目标：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感染猕猴血浆病毒设定点的假设；2)测试在实验性肺炎期间SIV复制在肺泡巨噬细胞(AM)中上调的假设，这种上调是因饮酒而增强的；3)测试由机会性肺部感染诱导的SIV复制增加与AM中的NF-kB激活存在机械联系的假设；以及4)测试该增殖的假设 由机会性感染和酒精增强的SIV的选择性复制导致了嗜巨噬细胞的SIV基因的选择性复制，并有助于新的表型和抗原变异体的进化。在明确的艾滋病毒感染模式的背景下解决这些具体目标，将为酒精消费宿主中艾滋病毒感染的发病机制提供新的和重要的信息。

Alcohol abuse and human immunodeficiency virus (HIV) infection are major public health problems in the United States and frequently coexist in the same individual. While several studies have shown a significant association between alcohol consumption and the risk of being infected with HIV, it remains to be determined whether this association is due to behavioral and/or biomedical mechanisms. Furthermore, existing data neither confirm nor disprove the hypothesis that alcohol can function as a cofactor to accelerate progression of HIV infection. Studies of HIV-infected patients are inherently limited in their ability to control for variables such as timing and dose of HIV exposure, nutrition, concurrent use of other drugs of abuse, use of highly active anti-retroviral therapy, as well as the frequency and amount of alcohol consumed. This lack of knowledge on the effect of alcohol on HIV infectivity and disease progression is a major impediment in understanding HIV-related morbidity and mortality. In order to study the impact of alcohol consumption on HIV infection, we have developed a model of chronic alcohol consumption in rhesus macaques infected with simian immunodeficiency virus (SIV). Our studies show that alcohol increases the viral set point in SIV-infected alcohol-consuming macaques, which is predictive of survival, and enhances the effect of an opportunistic infection on viral replication. We now plan to identify the immunologic mechanisms involved and propose 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 model of HIV infection will provide novel and important information on the pathogenesis of HIV infection in the alcohol-consuming host.