The Role Of Innate Immunity Genes In Viral Infection and

在过去十年中，在了解导致HIV-1传播和艾滋病进展的不同易感性的宿主因素方面取得了相当大的进展。遗传背景已被证明是HIV-1感染和艾滋病进展的重要决定因素。然而，很少有研究针对先天免疫基因多态性在HIV传播或艾滋病进展中的作用。toll样受体4 （TLR4）介导小鼠和人类对革兰氏阴性细菌（如脂多糖或内毒素）的反应，也被认为是体外HIV感染和病毒复制的决定因素。最近，人类TLR4有两个功能多态性被报道：896 A to G （Asp299Gly）和1190 A to G （Thr399Ile）。这两种功能突变的丧失已被证明与人类对内毒素的反应具有功能相关性。为了评估TLR4在HIV-1传播和艾滋病进展中的潜在作用，我们与NIAID资助的多中心艾滋病队列研究（MACS）建立了研究合作。我们设计了这项研究，以验证在MACS招募的同性恋男性中的以下假设：1)TLR4的Asp299Gly和Thr399Ile多态性增加了HIV-1传播的风险；2)TLR4多态性与hiv感染者向艾滋病进展缓慢有关。

Considerable progress has been made over the last decade towards understanding host factors that contribute to differential susceptibility to HIV-1 transmission and AIDS progression. Genetic background has been shown to be an important determinant of both HIV-1 infection and AIDS progression. However, little work has been directed to understanding the role(s) of polymorphisms in innate immunity genes in HIV transmission or AIDS progression. Toll-like receptor 4 (TLR4), which mediates responses to Gram-negative bacteria (e.g. lipopolysaccharide or endotoxin) in mouse and humans, has also been implicated as a determinant of HIV infection and viral replication in vitro. Recently, two functional polymorphisms in human TLR4 have been reported: 896 A to G (Asp299Gly) and 1190 A to G (Thr399Ile). Both loss of function mutations have been demonstrated to have functional relevance to human response to endotoxin. To evaluate the potential role of TLR4 in HIV-1 transmission and AIDS progression we established a research collaboration with the multicenter AIDS cohort study (MACS), which is funded by NIAID. We designed the study to test the following hypotheses in homosexual men recruited to MACS: 1) the Asp299Gly and Thr399Ile polymorphisms in TLR4 confers enhanced risk to HIV-1 transmission, and 2) the TLR4 polymorphisms are associated with slowed progression to AIDS in HIV-infected individuals. A second project has been designed to investigate the mechanisms of susceptibility to respiratory syncytial virus (RSV) infection and disease progression. RSV is the leading viral respiratory cause of hospitalization in infants and young children in the United States and in the world. The reason why some previously healthy infants develop LRI (bronchiolitis and pneumonia) while others remain asymptomatic or only develop upper respiratory tract symptoms after RSV infection is not well understood. Evidence exists that the degree of previous injury of the lung parenchyma in small infants could play a role in disease severity, as children with chronic lung disease are at high risk of RSV LRI. However, the majority of hospitalizations occur in previously healthy infants. Another potentially important factor that can cause lung injury during RSV LRI is innate immunity. The pulmonary infiltration during RSV LRI is composed overwhelmingly by neutrophils and macrophages and damage to the small airways (10-300 microns) affected by the virus could easily cause debris accumulation in the lumen, inflammation and edema of the small airways, and compromise ventilation. Further, most infants with RSV-associated wheezing do not respond to b2-bronchodilators, but may benefit from inhaled a-agonists that decrease edema/inflammation. Additionally, high levels of CXC chemokines (particularly MIP-1a, MCP-1 and IL-8) have been associated with increased RSV disease severity.