The Role Of Innate Immunity Genes In Viral Infection and

在过去十年中，在了解导致对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，很少有工作已经针对理解的作用（S）的先天免疫基因的多态性在艾滋病毒传播或艾滋病的进展。Toll样受体4（TLR 4）介导小鼠和人类对革兰氏阴性细菌（例如脂多糖或内毒素）的应答，也被认为是体外HIV感染和病毒复制的决定因素。最近，人类TLR 4的两个功能多态性被报道：896 A到G（Asp 299 Gly）和1190 A到G（Thr 399 Ile）。已证明两种功能缺失突变与人体对内毒素的反应具有功能相关性。为了评估TLR 4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。我们设计这项研究是为了在招募到MACS的同性恋男性中验证以下假设：1）TLR 4中的Asp 299 Gly和Thr 399 Ile多态性增加了HIV-1传播的风险，2）TLR 4多态性与HIV感染者向AIDS进展缓慢相关。 第二个项目旨在研究呼吸道合胞病毒（RSV）感染和疾病进展的易感性机制。RSV是美国和世界上导致婴幼儿住院的主要病毒性呼吸道疾病。为什么一些以前健康的婴儿发展LRI（细支气管炎和肺炎），而其他人保持无症状或仅在RSV感染后发展上呼吸道症状，原因尚不清楚。有证据表明，小婴儿肺实质的既往损伤程度可能在疾病严重程度中发挥作用，因为患有慢性肺病的儿童具有RSV LRI的高风险。然而，大多数住院治疗发生在以前健康的婴儿中。在RSV LRI期间可引起肺损伤的另一个潜在重要因素是先天免疫。RSV LRI期间的肺浸润主要由嗜中性粒细胞和巨噬细胞组成，受病毒影响的小气道（10-300微米）的损伤可能容易导致小气道管腔中的碎片积聚、炎症和水肿，并损害通气。此外，大多数患有RSV相关喘鸣的婴儿对b2-支气管扩张剂没有反应，但可能受益于减少水肿/炎症的吸入α-激动剂。此外，高水平的CXC趋化因子（特别是MIP-1 a、MCP-1和IL-8）与RSV疾病严重程度增加相关。

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.