Effects of HLA and KIR genotype on HIV and HCV

描述(申请人提供)：这项申请是为了研究女性中人类白细胞抗原(HLA)和杀伤免疫球蛋白样受体(KIR)基因多态性对(I)感染艾滋病毒的风险、(Ii)感染丙型肝炎病毒的风险以及(iii/iv)艾滋病毒和丙型肝炎病毒感染过程的影响。HLA分子是一种多态蛋白质，通过向T细胞递呈抗原在病毒免疫反应中发挥核心作用，并作为KIR(帮助调节自然杀伤细胞功能的多态分子)的配体。由于共同的危险因素，艾滋病毒和丙型肝炎病毒影响相似的人群，合并感染很常见。以往的流行病学研究表明，人类免疫缺陷病毒(HIV)和丙型肝炎病毒(HCV)的HLA型均与感染病程有关。然而，已知的人类白细胞抗原和KIR的生物相互作用直到最近才被考虑。我们小组在男性中进行的一项大型研究发现，人类白细胞抗原和KIR之间存在强烈而显著的相互作用，与艾滋病毒/艾滋病的进展有关。在其他免疫相关疾病中也观察到了HL A/KIR的相互作用。因此，重要的是既要了解人类白细胞抗原，又要了解KIR，以充分解释其中任何一种的数据；这些数据在以前的艾滋病毒和丙型肝炎研究中是不完整的。人类白细胞抗原(HLA型)对人类免疫缺陷病毒(HAART)影响的认识远远超出了考虑KIR的需要，到目前为止，尽管HIV自然病史中的性别差异，但女性的人类白细胞抗原数据仍然很少，令人惊讶的是，关于与HAART反应相关的HLA等位基因，甚至成为HIV感染的风险，也知之甚少。我们对丙型肝炎病毒和人类白细胞抗原分型的了解更是不完整。有关丙型肝炎病毒清除的研究几乎全部集中在人类白细胞抗原II类，但人类白细胞抗原Ia类在细胞毒性T细胞对丙型肝炎病毒的应答中起着核心作用。人们从未仔细研究过感染丙型肝炎病毒的风险。这项计划中的研究将首次仔细评估人类白细胞抗原和KIR对女性艾滋病毒/艾滋病进展、对HAART的反应、艾滋病毒感染风险、丙型肝炎病毒血症和丙型肝炎病毒感染风险的独立影响和相互作用。为了解决这些问题，我们将在妇女机构间艾滋病毒研究(WIHS)中进行高分辨率的人类白细胞抗原和KIR基因分型。WlHS是艾滋病毒(+)(n=2761，丙型肝炎病毒-40%(+))和艾滋病毒(-)妇女中具有相似危险因素(n=942，丙型肝炎病毒(+)-25%)的一个庞大的、种族和地理上多样化的队列。

DESCRIPTION (provided by applicant): This application is to study the effects of human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) polymorphisms in women on (i) risk of infection by HIV, (ii) risk of infection by HCV, and (iii/iv) the course of HIV and HCV infections. HLA molecules are polymorphic proteins that play a central role in the immune response to viruses through the presentation of antigens to T-cells, and act as ligand for KIR (polymorphic molecules that help regulate natural killer cell function). Due to shared risk factors, HIV and HCV affect similar populations, and coinfection is common. For both HIV and HCV, previous epidemiologic studies have indicated that HLA type is related to course of infection. However, the known biologic interaction of HLA and KIR has only recently been taken into consideration. A large study in men conducted by our group found strong significant interactions between HLA and KIR associated with HIV/AIDS progression. HLA/KIR interactions have also been observed in other immune-related diseases. Thus, it is important to know both HLA and KIR to fully interpret the data for either; data that were incomplete in prior studies of HIV and HCV. Critical gaps in our knowledge regarding the effects of HLA type go substantially beyond the need to consider KIR, To date, there is a paucity of HLA data in women despite gender differences in HIV natural history and, surprisingly, little is also known regarding the HLA alleles associated with response to HAART, or even risk of becoming HIV infected. Our understanding of HCV and HLA type is even more incomplete. Studies of HCV clearance have focused almost entirely on HLA class II, but it is HLA class Ia that plays a central role in the cytotoxic T-cell response to HCV. Risk of becoming HCV infected has never been carefully studied. The planned study will be the first to carefully assess the independent effects and interactions of HLA and KIR on HIV/AIDS progression among women, response to HAART, risk of HIV infection, HCV viremia, and risk of HCV infection. To address these issues, we will conduct high resolution HLA and KIR genotyping in the Women's Interagency HIV Study (WIHS). WlHS is a large, racially and geographically diverse cohort of HIV(+) (n=2761 with - 40% HCV(+)), and HIV(-) women who share similar risk factors (n=942 with - 25%HCV(+)).