Effects of genetic variation on infectious disease

HIV-1感染的临床过程和结果因人而异，取决于病毒、宿主和环境决定因素的组合。显然，对HIV-1的遗传抗性涉及一系列复杂的宿主遗传效应，包括对基因表达或蛋白质功能具有微妙但重要影响的变异。总的来说，与HIV-1疾病进展最强的遗传关联涉及人类白细胞抗原（HLA） I类位点，它似乎通过获得性和先天免疫反应以高度多样化的方式影响对艾滋病的抗性/易感性。HLA对HIV-1暴露和感染结果的影响的研究比任何其他传染病的研究都要彻底。许多相关报道尚未在多项研究中得到证实，但某些HLA I类等位基因或基因型所赋予的易感性或耐药性的一致模式已经出现。此外，HLA限制性T细胞识别介导的对感染因子的有效获得性免疫反应可以针对疾病发病的不同阶段。我们最近提交的一篇论文表明，已知在HIV-1感染后的不同时间间隔内，三种不同的HLA等位基因：B*27、B*57和B*35Px会改变艾滋病的总体进展速度。HLA等位基因影响的离散时间提示了针对这种动态和慢性免疫抑制疾病的免疫防御的其他功能机制。一些研究已经检查了HLA与HIV-1感染风险之间的关系，主要涉及来自非洲的个体。HLA对高活性抗逆转录病毒治疗（HAART）的影响只是刚刚被考虑，几乎所有HLA对艾滋病进展的研究都是在男性中进行的。为了解决我们对HIV-1发病机制的理解中的这些缺陷，我们与Howard Strickler博士和妇女机构间健康研究（WIHS）建立了合作，研究免疫反应基因对HIV-1暴露后三种疾病结局的影响：1) HIV+组和HIV-组的感染风险与入组地点和风险因素相匹配；2)从基线CD4计数和病毒载量的特定范围进展为艾滋病；3)对HAART的反应。WIHS队列是最大的女性HIV及其并发症的多中心前瞻性队列研究，涉及丙型肝炎病毒（HCV）和人乳头瘤病毒（HPV）感染率高的个体（见下文）。该队列在美国招募了大约4000名不同种族背景的女性，每六个月收集一次参与者的详细临床数据。参与WIHS的患者将被分型为HLA I类、II类和杀伤性免疫球蛋白样受体（KIR）。MIC基因的基因分型也正在考虑用于未来的研究。到目前为止，我们已经收到了大约1200个样品。已完成HLAⅰ类和ⅱ类基因分型。对数据的初步分析表明，特定HLA等位基因与流行的HPV感染以及鳞状上皮内病变之间存在许多显著关联。HLA I类分子也被证明作为KIR分子在自然杀伤细胞（NK）和CD8+细胞亚群上表达的配体参与先天免疫反应。NK细胞通过产生细胞因子和杀死病毒感染的细胞来防御病毒感染，这些功能是通过识别靶细胞上特定的I类同种异体来激活和抑制KIR分子来调节的。我们之前已经证明，编码抑制NK细胞受体KIR2DL3及其HLA-C1配体的基因可以传递相对较弱的抑制信号，从而提高HCV感染的分辨率。

The clinical course and outcome of HIV-1 infection are highly variable among individuals, depending on a combination of viral, host, and environmental determinants. Genetic resistance to HIV-1 clearly involves a complex array of host genetic effects involving variants that have subtle, but significant consequences on gene expression or protein function. Overall, the strongest genetic associations with HIV-1 disease progression have involved the human leukocyte antigen (HLA) class I loci, which appear to influence resistance/susceptibility to AIDS in a highly multifarious manner through both acquired and innate immune responses. The effects of HLA on outcome to HIV-1 exposure and infection have been studied more thoroughly than that pertaining to any other infectious disease. Many of the associations reported have not been confirmed in multiple studies, but consistent patterns of susceptibility or resistance conferred by certain HLA class I alleles or genotypes have emerged. In addition, an effective acquired immune response to infectious agents mediated by HLA restricted T cell recognition can target different stages of disease pathogenesis. We have recently submitted a manuscript showing that three distinct HLA alleles: B*27, B*57 and B*35Px, that are known to alter the overall rate of AIDS progression act during distinct intervals following HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. A few studies have examined the relationship between HLA on risk of HIV-1 infection, primarily involving individuals from Africa. Effects of HLA on highly active anti-retroviral therapy (HAART) are only just being considered and nearly all studies of HLA on progression to AIDS have been performed in men. To address these deficiencies in our understanding of HIV-1 pathogenesis, we have established a collaboration with Dr. Howard Strickler and the Women's Interagency Health Study (WIHS) to investigate effects of immune response genes on three disease outcomes to HIV-1 exposure: 1) risk of becoming infected in groups of HIV+ and HIV- individuals matched for site of enrollment and risk factors, 2) progression to AIDS from specific ranges of baseline CD4 counts and viral loads, and 3) response to HAART. The WIHS cohort is the largest multicenter prospective cohort study of HIV and its complications in women, involving individuals with high rates of hepatitis C virus (HCV) and human papilloma virus (HPV) infection (see below). The cohort has enrolled about 4,000 women of varied ethnic backgrounds in the U.S. and detailed clinical data is collected on the participants every six months. Patients participating in the WIHS will be typed for HLA class I, class II, and killer immunoglobulin-like receptors (KIR). Genotyping of the MIC genes is also being considered for future studies. Thus far we have received approximately 1200 samples. HLA class I and class II genotyping have been completed on these samples. Preliminary analysis of the data suggests there are a number of significant associations between particular HLA alleles and prevalent HPV infection as well as squamous intraepithelial lesions. HLA class I molecules have also been shown to participate in innate immune responses as ligands for KIR molecules expressed on natural killer (NK) cells and a subset of CD8+ cells. NK cells defend against viral infections by producing cytokines and killing virally infected cells, functions that are regulated by activating and inhibitory KIR molecules through recognition of specific class I allotypes on target cells. We have previously shown that genes encoding the inhibitory NK cell receptor KIR2DL3 and its HLA-C1 ligand, which transmit relatively weak inhibitory signals, enhance resolution of HCV infection.