Immunoglobulin Allotypes in Hepatitis C Virus Infection

描述（由申请人提供）：丙型肝炎病毒（HCV）是一种主要的健康问题，影响全球超过1.7亿人。在急性感染HCV的人中，约15%的人自发清除病毒。由于实验模型的局限性和对自然急性感染的认识不多，对病毒清除的机制知之甚少。有临床和流行病学线索表明宿主因素至关重要。在影响HCV感染结局的因素中，宿主遗传因素被认为起着主导作用。免疫球蛋白（IG）GM和KM同种异型-IgG重链和K-型轻链的遗传抗原决定簇，分别与病毒的免疫特性，因此是理想的候选遗传系统的调查，以确定在HCV发病的危险因素。我们假设GM和KM同种异型可能通过其对同种异型限制性抗体对病毒抗原的反应的可能影响而导致HCV感染的结果。此外，它们可以通过与Fc γ受体（Fc γ R）的差异相互作用来影响抗体依赖性T细胞对HCV的细胞毒性。GM和KM同种异型也可以调节该病毒逃避宿主免疫监视的策略-Ig分子模拟和Fc γ R样活性。为了验证我们的假设，我们设计了一项病例对照研究，其具体目的是：（1）进一步确定非裔美国人中HCV感染的结果与IG GM和KM同种异型之间的关联程度;（2）确定GM和KM同种异型是否与白人中HCV感染的结果相关;（3）检测抗HCV抗原的体液免疫反应的特异性和滴度（核心，E1，E2，NS 3，NS 4，NS 5），并确定这些抗体的产生是否受GM和KM同种异型的影响;（4）确定HCV编码的Fc γ R是否与携带不同GM同种异型的IgG分子差异结合。将通过血凝抑制、直接DNA测序和PCR-RFLP方法进行GM和KM同种异型分型。将通过ELISA测量HCV抗原的IgG抗体。将通过表面等离子体共振检测监测不同GM同种异型的IgG分子与HCV-Fc γ R的结合和比较亲和力。这项研究的结果将促进我们对宿主遗传因素在丙型肝炎病毒感染的清除和持续中的作用的理解。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major health problem, affecting over 170 million people worldwide. Of persons acutely infected with HCV, about 15% spontaneously clear the virus. Because of limitations in experimental models and the infrequent recognition of natural acute infection, the mechanisms of viral clearance are poorly understood. There are clinical and epidemiologic clues that suggest host factors are critical. Among the factors influencing the outcome of HCV infection, the host genetic factors are thought to play a predominant role. Immunoglobulin (Ig) GM and KM allotypes-hereditary antigenic determinants of IgG heavy chains and k-type light chains, respectively-are associated with viral immunological properties, and thus are ideal candidate genetic systems for investigations to identify risk-conferring factors in HCV pathogenesis. We hypothesized that GM and KM allotypes may contribute to the outcome of HCV infection through their possible influence on allotype-restricted antibody responses to the viral antigens. Additionally, they may influence antibody dependent T cell cytotoxicity to HCV by their differential interaction with Fcgamma receptors (FcgammaR). GM and KM allotypes could also modulate the strategies-Ig molecular mimicry and FcgammaR-like activity-employed by this virus to evade host immune surveillance. To test our hypothesis, a case control study has been designed with the following specific aims: (1) to further establish the magnitude of association between the outcome of HCV infection and Ig GM and KM allotypes in African Americans; (2) to determine if GM and KM allotypes are associated with the outcome of HCV infection in Caucasians; (3) to measure the specificity and titer of the humoral immune responses to HCV antigens (core, E1,E2,NS3,NS4,NS5) and determine if the production of these antibodies is influenced by GM and KM allotypes; (4) to determine if HCV-encoded FcgammaR binds differentially with IgG molecules carrying different GM allotypes. GM and KM allotyping will be done by hemagglutination-inhibition, direct DNA sequencing, and PCR-RFLP methods. IgG antibodies to HCV antigens will be measured by an ELISA. Binding and comparative affinities of IgG molecules of different GM allotypes to HCV-FcgammaR will be monitored by surface plasmon resonance detection. Results of this investigation will advance our understanding of the role of host genetic factors in clearance and persistence of hepatitis C virus infection.