Prior Antigenic Exposure and HIV Disease Progression

描述(由申请人提供)：决定艾滋病毒疾病进展速度的因素定义不清，但为了开发疫苗和治疗策略，必须了解这些因素。在HAART之前，美国艾滋病的平均进展率为10年。然而，少数人尽管仍未接受治疗，但仍保持着正常数量的CD4+T细胞，病毒RNA的拷贝很少，甚至无法检测到，并且在10年甚至20年内没有疾病的临床表现。人们对这些长期无进展因子(LTNP)在控制病毒复制和减缓疾病进展方面的独特能力知之甚少。我们和其他人发现，在LTNP中，HLA-B*57+个体的比例过高。在一些研究中，85%的LTNP是HLA-B*57+，这表明它们表达了一些独特的遗传特征，有助于减缓疾病的进展。因为人类白细胞抗原I类抗原是CTL的抗原表位，所以我们推测，人类白细胞抗原B*57通过影响对HIV的CTL反应来减缓疾病的进展。事实上，我们和其他人已经发现，人类白细胞抗原B*57+LTNP对3个或更多保守的病毒表位产生CTL反应，这将削弱病毒从表位特异性CTL突变的能力。然而，人类白细胞抗原-B*57的表达不足以授予LTNP状态，因为许多人类白细胞抗原-B*57+的人如果不治疗(进展者)，在10年内进展为艾滋病。这些进展者还对这些保守的表位进行CTL反应，这表明以这些表位为靶点不足以减缓疾病的进展。然而，对这一数据的一个主要警告是，这些研究都是在艾滋病毒感染确定数年后进行的，无法对早期免疫学事件做出确切的结论。有必要对HIV感染后不久的人类白细胞抗原-B*57+个体进行研究。我们假设，在HIV感染中，LTNP比进展者更早地启动对更保守表位的CTL反应。然而，由于疾病进展的速度可能是多因素的，我们进一步假设，在LTNP队列中，HLA-B*57男性的比例过高，因为在感染之前，这些人会遇到抗原，要么是HIV，要么是其他病原体，这些抗原启动了T细胞，能够快速地对HIV做出反应，并具有比在初级免疫反应中发现的更高亲和力的T细胞。再加上针对保守表位的能力，这种更快的反应允许宿主获得免疫控制。我们有人类白细胞抗原-B*57+个体在感染HIV之前和感染后早期的独特样本，我们将使用这些样本来检验我们的假设。

DESCRIPTION (provided by applicant): The factors that determine the rate of HIV disease progression are ill defined, yet essential to understand in order to develop vaccine and therapeutic strategies. Prior to HAART, the average rate of progression to AIDS in the United States was ten years. However, a minority of individuals, despite remaining untreated, maintain normal numbers of CD4+ T-cells, low to undetectable copies of viral RNA and do not present with clinical manifestations of disease for ten, or even twenty years. Little is known about what makes these long-term nonprogressors (LTNP) unique in their ability to control viral replication and slow disease progression. We, and others, have found that HLA-B*57+ individuals are over-represented in LTNP. In some studies 85% of LTNP are HLA-B*57+ suggesting they express some unique genetic feature that contributes to slower disease progression. Because HLA class I antigens present epitopes to CTL, we hypothesize that HLA-B*57 contributes to slower disease progression by influencing the CTL response to HIV. Indeed, we, and other, have found that HLA-B*57+ LTNP mount CTL responses to 3 or more conserved viral epitopes, which would diminish the ability of the virus to mutate away from epitope-specific CTL. However, expression of HLA-B*57 is not sufficient to confer LTNP status as many HLA-B*57+ people progress to AIDS within 10 years if left untreated (Progressors). These Progressors also mount CTL responses to these conserved epitopes, suggesting that targeting of these epitopes is not sufficient to slow disease progression. However, a major caveat to this data is that these studies have been all performed years after the establishment of HIV infection, and firm conclusions regarding early immunological events cannot be made. There is a need for studies to investigate HLA-B*57+ individuals soon after HIV infection. We hypothesize that LTNP mount CTL responses to more conserved epitopes earlier in HIV infection than Progressors. However, as the rate of disease progression is likely to be multifactorial, we further hypothesize that HLA-B*57 men are over-represented in cohorts of LTNP because, prior to infection, these individuals encounter antigen, either HIV or other pathogens, that prime T-cells capable of responding to HIV quickly and with higher affinity T-cells than found in a primary immune response. Together with the ability to target conserved epitopes, this faster response allows the host to gain immunological control. We have unique specimens from HLA-B*57+ individuals taken both prior to, and early after, HIV infection to that we will use to test our hypothesis.