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率的因素尚未明确，但对于开发疫苗和治疗策略至关重要。在HAART之前，美国发展为艾滋病的平均速度是10年。然而，少数个体，尽管未经治疗，保持CD4+ t细胞的正常数量，低到无法检测到的病毒RNA拷贝，并没有出现疾病的临床表现10年，甚至20年。对于这些长期非进展者（LTNP）在控制病毒复制和减缓疾病进展方面的独特能力，人们知之甚少。我们和其他人发现，HLA-B*57+个体在LTNP中比例过高。在一些研究中，85%的LTNP是HLA-B*57+，表明它们表达了一些独特的遗传特征，有助于减缓疾病进展。由于HLA I类抗原向CTL呈现表位，我们假设HLA- b *57通过影响CTL对HIV的反应来减缓疾病进展。事实上，我们和其他人已经发现HLA-B*57+ LTNP装载CTL对3个或更多保守的病毒表位产生反应，这将降低病毒从表位特异性CTL突变的能力。然而，HLA-B*57的表达并不足以确定LTNP状态，因为许多HLA-B*57阳性的患者如果不及时治疗，会在10年内发展为艾滋病（进展者）。这些进展蛋白也会对这些保守的表位产生CTL反应，这表明靶向这些表位不足以减缓疾病进展。然而，对这些数据的一个主要警告是，这些研究都是在确定HIV感染数年后进行的，并且无法得出关于早期免疫事件的确切结论。有必要对HIV感染后不久的HLA-B*57+个体进行调查研究。我们假设LTNP在HIV感染中比进展者更早地对更保守的表位产生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HLA-B*57男性在LTNP队列中过度代表，因为在感染之前，这些个体遇到抗原，无论是HIV还是其他病原体，这些原代t细胞能够快速响应HIV，并且具有比原代免疫应答更高的亲和力t细胞。结合靶向保守表位的能力，这种更快的反应使宿主获得免疫控制。我们有独特的HLA-B*57+个体在感染艾滋病毒之前和之后早期采集的标本，我们将用这些标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.