TCR Genes and HIV-Specific Cytotoxic T-lymphocytes

描述：（由申请人提供）HIV- 1特异性CTL应答早期出现 在感染过程中，并持续高频率，但不， 一般来说，控制艾滋病毒血症。尽管人们对CTL的大小了解很多， 对HIV表位的反应相对而言， TCR对免疫显性表位的所有组成部分以及TCR的宽度和亲合力如何影响免疫显性表位的表达， 影响随后的病毒血症。在此前的融资 在此期间，我们已经确定了免疫显性CTL反应限制 几个HLA等位基因，并已证明，个别克隆CTL， 反应能够在宿主中持续很长时间。我们有更多 最近将我们在TCR基因测序方面的专业知识与 分选活的抗原特异性CTL群体以评估TCR的宽度 病毒表位的所有组成部分。我们建议确定是否提示 产生具有针对优势表位的不同TCR库的CTL， 在没有HAART的情况下与随后的病毒血症控制相关。一 不同的CTL库要么更可能与潜在的HIV交叉反应， 1变体，或者更可能含有能够表达高亲和力CTL克隆， 为了有效地抑制病毒复制，在每种情况下都限制了 HIV-1逃避免疫识别。这些研究将使我们能够确定 TCR库的进化与免疫控制之间的关系 病毒血症具体而言，我们建议：1）确定TCR是否 在长期非进展者中，免疫显性CTL应答的谱系是 由于长期选择优势克隆种群，或 它们是否广泛，从而限制了HIV-1逃逸的可能性 变体。2)确定初始生成和维护的 在早期治疗的受试者中，不同的TCR库与病毒血症的控制相关 在出现急性逆转录病毒综合症后3)确定是否 不同TCR库的产生含有交叉反应性CTL， 识别潜在的HIV-1逃逸变体。4)确定是否生成 一个多样化的TCR库中含有高亲和力的CTL群体， 在慢性感染期间控制CTL群体并介导控制 HIV- 1的复制。

DESCRIPTION: (provided by applicant) HIV- 1 -specific CTL responses arise early during the course of infection, and persist at high frequencies, yet do not, in general, control HIV viremia. Although much is known about the magnitude of CTL responses to HIV epitopes comparatively little is known about the diversity of the TCR repertoire to immunodominant epitopes and how the breadth and avidity of this repertoire influences subsequent viremia. Over the previous funding period of this grant we have identified immunodominant CTL responses restricted by several HLA alleles, and have demonstrated that individual clonal CTL responses are able to persist in the host for prolonged periods. We have more recently combined our expertise in sequencing TCR genes with the ability to sort live, antigen-specific populations of CTL to assess the breadth of TCR repertoires to viral epitopes. We propose to determine whether the prompt generation of CTL with diverse TCR repertoires to dominant epitopes is associated with subsequent control of viremia in the absence of HAART. A diverse CTL repertoire is either more likely to cross-react with potential HIV- 1 variants, or is more likely to contain high-avidity CTL clones that are able to effectively suppress viral replication, in each case limiting the ability of HIV-1 to escape immune recognition. These studies will allow us to determine the relationship between the evolution of the TCR repertoire and immune control of viremia. Specifically we propose to: 1) Determine whether the TCR repertoires of immunodominant CTL responses in long-term nonprogressors are narrow due to the long-term selection of dominant clonal populations, or whether they are broad, thus limiting the potential generation of HIV-1 escape variants. 2) Determine whether the initial generation and maintenance of a diverse TCR repertoire is associated with control of viremia in subjects treated early after presentation with an acute retroviral syndrome. 3) Determine whether the generation of a diverse TCR repertoire contains cross-reactive CTL able to recognize potential HIV-1 escape variants. 4) Determine whether the generation of a diverse TCR repertoire contains populations of high-avidity CTL that come to dominate the population of CTL during chronic infection and mediate control of HIV- 1 replication.