CTL AND HIV POLYMORPHISMS IN HETEROSEXUAL TRANSMISSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：对HIV对人类白细胞抗原I类限制性免疫应答的适应性进行横断面分析；确定150对传递对中的CTL表位逃逸/逆转的动力学；确定长期非传播者是否在逃避特征上表现出偏见，从而导致缺乏传播。 在南非/赞比亚的两个HIV C分支感染人群中，我们试图阐明人类白细胞抗原-B*5703在HIV疾病结局中的作用。人类白细胞抗原B*5703限制性CTL反应以可预测的顺序选择三个Gag p24表位的逃逸突变。我们发现，在体外，这些突变的积累会依次降低病毒的复制能力。尽管如此，体内数据表明，最终病毒载量的增加伴随着逃避所有三种HLA-B*5703限制性CTL反应。这些数据表明，尽管以高昂的代价逃避CTL反应可以逐渐减弱病毒，但在缺乏足够的、持续的CTL反应的情况下，会产生高病毒载量。 在HIV-1中，至少有一些交替的阅读框有可能编码未知功能的蛋白质，其抗原性可以被认为是隐蔽表位(CES)。我们分析了一大批南非慢性感染者的HIV-1gag、pol1和nef基因中与人类白细胞抗原I类相关的多态。总共预测了391个CES和168个常规表位，其中大部分来自反义转录本。正义和反义编码的CES在感染的两个阶段都是免疫原性的。此外，CES经常在感染的第一年发生突变，这与逃逸变异体的免疫选择一致。这些发现表明，HIV-1基因组可能编码和部署大量潜在的非传统表位，以增强疫苗诱导的抗病毒免疫。 最后，来自9个队列的研究结果显示，某些表位变异的频率与限制人类白细胞抗原等位基因的丰度高度相关，这表明病毒在人群中适应了人类白细胞抗原的压力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objectives: Perform cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses; determine kinetics of CTL epitope escape/reversion in 150 transmission pairs as virus adapts in moving from one immunogenetic environment to another; determine if long-term non-transmitting partners display bias in escape signatures that contribute to lack of transmission. In two HIV C clade-infected populations in South Africa/Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in predictable order. We show accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in-vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in absence of adequate, continued CTL responses. At least some alternate reading frames in HIV-1 have potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). We analyzed HLA class I-associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with majority derived from antisense transcripts. Both sense- and antisense-encoded CEs were immunogenic at both stages of infection. In addition, CEs often mutated during first year of infection, which was consistent with immune selection for escape variants. These findings indicate that HIV-1 genome might encode and deploy a large potential repertoire of unconventional epitopes to enhance vaccine-induced antiviral immunity. Finally, results from a 9-cohort study showed the frequency of certain epitope variants was highly correlated with the abundance of the restricting HLA allele, suggesting viral adaptation to HLA pressure within the population.