HIV-1 Cellular Immunity in Exposed Seronegatives

描述(由申请人提供)：我们希望通过研究高危、多次暴露、血清阴性(ES)个体中HIV-1耐药的潜在机制，深入了解HIV保护的免疫相关性。采用标准化分析和纳入相关对照组进行比较分析，我们发现西雅图ES队列中的大多数人缺乏HIV-1特异性干扰素-伽马分泌T细胞反应。此外，他们对R5或X4依赖病毒的CD4+T细胞传染性水平与低风险控制人群中的水平相似。然而，存在明显的个别例外，随着时间的推移，一些ES的命运变得相当耐人寻味。一些人的血清转换后感染了与他们已知的长期感染的性伴侣不同的病毒。其他人的血清仍然是阴性的，但经过仔细的检查，HIV-1DNA的拷贝数极低。这些结果表明，这个队列中的少数成员可能具有不寻常的能力来控制HIV-1感染，这与CCR5辅助受体损伤不同。 我们提出了3个具体目标来检验总体假设，即一些长期、多次暴露于血清阴性的人对艾滋病毒感染具有相对抵抗力，这是由他们的免疫反应维持的。在目标1中，我们将确定和比较不同性暴露风险人群中ES中HIV-1特异性IL-2和干扰素-γ分泌T细胞反应的频率和重复性。在目标2中，我们将使用多参数流式细胞术和阵列技术评估ES中抗病毒细胞反应的完整谱系。在目标3中，我们将确定对HIV-1感染有异常控制的ES中HIV-1特异性T细胞反应的贡献，无论是在HIV-1水平非常低的情况下保持血清阴性，还是在后期血清转换之后。 我们将对不同地域的血清阴性人群进行调查，这些人群的病毒亚型和接触途径不同：1)来自西雅图ES队列的MSM，暴露于B亚型HIV-1；2)西雅图和秘鲁HPTN议定书039的高危MSM参与者，暴露于B HIV-1；以及3)来自南非共和国c德班三个队列研究的高危异性恋男女，暴露于C亚型HIV-1。这些结果将为我们决定在疫苗试验中使用的具体分析提供依据，指导对艾滋病毒流行地区高危活动的试验参与者的反应的解释，并有可能为疫苗设计和保护相关因素带来新的概念。

DESCRIPTION (provided by applicant): We wish to gain insight into the immune correlates of HIV protection by investigating potential mechanisms of HIV-1 resistance among high-risk, multiply exposed, seronegative (ES) individuals. Employing standardized assays and incorporating relevant control groups for comparative analyses, we found that most persons in the Seattle ES cohort lack HIV-1-specific IFN-gamma-secreting T cell responses. Moreover, their levels of CD4+ T cell infectivity with either R5- or X4-dependent viruses are similar to those in the lower risk control population. However, clear individual exceptions exist, and the fate of some ES over time has become quite intriguing. Some have seroconverted with viruses distinct from their known long-term infected sexual partners. Others remain seronegative but upon careful examination bear extremely low copy numbers of HIV-1 DNA. These results suggest that rare members within this cohort may have an unusual capacity to control HIV-1 infection that is distinct from CCR5 coreceptor impairment. We propose 3 specific aims to test the overall hypothesis that some long-term, multiply exposed seronegative persons have relative resistance to HIV infection that is maintained by their immune response. In Aim 1, we will ascertain and compare the frequency and reproducibility of HIV-1-specific IL-2- and IFN-gamma-secreting T cell responses in ES among different sexually-exposed risk groups. In Aim 2, we will assess the complete repertoire of anti-viral cellular responses in ES using multiparameter flow cytometry and array technology. In Aim 3, we will determine the contribution of HIV-1-specific T cell responses in ES who have unusual control of HIV-1 infection, either maintaining seronegativity with very low HIV-1 levels or following late seroconversion. We will conduct investigations in geographically diverse seronegative populations whose viral subtype and route of exposure differ: 1) MSM from the Seattle ES cohort, exposed to subtype B HIV-1; 2) high HIV risk MSM participants of HPTN Protocol 039 in Seattle and Peru, exposed to subtype B HIV-1, and 3) high risk heterosexual women and men from three cohort studies in cDurban, Republic of South Africa, exposed to subtype C HIV-1. The results will inform our decisions of the specific assays to employ in vaccine trials, guide interpretation of responses in trial participants with high-risk activities in HIV endemic areas, and potentially invoke new concepts for vaccine design and correlates of protection.