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耐药性的潜在机制，深入了解HIV保护的免疫相关性。 采用标准化检测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IFN-γ分泌T细胞应答。 此外，他们的CD 4 + T细胞对R5或X4依赖性病毒的感染性水平与较低风险对照人群相似。然而，存在明显的个别例外，随着时间的推移，一些ES的命运变得非常有趣。有些人的血清转化病毒与他们已知的长期感染的性伴侣不同。其他人保持血清阴性，但仔细检查后，携带极低的HIV-1 DNA拷贝数。这些结果表明，该队列中的罕见成员可能具有与CCR 5辅助受体损伤不同的控制HIV-1感染的不寻常能力。 我们提出了3个具体的目标，以测试的总体假设，一些长期，多次暴露的血清阴性的人有相对抵抗艾滋病毒感染，是由他们的免疫反应。 在目标1中，我们将确定和比较的频率和重复性的HIV-1特异性IL-2和IFN-γ分泌T细胞反应在ES之间的不同性暴露的风险群体。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中抗病毒细胞应答的完整库。在目标3中，我们将确定HIV-1特异性T细胞应答在ES中的作用，这些ES具有不寻常的HIV-1感染控制，或者在非常低的HIV-1水平下保持血清阴性，或者在后期血清转换后。 我们将在不同地理位置的血清阴性人群中进行调查，这些人群的病毒亚型和暴露途径不同：1）来自西雅图ES队列的MSM，暴露于B亚型HIV-1; 2）西雅图和秘鲁的HPTN方案039的高HIV风险MSM参与者，暴露于亚型B HIV-1，和3）来自南非共和国德班的三个队列研究的高风险异性恋女性和男性，感染了C亚型HIV-1这些结果将为我们决定在疫苗试验中采用的具体检测方法提供信息，指导对在艾滋病毒流行地区进行高风险活动的试验参与者的反应进行解释，并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.