HIV-1 Cellular Immunity in Exposed Seronegatives

描述（由申请人提供）：我们希望通过研究高风险、多重暴露、血清阴性（ES）个体中HIV-1耐药性的潜在机制，深入了解HIV保护的免疫相关因素。采用标准化分析并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细胞反应。此外，他们的CD4+ T细胞感染R5或x4依赖性病毒的水平与低风险控制人群相似。然而，存在明显的个别例外，并且随着时间的推移，一些ES的命运变得相当有趣。有些人血清转化的病毒不同于他们已知的长期感染的性伴侣。其他人仍然是血清阴性，但经过仔细检查，HIV-1 DNA拷贝数极低。这些结果表明，该队列中的罕见成员可能具有不同于CCR5共受体损伤的控制HIV-1感染的不寻常能力。

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.