HIV-1 Cellular Immunity in Exposed Seronegatives

暴露的血清阴性者中的 HIV-1 细胞免疫

基本信息

批准号：
7599701
负责人：
Margaret Juliana McElrath
金额：
$ 42.37万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7599701
关键词：
Abbreviations Anti-Retroviral Agents Antigen-Presenting Cells Area Biological Assay CCR5 gene CD4 Positive T Lymphocytes Cells Cellular Immunity Cohort Studies Control Groups DNA Dendritic Cells Enrollment Epidemic Female Flow Cytometry Frequencies Future Genomics HIV HIV Infections HIV Vaccine Trials Network HIV prevention trials network HIV-1 Heterosexuals Immune Immune response Immunity Impairment In Vitro Individual Infection Interferon Type II Interleukin-2 Investigation Microarray Analysis Participant Persons Peru Play Population Population Control Predisposition Proteomics Protocols documentation Relative (related person)Reproducibility Resistance Resistance to infection Risk Role Route Sexual Partners Sexually Transmitted Diseases South Africa Spottings Staining method Stains T-Lymphocyte Target Populations Technology Testing Time Ursidae Family Vaccine Design Vaccines Viral Viral Markers Viral Physiology Virus Woman cohort comparative cytokine efficacy trial high risk high risk men insight member men men who have sex with men response sex vaccine efficacy

项目摘要

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.

描述（由申请人提供）：我们希望通过研究高风险，多重暴露的，血清染色（ES）个体的HIV-1耐药性的潜在机制来深入了解HIV保护的免疫相关性。采用标准化测定并纳入了相关的对照组进行比较分析，我们发现西雅图ES队列中的大多数人都缺乏HIV-1特异性IFN-gamma分泌T细胞反应。此外，它们具有R5-或X4依赖性病毒的CD4+ T细胞感染水平与较低风险控制人群中的病毒相似。但是，存在明显的个人例外，并且随着时间的流逝，某些ES的命运变得非常有趣。有些人患有与已知的长期感染性伴侣不同的病毒。其他人则保持血清质，但经过仔细检查，HIV-1 DNA的拷贝数极低。这些结果表明，该队列中的罕见成员可能具有控制与CCR5共感染者损害不同的HIV-1感染的异常能力。我们提出了3个特定旨在检验总体假设，即某些长期，多重暴露的血清神经症患者具有对HIV感染的相对抗药性，而HIV感染的免疫反应维持。在AIM 1中，我们将确定和比较不同性暴露的风险组中ES中ES中HIV-1特异性IL-2-和IFN-GAMMA分泌T细胞反应的频率和可重复性。在AIM 2中，我们将使用多参数流式细胞仪和阵列技术评估ES中抗病毒细胞反应的完整曲目。在AIM 3中，我们将确定HIV-1特异性T细胞反应在具有异常控制HIV-1感染的ES中的贡献，要么保持非常较低的HIV-1水平或血清转化后期的血清神经性。我们将对其病毒亚型和暴露途径的地理多样性种群进行调查：1）MSM与西雅图ES同类群体，暴露于Subtype B HIV-1； 2）HPTN方案039的高艾滋病毒风险MSM参与者在西雅图和秘鲁，暴露于B HIV-1亚型，3）来自南非共和国Cdurban的三项队列研究的高风险异性恋男性和男性暴露于Subtype C HIV-1。结果将为我们的决定提供有关疫苗试验中采用的具体测定的决定，指导在艾滋病毒流行地区具有高风险活动的试验参与者中的反应解释，并可能引起疫苗设计和保护的新概念。