Minimal Levels of HIV-1 in Vaccinated & Exposed Persons

接种疫苗后的 HIV-1 水平极低

• 批准号: 6757272
• 负责人: TUOFU ZHU
• 金额: $ 36.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757272
• 关键词: Minimal; Levels; HIV; Vaccinated; Exposed

DESCRIPTION (provided by applicant): In late 1997, we initiated a study to identify minimal levels of HIV-1 infection in seronegative persons who reported repeated high-risk sexual exposures to HIV-1-infected partners, termed as exposed seronegative (ES). Among ten well-defined ES individuals with detectable HIV-1-specific cytotoxic T-lymphocytes (CTL) responses, we demonstrated presence of HIV-1 infection in two ES (Appendix A) at extraordinarily low levels (range: 0.1 - 0.01 copies per million cells) that are well below the detection limit of conventional assays. Using same methodologies, we identified parallel evidence for low levels of SIV infection in macaques that were transiently viremic or vaccine-protected by conventional testing. Most recently, we have found persistent low levels of HIV-1 infection in three vaccinated persons who were transiently viremic by conventional assays. These findings indicate that minimal levels of HIV-1 infection (MLHI) can be demonstrated in ES and vaccinated persons, only by improved technologies with hundreds or thousands of PCR amplifications and sequence analyses on large amounts of cells. Here, we propose to extend our preliminary results to mechanize the processes and to assess for MLHI more rigorously among our cohort of ES and vaccine recipients from NIH-funded vaccine trials, mainly the HIV Vaccine Trails Network (HVTN). We will also take advantage of the availability of virus or sequences isolated from our assays to characterize the genotype of virus in breakthrough MLHI infection and compare these characteristics with vaccine strains. The Specific Aims are: 1. To improve methodologies to identify transient or persistent minimal levels of HIV-1 infection in vaccine trial participants and ES individuals. We will ascertain the frequency and replication state of HIV-1 in persons who may have transient infection as indicated by conventional virologic, or serologic, or T cell-mediated immunologic assays. 2. To characterize the genotype of HIV-1 strains present in peripheral blood and tissues in MLHI persons and to determine if there is impact of vaccination or repeated exposures to HIV-1 on the attenuated minimal levels of HIV-1 infection. These studies should assist definition of virologic and immunologic characteristics required to attenuate and/or substantially control HIV-1 infection, a critical goal of AIDS vaccine development.

描述（由申请人提供）：1997 年末，我们发起了一项研究，以确定血清反应阴性者的 HIV-1 感染最低水平，这些人报告与 HIV-1 感染性伴侣反复发生高风险性接触，称为暴露血清反应阴性 (ES)。 在 10 名具有可检测到的 HIV-1 特异性细胞毒性 T 淋巴细胞 (CTL) 反应的明确 ES 个体中，我们证明了两名 ES 中存在 HIV-1 感染（附录 A），其水平极低（范围：每百万细胞 0.1 - 0.01 拷贝），远低于常规检测的检测限。 使用相同的方法，我们发现了猕猴中 SIV 感染水平较低的平行证据，这些猕猴通过常规检测出现暂时性病毒血症或疫苗保护。 最近，我们发现三名接种疫苗的人的 HIV-1 感染水平持续较低，通过常规检测，这些人出现短暂的病毒血症。 这些发现表明，只有通过改进技术，对大量细胞进行数百或数千次 PCR 扩增和序列分析，才能在 ES 和疫苗接种者中证明最低水平的 HIV-1 感染 (MLHI)。 在此，我们建议扩展我们的初步结果，以实现流程机械化，并在 NIH 资助的疫苗试验（主要是 HIV 疫苗试验网络 (HVTN)）的 ES 和疫苗接受者群体中更严格地评估 MLHI。 我们还将利用从我们的检测中分离出的病毒或序列来表征突破性 MLHI 感染中病毒的基因型，并将这些特征与疫苗株进行比较。 具体目标是： 1. 改进方法来识别疫苗试验参与者和 ES 个体中短暂或持续的最低 HIV-1 感染水平。 我们将根据常规病毒学、血清学或 T 细胞介导的免疫学检测确定可能短暂感染的人群中 HIV-1 的频率和复制状态。 2. 表征 MLHI 人群外周血和组织中存在的 HIV-1 毒株的基因型，并确定疫苗接种或反复接触 HIV-1 是否对 HIV-1 感染的最低减毒水平有影响。 这些研究应有助于确定减弱和/或实质性控制 HIV-1 感染所需的病毒学和免疫学特征，这是艾滋病疫苗开发的一个关键目标。