Minimal Levels of HIV-1 in Vaccinated & Exposed Persons

接种疫苗后的 HIV-1 水平极低

• 批准号: 6656051
• 负责人: TUOFU ZHU
• 金额: $ 19.5万
• 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/6656051
• 关键词: AIDS /HIV diagnosis; AIDS vaccines; HIV infections; T lymphocyte; clinical research; diagnosis design /evaluation; drug screening /evaluation; genetic strain; genetic techniques; human immunodeficiency virus 1; human subject; macrophage; monocyte; patient oriented research; virus load; virus replication

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年底，我们启动了一项研究，以确定血清阴性者中HIV-1感染的最低水平，这些人报告反复与HIV-1感染的伴侣发生高风险的性接触，称为暴露血清阴性（ES）。在10个具有可检测到HIV-1特异性细胞毒性t淋巴细胞（CTL）反应的明确定义的ES个体中，我们证明了HIV-1感染在两个ES（附录A）中的存在，其水平非常低（范围：0.1 - 0.01拷贝/百万细胞），远低于常规检测的检测极限。使用相同的方法，我们确定了在短暂病毒血症或受常规检测的疫苗保护的猕猴中低水平SIV感染的平行证据。最近，我们在三个接种疫苗的人中发现了持续低水平的HIV-1感染，他们通过常规检测是短暂的病毒血症。这些发现表明，只有通过对大量细胞进行数百或数千次PCR扩增和序列分析的改进技术，才能在ES和接种疫苗的人中证明最低水平的HIV-1感染（MLHI）。在这里，我们建议扩展我们的初步结果，以使过程机械化，并在我们的ES队列和来自nih资助的疫苗试验（主要是HIV疫苗试验网络（HVTN））的疫苗接受者中更严格地评估MLHI。我们还将利用从我们的检测中分离的病毒或序列的可用性来表征突破性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，以确定疫苗试验参与者和ES个体中短暂或持续最低水平的HIV-1感染。我们将通过常规病毒学、血清学或T细胞介导的免疫检测来确定HIV-1在短暂感染人群中的频率和复制状态。2. 表征MLHI患者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暴露于HIV-1是否会影响HIV-1感染的最低减毒水平。这些研究应有助于确定减少和/或基本上控制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。