HIV Vaccines on Latent Reservoirs in Young Adults on HAART

描述(申请人提供)：全世界有4000多万人感染了人类免疫缺陷病毒1型(HIV-1)。高效抗逆转录病毒疗法(HAART)可提高存活率，但由于HIV-1在病毒库(静止的CD4+T细胞)和血浆(病毒血症)中持续存在，因此复杂的方案必须是终生的。美国国立卫生研究院的疫苗研究中心(VRC)和儿科艾滋病临床试验小组(PACTG)将很快开始多中心临床试验，测试一种治疗性疫苗方法作为HAART的辅助手段，以增强HIV-1特异性免疫，可能最终停止治疗或简化治疗。然而，疫苗对病毒库和病毒血症的影响尚不清楚。我们建议测试这样一种假设，即作为HAART的辅助手段的治疗性疫苗方法将促进由于增强的HIV-1特异性免疫反应而导致的病毒库的腐烂和病毒血症。使用HIV-1疫苗策略的两个临床试验的样本作为有效的HAART在年轻人中的辅助，我们建议随着时间的推移测量和跟踪疫苗对1)潜伏感染的CD4+T细胞储存库的范围；2)病毒血症的水平；以及3)病毒储存库和病毒血症的基因组成的影响。我们开发的增强型病毒培养方法将用于评估静止的CD4+T细胞中具有复制能力的HIV-1的衰变。检测50拷贝/毫升以下血浆病毒的灵敏分子方法将用于测量低水平病毒血症的变化。我们将使用我们以前用来将病毒携带者和病毒血症联系起来的系统发育方法来分析CD4+T细胞储存库和病毒血症遗传成分的变化。来自VRC和PACTG的临床标本和分析资源为研究HIV-1感染者的病毒库的发病机制提供了一个独特的机会。

DESCRIPTION (provided by applicant): More than forty million individuals worldwide are infected with human immunodeficiency virus type 1 (HIV-1). Highly active antiretroviral therapy (HAART) improves survival, but the complex regimen must be lifelong due to persistence of HIV-1 in viral reservoirs (resting CD4+ T cells) and in plasma (viremia). The Vaccine Research Center (VRC) at the NIH and the Pediatric AIDS Clinical Trials Group (PACTG) will soon begin multi-center clinical trials testing a therapeutic vaccine approach as an adjunct to HAART to enhance HIV-1 specific immunity, perhaps allowing eventual treatment discontinuation or simplification. However, vaccines' impact on viral reservoirs and viremia is unknown. We propose to test the hypothesis that a therapeutic vaccine approach, given as an adjunct to HAART, will facilitate decay of viral reservoirs and viremia due to enhanced HIV-1 specific immune responses. Using samples from two clinical trials of HIV-1 vaccine strategies as an adjunct to effective HAART in young adults, we propose measuring and tracking over time the vaccines' effect on 1) the extent of the latently infected CD4+ T cell reservoir; 2) the level of viremia; and 3) the genetic composition of the viral reservoir and viremia. Enhanced virus culture methods we developed will be used to assess decay of replication-competent HIV-1 in resting CD4+ T cells. Sensitive molecular methods for detecting plasma virus below 50 copies/ml will be used to measure changes in low-level viremia. Shifts in the genetic composition of the CD4+ T cell reservoir and viremia will be analyzed using phylogenetic methods we previously used to link reservoir and viremia HIV-1 variants. Clinical specimens and analytic resources from VRC and PACTG provide a unique opportunity to study pathogenesis of viral reservoirs in HIV-1 infected individuals.