CD4 RESPONSES TO ANTIRETROVIRAL THERAPY (ART) ALONE OR ART WITH VACCINATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 假设和目标：HIV感染发病机制的研究人员一致认为，HIV疾病中最关键的问题之一是为什么免疫反应最终不能控制绝大多数感染者的HIV复制。 在已建立感染的个体中缺乏对HIV抗原的大淋巴细胞增殖反应（LPR），在急性感染期间治疗的受试者中这些反应的发展，以及它们在具有低病毒载量的长期无进展者（LTNP）中的存在，提供了这种类型的CD 4免疫反应和病毒复制控制之间的强关联。 LPR与HIV抗原和病毒学控制之间存在相关性，但HIV特异性CD 4细胞的其他测量值与病毒学控制之间的关系尚不清楚。在本方案中，在原发性HIV感染期间对多种CD 4功能进行连续测量，并结合在深入研究的子集中对具有识别HIV II类四聚体的T细胞应答（TCR）的CD 4细胞进行计数，应提供有关CD 4功能受到抑制的水平的数据。 类似地，比较急性感染期间接受治疗的受试者中HIV特异性CD 4功能的发展，以及拒绝治疗或近期感染且治疗延迟的受试者中的CD 4功能，可以深入了解抑制完全CD 4功能发展或解释其丧失的因素。 研究人员估计，在感染的急性期开始抗逆转录病毒治疗（ART）的受试者中，80%将产生强大的HIV特异性CD 4应答（通过LPR测量），并且这些受试者中的大多数将在停止ART后在一定程度上控制病毒载量。并且作为开始ART之前的时间的函数的下降的CD 4应答性的曲线的形状和斜率是未知的，但是在少数患者中的数据表明HIV特异性CD 4细胞的应答性将更低，但有些患者在急性感染发作后180天才开始接受抗逆转录病毒治疗（34）。 主要目的：确定每个分层中病毒载量最初被ART抑制，随后能够将血浆HIV RNA控制在<5，000拷贝/mL的平均值（在最终分析治疗中断（ATI）中停止ART后第16周和第18周测量）的受试者比例。 次要目的：a）确定给定患者从ATI开始直到达到重新开始ART的方案标准或直到ATI第48周（以先到者为准）的所有血浆HIV-RNA测量值的平均值。 B）确定在ATI的第16周和第18周将病毒载量控制到<1，000拷贝/mL、<400拷贝/mL和<50拷贝/mL平均值的每个层中的受试者的百分比。 c）确定急性分层的疫苗组和安慰剂组中将病毒载量控制至<5，000拷贝/mL的受试者的百分比。 d）确定近期感染分层的疫苗组和安慰剂组中将病毒载量控制在<5，000拷贝/mL的受试者的百分比。 e）确定从HIV感染的假定发作到开始ART的中位时间，其与受试者在中断ART后控制病毒载量的随后能力相关。f）确定从HIV感染的假定发作到开始ART的中位时间，其与随后对HIV抗原的强淋巴细胞增殖应答（LPR）的发展相关。 g）确定在疫苗组和安慰剂组中，对于在第16周和第18周将病毒载量控制在平均值<5，000拷贝/mL的任一层中的受试者，在随后的病毒学复发之前需要重新开始ART的中位时间。 研究设计和方法：这是一项在急性和近期HIV感染受试者中进行的有效抗逆转录病毒治疗（ART）单独与ART加治疗性HIV疫苗接种的随机对照临床试验，均监测治疗中断。 本研究包括诊断阶段、ART单独治疗阶段、ART加疫苗接种阶段、短暂计划治疗中断阶段和分析治疗中断阶段，并提供ART或疫苗接种或两者的再治疗。 将入组约92例受试者（46例急性感染和46例近期感染）。 这项研究将持续5年。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis and Objectives: Investigators of the pathogenesis of HIV infection agree that one of the most critical questions in HIV disease is why immune responses ultimately do not control HIV replication in the vast majority of infected individuals. The absence of large lymphocyte proliferation response (LPR) to HIV antigens in individuals with established infection, the development of these responses in subjects treated during acute infection, and their presence in long term nonprogressors (LTNPs) with low viral loads, provide strong associations between this type of CD4 immune response and the control of viral replication. A correlation exists between LPR to HIV antigens and virologic control, but the relationship between other measurements of HIV-specific CD4 cells and virologic control is less clear. The sequential measurements of multiple CD4 functions during primary HIV infection in this protocol, combined with the enumeration of CD4 cells with T-cell responses (TCR) recognizing HIV-class II tetramers in the intensively studied subset should provide data on the levels at which CD4 function is inhibited. Similarly, a comparison of HIV-specific CD4 function as it develops in subjects treated during acute infection and CD4 function in subjects who decline treatment or who have recent infection in whom treatment has been delayed, may provide insight into factors inhibiting the development of full CD4 function, or accounting for its loss. The investigators estimate that 80% of subjects initiating antiretroviral therapy (ART) during the acute phase of their infection will develop robust HIV-specific CD4 responses as measured by LPR, and that a majority of these will control viral load to some degree after stopping ART. The frequency and magnitude of LPR to HIV antigens that will develop when treatment is delayed, and the shape and slope of the curve of declining CD4 responsiveness as a function of the time before starting ART are unknown, but data in a small number of patients suggests that the responsiveness of HIV-specific CD4 cells will be will be lower, but may occur in some patients when ART is delayed as long as 180 days after the onset of acute infection (34). Primary Objective: To determine the proportion of subjects in each stratum whose viral load was initially suppressed with ART that are subsequently able to control plasma HIV RNA to a mean value of <5,000 copies/mL as measured at weeks 16 and 18 after stopping ART in the final analytical treatment interruption (ATI). Secondary Objectives: a) To determine the mean value of all measurements of plasma HIV-RNA in a given patient from the initiation of the ATI until protocol criteria for restarting ART have been reached, or until week 48 of the ATI, which ever comes first. b) To determine the percent of subjects in each stratum that control viral load to<1,000 copies/mL, to <400 copies/mL, and to <50 copies/mL mean value at weeks 16 and 18 of the ATI. c) To determine the percent of subjects in the vaccine arm and placebo arm of the acute stratum that control viral load to <5,000 copies/mL. d) To determine the percent of subjects in the vaccine arm and placebo arm of the recent infection stratum that control viral load to <5,000 copies/mL. e) To determine the median time from presumed onset of HIV infection to initiation of ART which is associated with the subsequent ability of subjects to control viral load after interruption of ART. f) To determine the median time from presumed onset of HIV infection to initiation of ART, which is, associated with the subsequent development of strong lymphocyte proliferative responses (LPR) to HIV antigens. g) To determine the median time before a subsequent virologic relapse that requires restarting ART in the vaccine and the placebo arms for subjects in either stratum who controlled viral load to a mean value of <5,000 copies/mL at 16 and 18 weeks. Study Design and Methods: This is a randomized controlled clinical trial of effective antiretroviral therapy (ART) alone versus ART plus therapeutic HIV vaccination, both with monitored treatment interruptions, in acutely and recently HIV infected subjects. This study contains a diagnosis phase, an ART alone treatment phase, an ART plus vaccination phase, a brief scheduled treatment interruption phase and an analytical treatment interruption, with provisions for retreatment with ART or vaccination or both. Approximately 92 subjects will be enrolled (46 acute and 46 recent infections). The study will last 5 years.