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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。假设和目的：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。在已确定感染的个体中缺乏对HIV抗原的大淋巴细胞增殖反应(LPR)，在急性感染期间接受治疗的受试者中这些反应的发展，以及在病毒载量较低的长期非进展者(LTNP)中的存在，提供了这种类型的CD4免疫反应与病毒复制控制之间的强烈关联。LPR与HIV抗原和病毒学控制之间存在相关性，但对HIV特异性CD4细胞的其他测量与病毒学控制之间的关系不太清楚。在这个方案中，在初次HIV感染期间对多个CD4功能的连续测量，结合在密集研究的亚群中识别HIV-II类四聚体的具有T细胞反应(TCR)的CD4细胞的计数，应该提供关于CD4功能被抑制的水平的数据。类似地，比较在急性感染期间接受治疗的受试者和拒绝治疗或最近感染但治疗被推迟的受试者中HIV特异性CD4功能的发展，可能有助于洞察抑制全部CD4功能发展的因素，或解释其丧失的原因。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，有80%将产生LPR测量的强大的HIV特异性CD4反应，其中大多数人在停止ART后将在一定程度上控制病毒载量。当治疗延迟时，LPR对艾滋病毒抗原的反应频率和幅度，以及作为开始抗逆转录病毒治疗前时间的函数的CD4反应性下降曲线的形状和斜率尚不清楚，但少数患者的数据表明，艾滋病毒特异性CD4细胞的反应性将较低，但在某些患者中，当抗逆转录病毒治疗延迟至急性感染发作后180天时，可能会发生这种情况(34)。主要目的：确定在终止分析治疗中断(ATI)的16周和18周停止ART后，每层中最初使用ART抑制病毒载量并随后能够将血浆HIV RNA控制在平均值为5,000拷贝/毫升的受试者的比例。次要目标：a)确定特定患者从ATI开始到达到重新启动ART的方案标准，或直到ATI 48周(以先出现者为准)期间所有血浆HIV-RNA测量的平均值。B)在ATI的第16周和第18周，确定每层受试者中将病毒载量控制在1000拷贝/毫升、400拷贝/毫升和50拷贝/毫升平均值的百分比。C)确定急性层组疫苗组和安慰剂组中将病毒载量控制在5000拷贝/毫升的受试者的百分比。D)确定在最近感染层的疫苗组和安慰剂组中，将病毒载量控制在5,000份/毫升的受试者的百分比。E)确定从假定的艾滋病毒感染到开始抗逆转录病毒疗法的中位时间，这与受试者在抗逆转录病毒疗法中断后随后控制病毒载量的能力有关。F)确定从假定的艾滋病毒感染到开始抗逆转录病毒治疗的中位时间，这与随后对艾滋病毒抗原产生强烈的淋巴细胞增殖反应(LPR)有关。G)确定病毒学复发之前的中位时间，这需要重新启动疫苗中的ART和安慰剂药物，用于在16周和18周将病毒载量控制在平均值5000拷贝/毫升的受试者。研究设计和方法：这是一项随机对照临床试验，在急性和新近感染艾滋病毒的受试者中，进行有效的抗逆转录病毒疗法(ART)和ART加治疗性HIV疫苗接种，两者都有监测的治疗中断。这项研究包括诊断阶段、ART单独治疗阶段、ART加疫苗接种阶段、短暂的预定治疗中断阶段和分析性治疗中断阶段，并提供ART或疫苗再治疗或两者兼而有之的规定。将招募大约92名受试者(46名急性感染和46名近期感染)。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.