Role of Viral Reservoirs in the Pathogenesis of HIV Disease

早在十多年前，我们就证明了静息CD4 + T细胞区室中的潜伏病毒库在几乎所有接受临床有效ART的HIV感染者中持续存在。此外，我们证明了HIV在长期接受ART的慢性感染者中持续以低水平复制。基于上述发现和其他组的类似观察，持续的病毒储存库已经成为在接受ART的受感染个体中根除HIV的主要障碍。因此，HIV治疗研究的主要当前推动力是开发消除HIV储存库和实现HIV感染治愈的策略。考虑到目前在大多数感染者中完全根除艾滋病毒是不可行的，即使在最好的情况下，包括早期开始治疗，目前正在考虑旨在遏制病毒复制的新方法。目的不一定是完全根除病毒，而是加强HIV特异性免疫应答或被动转移抗HIV抗体和其他免疫相关药物，以便在停止ART后控制血浆病毒血症。 为了解决这一问题，我们最近启动了一项临床试验，题为一个阶段I随机，双盲，安慰剂对照研究的多抗原DNA疫苗在体内电穿孔和重组水泡性口炎病毒（rVSV）加强疫苗在艾滋病毒感染的患者谁开始抗逆转录病毒治疗在急性/早期感染。这是一项随机、2组（1：1，每组15例患者）、双盲、安慰剂对照试验，评价HIV多抗原质粒DNA疫苗初免联合通过电穿孔体内递送的白细胞介素-12质粒DNA佐剂和rVSV疫苗加强在接受ART的受试者中的安全性和有效性，这些受试者在HIV感染的急性/早期阶段开始治疗。研究受试者在第0、4、12和36周随机接受安慰剂或多抗原HIV DNA疫苗，在第24和48周接受rVSV HIV gag加强疫苗。第56周访视后，所有受试者将接受治疗中断，以确定疫苗接种策略是否导致病毒复制减少，如通过减弱或不存在反弹HIV血浆病毒血症所证明的。该临床试验现已全部入组。20名研究参与者已经完成了研究的疫苗接种阶段，并停止了ART治疗。虽然研究仍处于盲态，但我们已经开始对从这些研究受试者中获得的纵向标本进行广泛的免疫学和病毒学分析。这些分析包括各种实验室试验，旨在测量1）CD4+和CD8 + T细胞群对研究疫苗的免疫应答; 2）疫苗接种对CD4 + T细胞区室中持续HIV储库的影响以及对ART停药后血浆病毒反弹的影响;以及3）在没有ART的情况下识别病毒学控制的预测因子和相关因子。我们预计所有研究参与者的数据集将在2016年9月完成。 抗体克隆技术的最新进展已经导致从HIV感染个体的B细胞中发现了许多高效和广泛中和的HIV特异性单克隆抗体。已经显示，某些广泛中和的HIV特异性抗体可以在动物模型和少量HIV感染的病毒血症个体中预防病毒的获得、抑制病毒复制、延迟和/或预防治疗中断后的血浆病毒反弹。然而，尚不清楚这些抗体在停止ART后对HIV感染个体的血浆病毒反弹可能具有何种体内作用。考虑到几乎所有在感染慢性期开始ART的感染个体在停止治疗后都会经历血浆病毒反弹，研究有效的HIV特异性单克隆抗体，如VRC01，可以防止已停用抗逆转录病毒药物的受感染个体的血浆病毒反弹。为了解决这一问题，我们启动了一项名为VRC01的探索性、开放标签研究的临床试验，该研究在接受分析治疗中断的慢性HIV感染受试者中进行。这是一项单臂、开放标签研究，旨在检查VRC01对30名HIV感染者血浆病毒反弹的影响，这些HIV感染者在感染的慢性期停止治疗后开始ART。所有研究参与者在研究第0、14、28天接受VRC01（40mg/kg）输注，并且此后每月接受一次，持续长达6个月。所有研究参与者在第3天停止ART，并且每2周监测他们的血浆病毒血症以评估VRC01的功效，如通过其对停止ART后的血浆病毒反弹的影响所确定的。细胞毒性T淋巴细胞反应）。目前，我们的试验入组了5例受试者（总计划招募30例受试者）。我们预计该研究将在2016年3月之前全部入组。

Well over a decade ago, we demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all HIV-infected individuals receiving clinically effective ART. In addition, we demonstrated that HIV continually replicates at low levels in chronically infected individuals who are consistently aviremic during prolonged periods of receiving ART. Based on the above findings and similar observations from other groups, the persistent viral reservoir has become a major impediment to the eradication of HIV in infected individuals receiving ART. Consequently, a major current thrust of HIV therapeutic research is the development of strategies to eliminate HIV reservoirs and to achieve a cure for HIV infection. Considering that a complete eradication of HIV is not currently feasible in the majority of infected individuals, even under the best of circumstances involving early initiation of therapy, new approaches aimed at containing viral replication are being considered. The aim is not necessarily to achieve complete eradication of the virus, but rather to boost HIV-specific immune responses or passively transfer anti-HIV antibodies and other immune related agents in order to keep plasma viremia in check upon discontinuation of ART. To address this issue, we recently launched a clinical trial entitled a phase I randomized, double-blind, placebo-controlled study of a multi-antigen DNA vaccine prime delivered by in vivo electroporation and a recombinant vesicular stomatitis virus (rVSV) booster vaccine in HIV-infected patients who began antiretroviral therapy during acute/early infection. This is a randomized, 2-arm (1:1, 15 patients per arm), double-blind, placebo-controlled trial evaluating the safety and efficacy of an HIV multi-antigen plasmid DNA vaccine prime, in combination with an interleukin-12 plasmid DNA adjuvant delivered in vivo by electroporation, and a rVSV vaccine boost in subjects receiving ART who initiated therapy during the acute/early phase of HIV infection. Study subjects were randomized to receive placebo or the multi-antigen HIV DNA vaccine at week 0, 4, 12, and 36 and the rVSV HIV gag booster vaccine at week 24 and 48. After the week 56 visit, all subjects will undergo treatment interruption to determine if the vaccination strategy resulted in a reduction of viral replication, as evidenced by blunted or absent rebound HIV plasma viremia. This clinical trial is now fully enrolled. Twenty study participants have already completed the vaccination phase of the study and have discontinued ART. Although the study remains blinded, we have begun extensive immunologic and virologic analyses on longitudinal specimens obtained from these study subjects. These analyses include a variety of laboratory assays that are designed to measure 1) immunologic responses of CD4+ and CD8+ T cell populations to the study vaccines; 2) the impact of vaccination on the persistent HIV reservoir in the CD4+ T cell compartment and on plasma viral rebound upon discontinuation of ART; and 3) identification of predictors and correlates of virologic control in the absence of ART. We expect data sets will be completed on all study participants by September 2016. Recent advances in antibody cloning technologies have led to the discovery of a number of highly potent and broadly neutralizing HIV-specific monoclonal antibodies from B cells of HIV-infected individuals. It has been shown that certain broadly neutralizing HIV-specific antibodies can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in animal models and a small number of HIV-infected viremic individuals. However, it has been unclear what in vivo effects these antibodies might have on plasma viral rebound in HIV-infected individuals following discontinuation of ART. Given that virtually all infected individuals who initiated ART during the chronic phase of infection experience plasma viral rebound upon cessation of therapy, it is of great interest to investigate whether a potent HIV-specific monoclonal antibody, such as VRC01, can prevent plasma viral rebound in infected individuals whose antiretroviral drugs have been discontinued. To address this issue, we have launched a clinical trial entitled an exploratory, open-label study of VRC01 in subjects with chronic HIV infection undergoing analytical treatment interruption. This is a single-arm, open-label study to examine the effect of VRC01 on plasma viral rebound in 30 HIV-infected individuals who initiated ART during the chronic phase of infection following discontinuation of therapy. All study participants receive infusions of VRC01 (40mg/kg) at study days 0, 14, 28, and monthly thereafter for up to 6 months. All study participants discontinue ART on day 3 and their plasma viremia is monitored every 2 weeks to evaluate the efficacy of VRC01 as determined by its effect on plasma viral rebound following discontinuation of ART. Additionally, the kinetics of the emergence of VRC01-resistant HIV and the development of anti-HIV immunity (i.e., cytotoxic T lymphocyte response) in the study participants will be studied. Currently, 5 subjects (total planned accrual of 30 subjects) are enrolled in our trial. We anticipate that the study will be fully enrolled by March 2016.