Role of Viral Reservoirs in the Pathogenesis of HIV Disease

病毒库在 HIV 疾病发病机制中的作用

• 批准号: 9161520
• 负责人: Anthony S. Fauci
• 金额: $ 138.42万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161520
• 关键词: Acute; Address; Adjuvant; Animal Model; Anti-Retroviral Agents; Antibodies; Antigens; B-Lymphocytes; Biological Assay; Blinded; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic; Chronic Phase; Clinical Trials; Cloning; Cytotoxic T-Lymphocytes; DNA Vaccines; Data Set; Development; Disease; Disease remission; Double-Blind Method; Electroporation; Enrollment; Gagging; Goals; HIV; HIV Antibodies; HIV Antigens; HIV Infections; Immune; Immune response; Immunity; Immunologics; Individual; Infection; Infusion procedures; Interleukin-12; Interruption; Kinetics; Laboratories; Measures; Monitor; Monoclonal Antibodies; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Population; Randomized; Recombinants; Research; Resistance; Rest; Role; Safety; Specimen; Study Subject; T-Lymphocyte; Technology; Therapeutic Human Experimentation; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viremia; Virus; Visit; antiretroviral therapy; arm; base; booster vaccine; design; double-blind placebo controlled trial; experience; in vivo; interest; novel strategies; novel therapeutics; open label; placebo controlled study; plasmid DNA; prevent; response; therapeutic vaccine; vaccination strategy; vaccine trial

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.

十多年前，我们证明静息 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，我们还证明，在长期接受抗逆转录病毒疗法期间始终无病毒血症的慢性感染者中，艾滋病毒持续以低水平复制。基于上述发现和其他群体的类似观察结果，持久的病毒库已成为接受抗逆转录病毒治疗的感染者中根除艾滋病毒的主要障碍。因此，当前艾滋病毒治疗研究的一个主要目标是制定消除艾滋病毒储存库并治愈艾滋病毒感染的策略。考虑到即使在早期开始治疗的最佳情况下，目前在大多数感染者中完全根除艾滋病毒也是不可行的，因此正在考虑旨在遏制病毒复制的新方法。其目的不一定是完全根除病毒，而是增强 HIV 特异性免疫反应或被动转移抗 HIV 抗体和其他免疫相关制剂，以便在停止 ART 时控制血浆病毒血症。 为了解决这个问题，我们最近启动了一项临床试验，名为 I 期随机、双盲、安慰剂对照研究，针对在急性/早期感染期间开始抗逆转录病毒治疗的 HIV 感染患者，通过体内电穿孔提供多抗原 DNA 初免疫苗和重组水泡性口炎病毒 (rVSV) 加强疫苗。这是一项随机、2 组（1:1，每组 15 名患者）、双盲、安慰剂对照试验，评估 HIV 多抗原质粒 DNA 初免疫苗与电穿孔体内递送的白细胞介素 12 质粒 DNA 佐剂相结合，以及在急性/早期阶段开始治疗的接受 ART 的受试者中使用 rVSV 疫苗加强疫苗的安全性和有效性。 HIV感染阶段。研究受试者被随机分配在第 0、4、12 和 36 周接受安慰剂或多抗原 HIV DNA 疫苗，并在第 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 HIV 血浆病毒血症反弹减弱或消失所证明的那样。该临床试验现已全部入组。二十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。尽管该研究仍然是盲法，但我们已经开始对从这些研究对象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测定，旨在测量 1) CD4+ 和 CD8+ T 细胞群对研究疫苗的免疫反应； 2) 疫苗接种对 CD4+ T 细胞室中持续存在的 HIV 储存库以及对停止 ART 后血浆病毒反弹的影响； 3) 在缺乏抗逆转录病毒治疗的情况下，确定病毒学控制的预测因素和相关因素。我们预计所有研究参与者的数据集将于 2016 年 9 月完成。 抗体克隆技术的最新进展使得人们从 HIV 感染者的 B 细胞中发现了许多高效且广泛中和的 HIV 特异性单克隆抗体。已经表明，在动物模型和少数感染艾滋病毒的病毒血症个体中，某些广泛中和艾滋病毒特异性抗体可以防止病毒获得、抑制病毒复制、延迟和/或防止治疗中断后血浆病毒反弹。然而，目前尚不清楚这些抗体对停止 ART 后 HIV 感染者的血浆病毒反弹有何体内影响。鉴于几乎所有在感染慢性期开始 ART 的感染者在停止治疗后都会经历血浆病毒反弹，因此研究有效的 HIV 特异性单克隆抗体（例如 VRC01）是否可以防止已停用抗逆转录病毒药物的感染者的血浆病毒反弹非常有意义。为了解决这个问题，我们启动了一项临床试验，名为 VRC01 的探索性、开放标签研究，对象是接受分析治疗中断的慢性 HIV 感染受试者。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，这些感染者在停止治疗后的慢性感染期开始接受 ART。所有研究参与者在研究第 0、14、28 天以及此后每月接受 VRC01（40 毫克/千克）输注，持续长达 6 个月。所有研究参与者在第 3 天停止 ART，每两周监测一次血浆病毒血症，以评估 VRC01 的功效，根据其对停止 ART 后血浆病毒反弹的影响来确定。此外，还将研究研究参与者中 VRC01 耐药性 HIV 出现的动力学以及抗 HIV 免疫（即细胞毒性 T 淋巴细胞反应）的发展。目前，5 名受试者（计划总共 30 名受试者）参加了我们的试验。我们预计该研究将于 2016 年 3 月完成全部入组。