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，我们证明了静止的CD4+ T细胞室中的潜在病毒储存室几乎持续存在于所有接受临床有效ART的HIV感染者中。此外，我们证明了艾滋病毒在长期接受ART期间始终处于持续的恶毒性中的慢性感染者中不断复制。基于上述发现和其他群体的类似观察结果，持续的病毒储层已成为受感染的受感染者消除HIV的主要障碍。因此，HIV治疗研究的主要目前的主要目前是消除艾滋病毒水库并实现HIV感染的策略的制定。考虑到，即使在涉及早期开始治疗的最佳情况下，目前在大多数感染者中完全消除了艾滋病毒也不是可行的，旨在包含病毒复制的新方法。目的不一定是为了完全消除病毒，而是为了增强HIV特异性免疫反应或被动地转移抗HIV抗体和其他免疫相关剂，以使血浆病毒血症保持对艺术中断时的检查。 为了解决这个问题，我们最近发起了一项临床试验，题为I阶段的一项随机，双盲，安慰剂对照的研究，对体内电穿孔和重组囊泡病毒病毒（RVSV）的重组囊泡性疫苗（RVSV）促进抗抗病毒抗体的患者的多组成囊炎病毒（RVSV）进行了抗生素抗逆转录病毒抗体治疗。这是一项随机的2臂（1：1，15例患者），双盲，安慰剂对照试验，评估HIV HIV多抗原质粒DNA疫苗的安全性和有效性，结合Interleukin-12 HIV感染期。 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.该临床试验现在已完全注册。二十名研究参与者已经完成了研究的疫苗接种阶段，并停止了艺术。尽管这项研究仍然视而不见，但我们已经开始对从这些研究受试者获得的纵向标本进行广泛的免疫学和病毒学分析。这些分析包括旨在测量的各种实验室测定1）CD4+和CD8+ T细胞种群对研究疫苗的免疫反应； 2）疫苗接种对CD4+ T细胞室中持续的HIV储量的影响以及停用ART时的血浆病毒反弹； 3）在没有艺术的情况下，鉴定病毒控制的预测因子和相关性。我们预计将在2016年9月之前完成所有研究参与者的数据集。 抗体克隆技术的最新进展导致发现了许多高度有效且广泛中和的HIV特异性单克隆抗体，来自HIV感染个体的B细胞。已经表明，某些广泛中和的HIV特异性抗体可以防止获取病毒，抑制病毒复制，延迟和/或预防动物模型治疗后血浆病毒反弹，以及少数HIV感染的VIREAMIC患者。但是，目前尚不清楚这些抗体在中止ART后可能对HIV感染的个体中血浆病毒反弹产生什么影响。鉴于几乎所有受感染的人在慢性感染阶段停止治疗后血浆病毒反弹，因此，研究有效的HIV特异性单克隆抗体（例如VRC01）（例如VRC01）是否可以预防抗雷诺病毒药物抗逆转录病毒药物的感染者的血浆病毒反弹。为了解决这个问题，我们发起了一项临床试验，该试验名为VRC01的探索性开放标签研究，对经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的研究，旨在检查VRC01对30个HIV感染的个体的血浆病毒反弹的影响，这些个体在暂停的感染阶段在暂停治疗后发起了ART。所有研究参与者在研究第0、14、28天以及此后每月收到VRC01（40mg/kg）的输注，最多6个月。所有研究参与者在第3天停止ART及其血浆病毒血症每2周进行一次监测，以评估VRC01的疗效，这取决于其对ART中断后对等离子体病毒反弹的影响。此外，将研究研究参与者中VRC01抗HIV的出现动力学和抗HIV免疫（即细胞毒性T淋巴细胞反应）的发展。目前，我们的审判中注册了5名受试者（总计30受试者的总计划应计）。我们预计这项研究将在2016年3月之前完全参加。