Functional cure and virus eradication by early HAART plus vaccination with live attenuated rubella virus vectors in macaque infants and neonates

通过早期HAART加疫苗接种减毒风疹病毒载体对猕猴婴儿和新生儿进行功能性治愈和病毒根除

• 批准号: 9139875
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 125.54万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-08 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139875
• 关键词: Animals; Anti-HIV Agents; Antibodies; Antiviral Agents; Antiviral Therapy; Attenuated; Attenuated Live Virus Vaccine; Autologous; Birth; Blood Volume; Bottle feeding; CD8-Positive T-Lymphocytes; CD8B1 gene; Caring; Child; Clinical Trials; Collection; Combined Modality Therapy; Coupled; DNA Vaccines; Data; Development; Disease remission; Dose; Gene Expression; Genes; Goals; HIV; HIV Infections; HIV Seropositivity; HIV vaccine; HIV-1; Highly Active Antiretroviral Therapy; Hybrids; Immune; Immune response; Immunity; Immunization; Infant; Infection; Infection Control; Interferons; Lead; Life; Longevity; Macaca; Macaca mulatta; Mississippi; Modeling; Mothers; Natural Killer Cells; Neonatal; Perinatal; Pharmaceutical Preparations; Prevention; Primates; Proteins; Proviruses; Recurrence; Regimen; Relapse; Rubella; Rubella virus; SIV; System; T cell response; T-Lymphocyte; Tenofovir; Testing; Time; Vaccinated; Vaccination; Vaccines; Viral; Viral Genes; Viral Proteins; Viral Vaccines; Viral reservoir; Viremia; Virus; base; cost; early onset; emtricitabine; immunogenic; immunogenicity; neonate; pediatrician; prevent; public health relevance; safety testing; seroconversion; simian human immunodeficiency virus; transmission process; vaccine safety; vector; vector vaccine; vector-based vaccine

 DESCRIPTION (provided by applicant): Highly active anti-retroviral therapy (HAART) can completely suppress viremia but does not lead to functional cure (HIV remission; i.e., no rebound viremia after stopping HAART). The "Mississippi baby" seemed exceptional. She was given HAART from 30 h after birth for 11/2 years and remained aviremic for 2.3 years off HAART. However, HAART was restarted recently due to recurrent viremia and seroconversion. In rhesus macaques (RMs), onset of HAART on day 3 post SIV inoculation prevented viremia and seroconversion (but not when started on later days). Although viremia was suppressed in all drug-treated RMs, it recurred in all animals after HAART was stopped at week 24. Together, these data indicate that HIV or SIV reservoirs are difficult to eradicate. We postulate that early-onset HAART - coupled with induction of strong T-cell immunity via multi-targeted live viral vaccine vectors will achieve functional cures and eradicate infectious virus from reservoirs. Functional cures will be manifested by lack of viral rebound when HAART is stopped. To probe for eradication, CD8+ cells will be depleted in RMs with viral remission; no infectious virus will reemerge. HAART + vaccination may also protect against subsequent virus challenges. We will test our hypothesis by combining HAART with a live attenuated vaccine vector that was safe and highly immunogenic in RMs: rubella virus expressing SIV Gag (rub-gag). When tested in RMs, rub-gag replicated vigorously, and the Gag insert was highly immunogenic. We plan to use the clade C simian-human immunodeficiency virus (SHIV-C) system, which has the advantage of allowing direct testing of immune responses against some HIV viral targets in RMs (e.g., Tat and Env). We will test our central hypothesis in the following Specific Aims: Aim 1: to test whether rub-gag immunization under HAART coverage will yield functional cures in infant RMs and to probe for SHIV-C eradication with CD8 depletion. HAART will be given from 48 h to week 24. Aim 2: to construct rubella/HIV Tat (rub-tat) vectors. We postulate that together with HAART, rub-gag + rub- tat will eradicate SHIV-C, as shown by CD8 depletion of RMs that show no rebound after stopping HAART. Aim 3: to test the longevity of the T-cell responses to rub-gag + rub-tat vaccine given under HAART coverage and to assess whether they protect the RMs against subsequent SHIV-C rechallenge. Aim 4: to test whether boosting with autologous virus will yield optimal immunity. These studies will parallel planned clinical trials in perinatally exposed infants who will be vaccinated with thir own inactivated virus while on HAART. The primate model will dissect mechanisms and probe viral reservoirs by CD8 depletion. Initial immunogenicity studies will be conducted in 4-month old RM infants that no longer need bottle feeding and permit collection of larger volumes of blood to analyze vaccine safety and immunogenicity. Once we have found a promising HAART/vaccine regimen that can achieve viral eradication in some of the treated RM infants, we will perform a more definitive study in neonatal RMs challenged orally with SHIV-C.

 描述(申请人提供)：高效抗逆转录病毒疗法(HAART)可以完全抑制病毒血症，但不能导致功能性治愈(艾滋病毒缓解；即停止HAART后没有反弹病毒血症)。“密西西比州的婴儿”看起来很特别。她从出生后30h开始接受HAART治疗11年半，并在脱离HAART后2.3年内一直处于无菌状态。然而，由于反复出现的病毒血症和血清转换，HAART最近重新启动。在恒河猴(RMS)中，接种SIV后第3天开始进行HAART可以防止病毒血症和血清转换(但在以后开始时不会)。虽然病毒血症在所有药物治疗的RMS中都被抑制，但在24周HAART停止后，所有动物的病毒血症都复发了。总而言之，这些数据表明，艾滋病毒或SIV病毒的宿主很难根除。我们推测，早期发病的HAART结合通过多靶点活病毒疫苗载体诱导强大的T细胞免疫将实现功能性治疗并从宿主中消除传染性病毒。当HAART停止时，功能性治疗将表现为缺乏病毒反弹。为了探测根除，随着病毒的缓解，CD8+细胞将在RMS中耗尽；不会再次出现传染性病毒。HAART+疫苗接种还可以预防后续的病毒挑战。我们将通过将HAART与一种在RMS中安全且具有高度免疫原性的减毒活疫苗载体相结合来验证我们的假设：表达SIV Gag的风疹病毒(RUB-Gag)。当在RMS中测试时，RUB-GAG复制旺盛，并且GAG插入具有高度的免疫原性。我们计划使用C分支猴-人类免疫缺陷病毒(SHIV-C)系统，该系统的优势是可以在RMS中直接测试针对某些HIV病毒靶标(如TAT和Env)的免疫反应。我们将在以下具体目标中测试我们的中心假设： 目的1：测试HAART覆盖下的RUB-Gag免疫能否在婴幼儿RMS中产生功能性治疗，并探讨在CD8耗尽的情况下根除SHIV-C。HAART治疗时间为48小时至24周。 目的2：构建风疹/HIV TAT(RUB-TAT)载体。我们推测，与HAART一起，RUB-GAG+RUB-TAT将根除SIV-C，正如停止HAART后显示没有反弹的RMS的CD8耗竭所示。 目的：测试在HAART覆盖范围内给予RUB-GAG+RUB-TAT疫苗后T细胞反应的寿命，并评估它们是否能保护RMS免受随后的SIV-C再攻击。 目的4：测试用自体病毒加强免疫是否会产生最佳免疫效果。这些研究将在围产期暴露的婴儿中进行计划的临床试验，这些婴儿将在HAART期间接种自己的灭活病毒。灵长类动物模型将剖析机制，并通过CD8耗尽来探测病毒库。最初的免疫原性研究将在4个月大的RM婴儿身上进行，这些婴儿不再需要奶瓶喂养，并允许采集更大量的血液来分析疫苗的安全性和免疫原性。一旦我们发现了一种有希望的HAART/疫苗方案，可以在一些接受治疗的RM婴儿中实现病毒根除，我们将在口服SIV-C挑战的新生儿RMS中进行更明确的研究。