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: 8924693
• 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/8924693
• 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; Gagging; 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; 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（由适用提供）：高度活跃的抗逆转录病毒疗法（HAART）可以完全抑制病毒血症，但不会导致功能治愈（HIV缓解；即停止HAART后无反弹病毒血症）。 “密西西比宝贝”似乎很出色。她从出生后30小时从11/2年开始给予Haart，并在Haart离职2。3年。但是，由于复发性病毒血症和血清转化，HAART最近重新启动。在恒河猕猴（RMS）中，SIV后第3天的HAART发作可预防病毒血症和血清转化（但在以后的几天开始时）。尽管在所有药物治疗的RMS中都抑制了病毒血症，但在HAART在第24周停止后，所有动物都会重复出现。这些数据共同表明HIV或SIV储层难以放射。我们假设早期发作，早发 - 加上通过多靶向的活病毒疫苗载体诱导强T细胞免疫，将获得功能性治疗和储层中的放射性感染性病毒。停止HAART时缺乏病毒反弹，功能治疗将表现出来。为了探测放疗，CD8+细胞将在病毒缓解的RMS中耗尽。没有传染病会重新出现。 HAART +疫苗也可以防止随后的病毒挑战。我们将通过将HAART与RMS中安全且高度免疫原性的活疫苗载体结合在一起来检验我们的假设：表达SIV GAG（RUB-GAG）的风疹病毒。当在RMS中测试时，会剧烈复制摩擦，并且GAG插入物具有高度免疫原性。我们计划使用进化枝C Simian-Human免疫缺陷病毒（SHIV-C）系统，该系统具有允许对RMS中某些HIV病毒靶标的免疫反应进行直接测试（例如TAT和ENV）。我们将在以下特定目的中检验我们的中心假设： AIM 1：测试HAART覆盖范围下的摩擦-GAG免疫是否会在婴儿RMS中产生功能疗法，并用CD8耗竭探测消除Shiv-C。 Haart将从48小时到24周提供。 目标2：构造风疹/艾滋病毒tat（rub-tat）向量。我们假设，与Haart一起，Rub-Gag + rub-tat将放射性湿透-C-C，如CD8的RMS部署所示，停止Haart后没有反弹。 目标3：测试T细胞响应对HAART覆盖范围下给出的T细胞响应的寿命，并评估它们是否保护RMS免受随后的SHIV-C RECHALLENGE的影响。 目标4：测试自体病毒的增强是否会产生最佳的免疫组织化学物质。这些研究将在围产期暴露的婴儿中平行计划的临床试验，这些试验将在HAART上接种thir自己的灭活病毒。私有模型将通过CD8耗竭剖析机制和探测病毒储存。最初的免疫原性研究将在4个月大的RM婴儿中进行，该研究不再需要奶瓶喂养，并允许收集大量的血液来分析疫苗的安全性和免疫原性。一旦我们找到了可以在某些经过治疗的RM婴儿中实现病毒放射治疗的HAART/疫苗方案，我们将在SHIV-C口服口服挑战的新生儿RMS中进行更确定的研究。