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，但不会导致功能性治愈（HIV缓解；即停止HAART后病毒血症不反弹）。 “密西西比婴儿”似乎很特别。她从出生后 30 小时开始接受 HAART，持续 11/2 年，在停止 HAART 后 2.3 年仍保持无病毒血症。然而，由于病毒血症复发和血清转化，HAART 最近重新启动。在恒河猴 (RM) 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化（但在以后几天开始时则不然）。尽管所有接受药物治疗的 RM 中病毒血症均得到抑制，但在第 24 周停止 HAART 后，所有动物中病毒血症均复发。总而言之，这些数据表明 HIV 或 SIV 储存库难以根除。我们假设，早发性HAART，加上通过多靶点活病毒疫苗载体诱导强T细胞免疫，将实现功能性治愈并根除病毒储存者中的传染性病毒。功能性治愈表现为停止 HAART 后病毒没有反弹。为了探索根除情况，病毒缓解的 RM 中的 CD8+ 细胞将被耗尽；不会再出现传染性病毒。 HAART + 疫苗接种还可以预防随后的病毒挑战。我们将通过将 HAART 与在 RM 中安全且具有高免疫原性的减毒活疫苗载体相结合来检验我们的假设：表达 SIV Gag (rub-gag) 的风疹病毒。当在 RM 中进行测试时，rub-gag 复制强劲，并且 Gag 插入物具有高度免疫原性。我们计划使用进化枝 C 猿-人类免疫缺陷病毒 (SHIV-C) 系统，该系统的优点是可以直接测试 RM 中针对某些 HIV 病毒靶标（例如 Tat 和 Env）的免疫反应。我们将在以下具体目标中检验我们的中心假设： 目标 1：测试 HAART 覆盖下的 rub-gag 免疫是否会对婴儿 RM 产生功能性治愈，并探索通过 CD8 消除来根除 SHIV-C。 HAART 将在 48 小时至第 24 周期间进行。 目标 2：构建风疹/HIV Tat (rub-tat) 载体。我们假设与HAART一起，rub-gag + rub-tat将根除SHIV-C，如RMs的CD8耗尽所示，在停止HAART后没有反弹。 目标 3：测试 T 细胞对 HAART 覆盖范围内给予的 rub-gag + rub-tat 疫苗的反应寿命，并评估它们是否可以保护 RM 免受随后的 SHIV-C 再次攻击。 目标 4：测试自体病毒加强是否能产生最佳免疫力。这些研究将与计划中的围产期暴露婴儿临床试验并行，这些婴儿将在接受 HAART 期间接种自己的灭活病毒疫苗。灵长类动物模型将通过 CD8 耗竭来剖析机制并探测病毒库。初步免疫原性研究将在 4 个月大的 RM 婴儿中进行，这些婴儿不再需要奶瓶喂养，并允许收集更多的血液来分析疫苗的安全性和免疫原性。一旦我们找到了一种有前景的 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，我们将对口服 SHIV-C 的新生儿 RM 进行更明确的研究。