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后无病毒血症反弹）。“密西西比婴儿”似乎是个例外。她从出生后30小时开始接受HAART治疗1年半，停药后2.3年仍保持无病毒血症。然而，HAART最近重新开始，由于复发的病毒血症和血清转换。在恒河猴（RM）中，在SIV接种后第3天开始的HAART预防了病毒血症和血清转化（但在随后几天开始时不能）。尽管所有药物治疗RM中的病毒血症均受到抑制，但在第24周停止HAART后，所有动物的病毒血症均复发。总之，这些数据表明，艾滋病毒或SIV宿主难以根除。我们假设，早发性HAART -加上通过多靶向活病毒疫苗载体诱导强T细胞免疫将实现功能性治愈并从宿主中根除感染性病毒。当HAART停止时，功能性治愈将表现为缺乏病毒反弹。为了探索根除，将在病毒缓解的RM中耗尽CD 8+细胞;不会再出现感染性病毒。HAART +疫苗接种也可以预防随后的病毒攻击。我们将通过将HAART与在RM中安全且具有高度免疫原性的减毒活疫苗载体：表达SIV Gag的风疹病毒（rub-gag）相结合来检验我们的假设。当在RM中测试时，rub-gag剧烈复制，并且Gag插入物具有高度免疫原性。我们计划使用进化枝C类人猿-人类免疫缺陷病毒（SHIV-C）系统，其优点是允许直接测试RM中针对某些HIV病毒靶标的免疫应答（例如，达特和Env）。我们将在以下具体目标中检验我们的中心假设： 目标1：测试在HAART覆盖下的rub-gag免疫接种是否会在婴儿RM中产生功能性治愈，并探索用CD 8耗竭根除SHIV-C。HAART将从48小时至第24周进行。 目的2：构建风疹/HIV达特（rub-tat）载体。我们假设，与HAART一起，rub-gag +达特将根除SHIV-C，如RM的CD 8耗竭所示，其在停止HAART后未显示反弹。 目标3：测试在HAART覆盖下给予的rub-gag + rub-tat疫苗的T细胞应答的寿命，并评估它们是否保护RM免受随后的SHIV-C再激发。 目的4：测试用自体病毒加强是否会产生最佳免疫力。这些研究将平行计划在围产期暴露的婴儿中进行的临床试验，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CD 8耗竭探测病毒储库。将在4个月大的RM婴儿中进行初始免疫原性研究，这些婴儿不再需要奶瓶喂养，并允许采集更大体积的血液，以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，可以在一些治疗的RM婴儿中实现病毒根除，我们将在口服SHIV-C的新生儿RM中进行更明确的研究。