Rapid disease progression and viral reservoir formation in SIV-infected infant macaques

尽管母婴传播艾滋病毒(母婴传播)显著减少，但母乳喂养期间的艾滋病毒感染 仍然以令人无法接受的高比率发生，每年造成15万新感染。孩子们更多 比成年人更容易感染艾滋病相关疾病，两岁以下的人更有可能死亡 比任何其他年龄段的人疾病进展都要快。婴儿进展迅速的特点是免疫 功能障碍，包括CD4T细胞耗尽、B细胞功能障碍和低丙种球蛋白血症(低血浆 Ig M/Ig G水平)。探讨婴儿、SIV感染(SIV)婴儿的不同疾病进展速度 恒河猴已被证明是一个有价值的模型系统，概括了儿童艾滋病毒的几个方面 感染。利用这一模型，索多拉实验室确定了一种快速进展型(RP)表型，包括 SIV血浆病毒血症高，SIV特异性抗体水平低或检测不到。更多分析揭示 Rp婴儿猕猴在急性期后表现出持续的1型干扰素水平升高 在感染中，干扰素诱导B细胞滤泡(BCF)内的蛋白表达，这些变化是 与淋巴组织内生发中心功能障碍有关。这些差异提出了重要的问题 关于持续的干扰素-1信号可能导致快速的HIV/SIV疾病的机制 进展以及进展率与联合抗逆转录病毒疗效之间的关系 治疗(CART)，治疗后的免疫恢复，以及潜伏病毒的建立和维持 水库。Chahroudi博士的实验室(提案合作调查员)之前的研究表明， 婴儿与成年猕猴潜伏的SIV储存库的比较，包括偏向幼稚的CD4T细胞 大多数潜伏感染的细胞在婴儿中。这些发现引出了我们的中心假设：1.快速 SIV婴儿猕猴的进展是由于抑制1型干扰素反应的升高和延长所致 淋巴结中有效生发中心的形成以及抗SIV体液免疫不足 回应。2.婴儿的快速进展会导致免疫恢复延迟，并导致更大的潜在蓄水池 给予联合抗逆转录病毒治疗。目标1将评估瞬时给药的干扰素- 1受体拮抗剂，在急性感染后影响疾病进展和免疫 幼年猕猴的结局。AIMS 2和AIMS 3将评估抗逆转录病毒治疗对免疫的效果 恢复期和潜伏病毒库在反相猕猴和典型的进展期婴儿猕猴中都存在。在过去的20年里 多年来，索多拉实验室一直在研究调节SIV口腔传播和疾病的免疫因素 恒河猴模型的进展，这里概述的实验是在以前这些实验的基础上扩展的 学习。进行本提案中概述的实验有可能确定治疗靶点 HIV婴儿具有不同的疾病轨迹，并将为免疫治疗方法提供见解 以帮助恢复免疫力和减少蓄水池。

Despite significant reductions in mother-to-child HIV transmission (MTCT), HIV infection during breastfeeding still occurs at unacceptably high rates, contributing to 150,000 new infections annually. Children are more susceptible to AIDS-related illnesses than adults, with those under two years of age being more likely to succumb to rapid disease progression than any other age group. Rapid progression in infants is characterized by immune dysfunction that can include CD4 T cell depletion, B cell dysfunction and hypo-gammaglobulinemia (low plasma levels of IgM/IgG). To investigate different rates of disease progression in infants, SIV-infected (SIV+) infant rhesus macaques have proven to be a valuable model system, recapitulating several aspects of pediatric HIV infection. Using this model, the Sodora laboratory identified a rapid progressor (RP) phenotype encompassing high SIV plasma viremia and low or undetectable levels of SIV-specific antibodies. Additional analyses revealed that RP infant macaques exhibit elevated and sustained type-1 Interferon (IFN-1) levels following the acute stage of the infection, IFN-induced protein expression within B cell follicles (BCF), and that these changes were associated with germinal center dysfunction within lymphoid tissues. These differences raise important questions about the mechanism by which sustained IFN-1 signaling potentially contributes to rapid HIV/SIV disease progression, as well as the relationship between progression rate and response to combination antiretroviral therapy (cART), immune recovery following treatment, and establishment and maintenance of the latent viral reservoir. Previous studies from Dr. Chahroudi’s laboratory (proposal co-investigator) revealed differences in the latent SIV reservoir in infant compared to adult macaques, including a bias toward naïve CD4 T cells in harboring the majority of latently infected cells in infants. These findings lead to our central hypotheses: 1. Rapid progression in SIV+ infant macaques results from an elevated and prolonged type-1 IFN response that inhibits formation of effective germinal centers in lymph nodes as well as an insufficient anti-SIV humoral immune response. 2. Rapid progression in infants results in delayed immune recovery and a larger latent reservoir during administration of combination antiretroviral therapy. Aim 1 will assess the ability of transiently administered IFN- 1 receptor antagonist, during the post-acute infection period to influence disease progression and immune outcome in infant macaques. Aims 2 and 3 will evaluate the effectiveness of antiretroviral therapy on immune recovery and latent viral reservoirs in both the RP and typically progressing infant macaques. Over the last 20 years, the Sodora laboratory has investigated immune factors that modulate SIV oral transmission and disease progression in the rhesus macaque model, and the experiments outlined here expand upon these previous studies. Undertaking experiments outlined in this proposal has the potential to identify therapeutic targets for HIV+ infants with distinct disease trajectories and will provide insights into immune therapeutic approaches that to aid in immune recovery and reservoir reduction.