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

感染 SIV 的幼年猕猴的疾病快速进展和病毒库形成

基本信息

批准号：
10640931
负责人：
Donald L Sodora
金额：
$ 88.64万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640931
关键词：
2 year old Acquired Immunodeficiency Syndrome Acute Adult Anti-Retroviral Agents Antibodies Antibody Response Antibody titer measurement B-Lymphocytes Biological Assay Biological Models Blood Breast Feeding CD4 Positive T Lymphocytes Cells Cessation of life Child Childhood Collaborations DNA Data Disease Disease Outcome Disease Progression Event Exclusive Breastfeeding Exhibits Frequencies Functional disorder Future Genes Goals HIV HIV Infections Health Helper-Inducer T-Lymphocyte Human Milk Immune Immune System Diseases Immune response Immunoglobulin G Immunoglobulin M Immunologic Factors Immunologics Immunotherapy Impairment Infant Infection Interferon Receptor Interferons Laboratories Laboratory Study Lead Lymphoid Tissue Macaca Macaca mulatta Maintenance Measures Memory B-Lymphocyte Modeling Morbidity - disease rate Mother-to-child HIV transmission Oral Outcome Pathologic Pharmaceutical Preparations Phenotype Plasma Predisposition Productivity RNA Recommendation Recovery Research Research Personnel Role Route SIV Severity of illness Signal Transduction Site Spleen Structure of germinal center of lymph node T-Cell Depletion Tissues Vaccination Viral Load result Viral reservoir Viremia Virus Latency Virus Replication Vulnerable Populations Water acute infection age group antagonist antiretroviral therapy effectiveness evaluation experience experimental study human old age (65+)hypogammaglobulinemia immune function improved infant infection insight low income country lymph nodes mortality pediatric human immunodeficiency virus infection peripheral blood protein expression response therapeutic target transmission process

项目摘要

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.

尽管母婴艾滋病毒传播（MTCT）显着减少，但母乳喂养期间的艾滋病毒感染其发病率仍然高得令人难以接受，每年新增感染病例达 15 万人。比成年人更容易感染艾滋病相关疾病，两岁以下的人更容易死亡婴儿疾病进展快的特点是免疫。功能障碍，包括 CD4 T 细胞耗竭、B 细胞功能障碍和低丙种球蛋白血症（低血浆 IgM/IgG 水平）旨在研究婴儿、SIV 感染 (SIV+) 婴儿的不同疾病进展率。恒河猴已被证明是一个有价值的模型系统，概括了儿科艾滋病毒的几个方面使用该模型，Sodora 实验室确定了一种快速进展者 (RP) 表型，其中包括：其他分析显示，SIV 血浆病毒血症较高，SIV 特异性抗体水平较低或检测不到。 RP 婴儿猕猴在急性期后表现出持续升高的 1 型干扰素 (IFN-1) 水平感染的影响、B 细胞滤泡 (BCF) 内 IFN 诱导的蛋白表达，并且这些变化是与淋巴组织内的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 IFN-1 信号传导可能导致快速 HIV/SIV 疾病的机制进展，以及进展率与联合抗逆转录病毒药物反应之间的关系治疗（cART）、治疗后的免疫恢复以及潜伏病毒的建立和维持 Chahroudi 博士实验室（提案共同研究员）之前的研究揭示了水库的差异。与成年猕猴相比，婴儿体内存在潜在的 SIV 储存库，包括倾向于储存幼稚的 CD4 T 细胞这些发现引出了我们的中心假设： 1. 快速感染。 SIV+ 幼年猕猴的疾病进展是由于 1 型 IFN 反应升高且延长所致，该反应抑制了淋巴结中有效生发中心的形成以及抗 SIV 体液免疫不足 2. 婴儿的快速进展导致免疫恢复延迟和更大的潜在储存库。联合抗逆转录病毒疗法的施用目标 1 将评估瞬时施用 IFN-的能力。 1受体拮抗剂，在急性感染后影响疾病进展和免疫目标 2 和 3 将评估抗逆转录病毒疗法对免疫的有效性。过去 20 只恒河猴和典型进展的婴儿猕猴中的恢复情况和潜伏病毒库。多年来，Sodora 实验室研究了调节 SIV 口腔传播和疾病的免疫因素恒河猴模型的进展，以及这里概述的实验扩展了之前的这些进行本提案中概述的实验有可能确定治疗靶点。 HIV+ 婴儿具有独特的疾病轨迹，将为免疫治疗方法提供见解，帮助免疫恢复和减少病毒库。