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

• 批准号: 10428674
• 负责人: Donald L Sodora
• 金额: $ 88.85万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10428674
• 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; 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; RNA; 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; hypogammaglobulinemia; immune function; improved; infant infection; insight; interferon antagonist; low income country; lymph nodes; mortality; pediatric human immunodeficiency virus infection; peripheral blood; protein expression; receptor; response; therapeutic target; transmission process

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150 000例新感染。儿童更 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于艾滋病 比其他任何年龄组的人更容易发生疾病。婴儿的快速进展的特点是免疫 可包括CD 4 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）。为了研究婴儿疾病进展的不同速率，SIV感染（SIV+）婴儿 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 感染使用该模型，Sodora实验室鉴定了一种快速进展（RP）表型， 高SIV血浆病毒血症和低水平或检测不到SIV特异性抗体。其他分析显示， RP幼年猕猴在急性期后表现出升高和持续的1型干扰素（IFN-1）水平， 感染后，IFN诱导的蛋白质表达在B细胞卵泡（BCF）内，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治疗应答之间的关系 治疗（cART）后的免疫恢复，以及潜伏病毒的建立和维持。 水库Chahroudi博士实验室（提案共同研究者）的先前研究显示， 与成年猕猴相比，婴儿中潜在的SIV储库，包括对幼稚CD 4 T细胞的偏好， 大多数潜伏感染的细胞在婴儿体内。这些发现导致我们的中心假设：1。快速 SIV+婴儿猕猴的进展是由升高和延长的1型IFN应答引起的， 淋巴结中有效生发中心的形成以及抗SIV体液免疫不足 反应2.婴儿的快速进展导致免疫恢复延迟， 联合抗逆转录病毒疗法的施用。目的1将评估瞬时施用IFN-γ的能力。 1受体拮抗剂，在急性感染后期间影响疾病进展和免疫 结果在婴儿猕猴。目的2和3将评估抗逆转录病毒治疗对免疫系统的有效性。 在RP和典型进展的幼年猕猴中的恢复和潜伏病毒库。在过去20 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 在恒河猴模型中的进展，这里概述的实验扩展了这些以前的实验。 问题研究进行这项建议中概述的实验有可能确定治疗靶点， 艾滋病毒阳性婴儿具有不同的疾病轨迹，并将提供对免疫治疗方法的见解， 以帮助免疫恢复和水库减少。