Understanding Co-morbidities: COVID-19 in individuals living with HIV/AIDS

了解合并症：HIV/AIDS 患者中的 COVID-19

• 批准号: 10557898
• 负责人: Dhiraj Kumar Singh
• 金额: $ 98.98万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557898
• 关键词: 2019-nCoV; Ablation; Acceleration; Acquired Immunodeficiency Syndrome; Acute; Affect; Animals; Automobile Driving; CD4 Positive T Lymphocytes; COVID-19; COVID-19 impact; COVID-19 severity; COVID-19 susceptibility; COVID-19 therapeutics; Cell Compartmentation; Cells; Cessation of life; Chronic; Clinical; Clinical Management; Development; Disease; Exhibits; Foundations; Generations; Goals; HIV; HIV Infections; HIV/AIDS; Health; Immune; Immune response; Immunologic Deficiency Syndromes; Immunologic Factors; Immunologic Techniques; Immunologics; Immunotherapeutic agent; Individual; Infection; Intervention; Knowledge; Long COVID; Macaca; Macaca mulatta; Modeling; Monitor; Mutation; PET/CT scan; Pathogenesis; Pathogenicity; Pathology; Patient Care; Persons; Phase; Post-Acute Sequelae of SARS-CoV-2 Infection; Predisposition; Probability; Radiology Specialty; Reporting; Risk; Role; SARS-CoV-2 infection; SARS-CoV-2 variant; SIV; Therapeutic Intervention; Tissues; Validation; Variant; Viral; Virus; Virus Replication; cell type; co-infection; comorbidity; comparative; experience; immune activation; insight; nonhuman primate; pandemic disease; pathogen; prevent; reconstitution; severe COVID-19; vaccine development; vaccine hesitancy

Summary While COVID-19 continues to be a health challenge, very little is known about how COVID-19 affects people living with HIV (PLHIV). Based on the most recent reports originating from CDC and WHO, however, it appears that people with HIV may have a 30% greater likelihood of developing severe COVID-19 disease when infected with SARS-CoV-2. We will leverage the established rhesus macaque models of SARS-CoV-2 infection resulting in COVID-19 and SIV infection to characterize the effects of underlying SIV infection on the manifestation of both acute and post-acute COVID-19 sequelae. Our group was amongst few that established the rhesus macaque models of COVID-19 infection early on during the pandemic. Our model has been utilized to both study the immunological mechanisms of protection from SARS-CoV-2 infection, as well as for accelerated development of vaccine and therapeutics against COVID-19. Here we propose to couple this model with the long-standing, highly validated, pathogenic AIDS NHP model in SIV infected rhesus macaques to study a central hypothesis that underlying SIV infection and the resulting immunodeficiency/immune activation promotes the progression of a more severe COVID-19 presentation due to SARS-CoV-2 infection. As corollary, we hypothesize that ART does not completely suppress the ill effects of chronic immune activation due to SIV, it will not completely prevent the progression of severe COVID-19 due to SARS-CoV-2 infection in the macaque model. We have the experience in infecting rhesus macaques with SIV and treating these animals with ART to suppress viral replication and study immune mechanisms. By profiling the differences in dynamics of viral titers, induced tissue pathology, and underlying immunological perturbations, we will provide definitive knowledge in whether SIV infected rhesus macaques exhibit higher susceptibility to severe COVID-19. Furthermore, our studies will also be able to hint at the specific mechanisms which result in this susceptibility. Delineating these comorbid immunological factors driving susceptibility will enable better clinical monitoring and informed decisions for patient care. Mechanistic insights developed by this study is also imperative for the development of host-directed immunotherapeutic interventions for combating COVID-19 in PLHIV.

概括 尽管 COVID-19 仍然是一项健康挑战，但人们对 COVID-19 如何影响人们知之甚少 艾滋病毒感染者（PLHIV）。然而，根据疾病预防控制中心和世界卫生组织的最新报告，似乎 HIV 感染者在感染后患上严重 COVID-19 疾病的可能性可能会增加 30% 与 SARS-CoV-2。我们将利用已建立的 SARS-CoV-2 感染恒河猴模型 在 COVID-19 和 SIV 感染中描述潜在的 SIV 感染对两者表现的影响 急性和急性后 COVID-19 后遗症。我们的团队是少数建立恒河猴的团队之一 大流行早期的 COVID-19 感染模型。我们的模型已被用来研究 防止 SARS-CoV-2 感染的免疫机制，以及加速发展 针对 COVID-19 的疫苗和疗法。在这里，我们建议将该模型与长期存在的、高度重视的模型结合起来。 在感染 SIV 的恒河猴中验证了致病性 AIDS NHP 模型，以研究一个中心假设： 潜在的 SIV 感染和由此产生的免疫缺陷/免疫激活促进了疾病的进展 由于 SARS-CoV-2 感染，COVID-19 表现更为严重。作为推论，我们假设 ART 确实 不能完全抑制 SIV 引起的慢性免疫激活的不良影响，也不能完全预防 猕猴模型中因 SARS-CoV-2 感染而导致严重 COVID-19 的进展。我们有经验 用 SIV 感染恒河猴并用 ART 治疗这些动物以抑制病毒复制 研究免疫机制。通过分析病毒滴度动态的差异、诱导的组织病理学和 潜在的免疫扰动，我们将提供关于 SIV 是否感染恒河猴的明确知识 猕猴对严重的 COVID-19 表现出更高的易感性。此外，我们的研究还将能够暗示 导致这种易感性的具体机制。描述这些共病免疫学因素 提高敏感性将有助于更好的临床监测和患者护理的明智决策。机械论 这项研究得出的见解对于宿主定向免疫治疗的开发也至关重要 对抗 PLHIV 中的 COVID-19 的干预措施。