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Innate Immune Response Genetics and T cell Activation in Treated HIV Infection

HIV 感染治疗中的先天免疫反应遗传学和 T 细胞激活

基本信息

批准号：
7847584
负责人：
PETER W HUNT
金额：
$ 18.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-22 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847584
关键词：
Acquired Immunodeficiency Syndrome Activated Natural Killer Cell Address Affect Africa South of the Sahara African Anti-Retroviral Agents Applications Grants Binding CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cells Clinical Cohort Studies Collaborations Core Facility Death Rate Effectiveness Enrollment Event Funding Genetic Genetic Polymorphism Genomics Goals Grant HIV HIV Infections HIV-1 HLA Antigens Immune Immune response Immune system Immunologic Deficiency Syndromes Individual Infection Inflammatory Integration Host Factors International Intervention Laboratories Lead Life Malaria Mediating Mediator of activation protein Participant Pathway interactions Patients Pharmaceutical Preparations Population Prevalence Public Health Recovery Research Research Project Grants Residual state Resources Role Sampling T-Cell Activation T-Lymphocyte Toll-like receptors Treatment Protocols Treatment outcome Tuberculosis Uganda Viral Work antiretroviral therapy clinically significant cohort experience follow-up immune activation immune function improved killer immunoglobulin-like receptor mortality prevent public health relevance restoration treatment program

项目摘要

DESCRIPTION (provided by applicant): While millions of HIV-infected patients in sub-Saharan Africa are now receiving life-saving antiretroviral therapy, early mortality is much higher than expected, and the extent of CD4+ T cell recovery is highly variable. Understanding the predictors of CD4+ T cell recovery will be important to optimize the effectiveness of antiretroviral treatment programs in sub-Saharan Africa. We hypothesize that persistent generalized T cell activation is an important determinant of blunted CD4+ T cell recovery in sub-Saharan Africans. While T cell activation declines significantly during suppressive antiretroviral therapy, it remains abnormally elevated and has been associated with blunted CD4+ T cell recovery in resource-rich settings. While the determinants of T cell activation remain unknown, stimulation of innate immune responses by residual HIV replication and by other co- infections are likely mechanisms. HIV and co-infections may stimulate innate immune responses by activating natural killer (NK) cells through killer immunoglobulin-like receptor (KIR) - human leukocyte antigen (HLA) interactions and by binding toll-like receptors (TLR). Several KIR/HLA allotypes and TLR polymorphisms have been associated with activation or inhibition of innate immune responses to HIV and prevalent co-infections and with clinical progression during untreated HIV-1 infection. Whether these host genetic factors are associated with T cell activation and CD4+ T cell recovery during suppressive antiretroviral therapy remains unknown. We propose to assess whether KIR/HLA allotypes and TLR polymorphisms are associated with persistent T cell activation (% CD38+ HLA-DR+ CD8+ T cells) and the rate of CD4+ T cell recovery in 400 HIV-infected Ugandans maintaining viral suppression on their first antiretroviral treatment regimen and followed every 3 months for a median of 24 months. We will perform these studies using samples from the well- characterized UARTO cohort in Mbarara, Uganda (a representative cohort of HIV- infected Ugandans intiating antiretroviral therapy) and in collaboration with the Carrington lab at NCI-Frederick; the UCSF Genomics Core Facility; and the Cao Laboratory in Kampala, Uganda. This work will help identify inflammatory pathways influencing treatment-mediated CD4+ T cell recovery, identifying targets for interventions to optimize the effectiveness of antiretroviral therapy in sub-Saharan Africa. PUBLIC HEALTH RELEVANCE: While millions of HIV-infected patients in sub-Saharan Africa are finally receiving life- saving HIV medications, death rates remain high, and many fail to regain normal immune function. Excessive stimulation of the innate immune system by residual HIV replication and other prevalent infections like tuberculosis and malaria may prevent full recovery of the immune system in these patients. This research project will help identify inflammatory pathways that prevent immune system recovery in these patients, eventually leading to targeted interventions to improve immune system recovery.

描述（由申请人提供）：虽然撒哈拉以南非洲数百万艾滋病毒感染患者目前正在接受挽救生命的抗逆转录病毒治疗，但早期死亡率远高于预期，CD4+ T细胞恢复的程度变化很大。了解CD4+ T细胞恢复的预测因素对于优化撒哈拉以南非洲地区抗逆转录病毒治疗方案的有效性非常重要。我们假设持续的广义T细胞激活是撒哈拉以南非洲地区CD4+ T细胞恢复迟钝的重要决定因素。在抗逆转录病毒抑制性治疗期间，T细胞活化显著下降，但在资源丰富的环境中，它仍然异常升高，并与CD4+ T细胞恢复迟钝有关。虽然T细胞活化的决定因素尚不清楚，但通过残留的HIV复制和其他共感染刺激先天免疫反应可能是机制。HIV和合并感染可能通过杀伤免疫球蛋白样受体(KIR) -人白细胞抗原（HLA）相互作用和结合toll样受体（TLR）激活自然杀伤（NK）细胞，从而刺激先天免疫反应。在未经治疗的HIV-1感染期间，一些KIR/HLA同种异体和TLR多态性与对HIV和普遍合并感染的先天免疫反应的激活或抑制以及临床进展有关。在抑制性抗逆转录病毒治疗期间，这些宿主遗传因素是否与T细胞活化和CD4+ T细胞恢复有关尚不清楚。我们建议评估400名乌干达hiv感染者在第一次抗逆转录病毒治疗方案中保持病毒抑制，每3个月随访一次，中位时间为24个月，KIR/HLA同种异体和TLR多态性是否与持续T细胞激活（% CD38+ HLA- dr + CD8+ T细胞）和CD4+ T细胞恢复率相关。我们将与NCI-Frederick的卡灵顿实验室合作，使用来自乌干达姆巴拉拉的特征明确的UARTO队列（开始抗逆转录病毒治疗的艾滋病毒感染乌干达人的代表性队列）的样本进行这些研究；加州大学旧金山分校基因组学核心设施；以及乌干达坎帕拉的Cao实验室。这项工作将有助于确定影响治疗介导的CD4+ T细胞恢复的炎症途径，确定干预目标，以优化撒哈拉以南非洲抗逆转录病毒治疗的有效性。公共卫生相关性：虽然撒哈拉以南非洲数百万艾滋病毒感染者最终接受了挽救生命的艾滋病毒药物，但死亡率仍然很高，许多人未能恢复正常的免疫功能。残留的HIV复制和其他流行感染（如结核病和疟疾）对先天免疫系统的过度刺激可能会阻止这些患者免疫系统的完全恢复。该研究项目将有助于确定阻止这些患者免疫系统恢复的炎症途径，最终导致有针对性的干预措施，以改善免疫系统的恢复。