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

虽然撒哈拉以南非洲数百万艾滋病毒感染者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，CD 4 + T细胞恢复的程度差异很大。了解CD 4 + T细胞恢复的预测因素对于优化撒哈拉以南非洲抗逆转录病毒治疗项目的有效性非常重要。我们假设，持续的广义T细胞活化是一个重要的决定因素钝化的CD 4 + T细胞在撒哈拉以南非洲的恢复。虽然T细胞活化在抑制性抗逆转录病毒治疗期间显著下降，但它仍然异常升高，并且与资源丰富环境中的钝化CD 4 + T细胞恢复相关。虽然T细胞活化的决定因素仍然未知，但通过残留的HIV复制和其他合并感染刺激先天免疫应答是可能的机制。HIV和合并感染可通过杀伤免疫球蛋白样受体（KIR）-人白细胞抗原（HLA）相互作用激活自然杀伤（NK）细胞和通过结合Toll样受体（TLR）来刺激先天性免疫应答。几种KIR/HLA同种异型和TLR多态性与对HIV的先天免疫应答的激活或抑制和流行的合并感染以及与未经治疗的HIV-1感染期间的临床进展相关。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CD 4 + T细胞恢复相关仍不清楚。我们建议评估KIR/HLA同种异型和TLR多态性是否与持续的T细胞活化（%CD 38 + HLA-DR+ CD 8 + T细胞）和CD 4 + T细胞恢复率相关，400名HIV感染的乌干达人在首次抗逆转录病毒治疗方案中维持病毒抑制，并每3个月随访一次，中位数为24个月。我们将使用来自乌干达姆巴拉拉的充分表征的UARTO队列（启动抗逆转录病毒治疗的HIV感染乌干达人的代表性队列）的样本，并与NCI-Frederick的Carrington实验室、UCSF基因组学核心设施和乌干达坎帕拉的Cao实验室合作进行这些研究。这项工作将有助于确定影响治疗介导的CD 4 + T细胞恢复的炎症途径，确定干预措施的目标，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治疗，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，以改善免疫系统恢复。

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.