Pathogenesis and Treatment of HIV Infection

HIV感染的发病机制和治疗

基本信息

批准号：
9774720
负责人：
H. Clifford Lane
金额：
$ 166.41万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9774720
关键词：
Acquired Immunodeficiency Syndrome Age Analysis of Covariance Animals Biological Markers Blood Blood Vessels Brain Brain imaging CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cell Count Cell Survival Cells Cerebrospinal Fluid Cessation of life Clinical Coagulation Process DNA Data Development Disease Progression Environment Event Fibrin fragment D Gender Genome HIV HIV Infections Homeostasis Imagery Immune Immune system Immunization Immunoglobulin Fragments Immunologic Deficiency Syndromes Immunosuppression Individual Inflammation Inflammatory Injury Interleukin-6 Interruption Knowledge L Cells Label Lymph Node Tissue Lymphocyte Lymphocyte Count Lymphoid Tissue Measures Modeling Participant Pathogenesis Patients Pharmaceutical Preparations Plasma Production Proteins Proviruses RNA RNA Viruses Randomized Risk SIV Secondary to T-Lymphocyte Viremia Virus Virus Replication antiretroviral therapy arm clinical predictors clinical risk cohort cytokine fluorodeoxyglucose positron emission tomography follow-up glucose metabolism immune reconstitution in vivo imaging innovation lymph nodes novel peripheral blood reconstitution simian human immunodeficiency virus therapeutic target trafficking treatment group treatment trial

项目摘要

The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that patients with HIV infection treated early (CD4+ >500 cells/L) with combination antiretroviral therapy (cART) did better than patients treated late (CD4+ <350 cells/L or AIDS) with respect to development of AIDS-related and serious non-AIDS related illnesses. In the present study we investigated associations of biomarkers of inflammation, coagulation, and vascular injury biomarkers with clinical manifestations of disease progression (AIDS and serious non-AIDS illnesses) or death, and the impact of early initiation of cART on these biomarkers. Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Baseline biomarker levels were measured on 4299 START participants (92% of the entire cohort). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with the combined risk for AIDS, serious non-AIDS illnesses or death, as well as the individual components of AIDS and serious non-AIDS events (HRs ranged 1.37-1.41 per 2-fold increase in either marker). This finding was independent of baseline CD4+ count, HIV-RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%. These data demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-nave and treated and identify IL-6 and D-dimer as potential therapeutic targets. The peripheral blood represents only a small fraction of the total number of lymphocytes in the body. To develop a more thorough understanding of T cell dynamics, including the effects of SIV/SHIV/HIV infection on immune cell depletion and immune reconstitution following combination antiretroviral therapy (cART), one needs to utilize approaches that allow direct visualization of lymphoid tissues. In the present study, noninvasive in vivo imaging of the CD4+ T cell pool using a labelled and-CD4 antibody fragment has revealed that at 4 weeks following initiation or interruption of cART, the changes observed in peripheral blood (PB) are primarily related to changes in the whole-body CD4 pool rather than changes in lymphocyte trafficking. The timing of lymph node tissue reconstitution was found to be random among clusters of lymph nodes within the same host and lymph nodes did not reconstitute to the same level seen in healthy controls. In contrast, a statistically significant increase in the size of the splenic CD4+T cell pool was consistently seen as early as 4 weeks after the initiation of cART and splenic CD4 pools appeared similar between treated, infected animals and healthy controls. Overall, our data suggest that the dynamics of the CD4+ cell pool following initiation or interruption of ART in SIV-infected NHPs are only approximated by the dynamics observed in peripheral blood CD4 counts. In a related study, using FDG PET imaging of the brain, discontinuation of cART was associated with increased brain glucose metabolism in association with increased levels of pro-inflammatory cytokines in the spinal fluid.

抗逆转录病毒治疗的战略时机 (START) 试验表明，早期接受联合抗逆转录病毒治疗 (cART) 治疗的 HIV 感染患者（CD4+ >500 个细胞/L）比晚期接受联合抗逆转录病毒治疗（CD4+ <350 个细胞/L 或艾滋病）的患者效果更好。尊重艾滋病相关疾病和严重的非艾滋病相关疾病的发展。在本研究中，我们调查了炎症、凝血和血管损伤生物标志物的生物标志物与疾病进展（艾滋病和严重的非艾滋病疾病）或死亡的临床表现的关联，以及早期开始 cART 对这些生物标志物的影响。在随机化前和第 8 个月时对储存的血浆进行生物标志物测量。基线生物标志物与事件风险的关联通过 Cox 回归进行估计，跨组汇总，根据年龄、性别和治疗组进行调整，并按区域分层。使用协方差模型分析（根据进入时的水平进行调整）来估计和比较立即和延迟 ART 组之间 8 个月的平均变化。对 4299 名 START 参与者（占整个队列的 92%）测量了基线生物标志物水平。平均随访时间为 3.2 年。 IL-6 和 D-二聚体水平较高是唯一与艾滋病、严重非艾滋病疾病或死亡的综合风险以及艾滋病和严重非艾滋病事件的各个组成部分相关的生物标志物（HR 范围为 1.37-1.41）任一标记每增加 2 倍）。这一发现与基线 CD4+ 计数、HIV-RNA 水平和其他生物标志物无关。第 8 个月时，直接治疗组的生物标志物水平降低了 12%-21%。这些数据表明，IL-6 和 D-二聚体能够一致地预测未接受 ART 和已接受 ART 治疗的患者的广泛 CD4 计数的临床风险，并将 IL-6 和 D-二聚体确定为潜在的治疗靶点。外周血仅占体内淋巴细胞总数的一小部分。为了更全面地了解 T 细胞动力学，包括 SIV/SHIV/HIV 感染对联合抗逆转录病毒治疗 (cART) 后免疫细胞耗竭和免疫重建的影响，需要利用能够直接观察淋巴组织的方法。在本研究中，使用标记的和-CD4 抗体片段对 CD4+ T 细胞库进行无创体内成像表明，在开始或中断 cART 后 4 周，外周血 (PB) 中观察到的变化主要与全身 CD4 池的变化而不是淋巴细胞运输的变化。发现同一宿主内的淋巴结簇之间淋巴结组织重建的时间是随机的，并且淋巴结没有重建到健康对照中所见的相同水平。相比之下，早在 cART 开始后 4 周，脾脏 CD4+T 细胞库的大小就一直出现统计学上显着的增加，并且在治疗的感染动物和健康对照之间，脾脏 CD4 细胞库看起来相似。总体而言，我们的数据表明，SIV 感染的 NHP 中 ART 开始或中断后 CD4+ 细胞库的动态仅通过外周血 CD4 计数中观察到的动态来近似。在一项相关研究中，使用大脑 FDG PET 成像发现，cART 的终止与大脑葡萄糖代谢增加以及脊髓液中促炎细胞因子水平增加有关。