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（Start）试验的策略时机表明，使用抗逆转录病毒疗法（CART）治疗的HIV感染患者（CD4+> 500个细胞/L）比治疗的患者（CD4+ <350细胞/L或AIDS）在与AIDS相关的和严重的非AIDS相关疾病的发展方面更好。在本研究中，我们调查了炎症，凝结和血管损伤生物标志物与疾病进展的临床表现（AIDS和严重的非AIDS疾病）或死亡的临床表现的关联，以及购物车对这些生物标志物的早期启动的影响。生物标志物是在随机分组之前从存储的血浆中测量的。在第8个月中，基线生物标志物与事件风险的关联估计与COX回归估计，跨组汇总，对年龄，性别和治疗组进行了调整，并按地区分层。使用协方差模型的分析，对8个月的平均变化进行了估算，并在直接和递延的ART ARM之间进行了比较，并针对进入水平进行了调整。在4299名参与者（整个队列的92％）上测量了基线生物标志物水平。平均随访时间为3。2年。较高水平的IL-6和D-二聚体是与艾滋病，严重的非辅助疾病或死亡的综合风险以及艾滋病和严重非AIDS事件的个体组成部分相关的唯一生物标志物（HRS的范围为1.37-1.41范围为1.37-1.41，每2倍增加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。在第8个月，直接手臂的生物标志物水平较低12％-21％。这些数据表明，IL-6和D-Dimer始终预测那些Art-Nave和Art-Nave的CD4计数中的临床风险，并识别IL-6和D-二聚体作为潜在的治疗靶标。外周血仅占体内淋巴细胞总数的一小部分。为了对T细胞动力学有更透彻的了解，包括SIV/SHIV/HIV感染对抗逆转录病毒疗法（CART）后免疫细胞耗竭和免疫重建的影响，需要采用允许直接可视化淋巴机构组织的方法。在本研究中，使用标记的和CD4抗体片段对CD4+ T细胞池进行无创的体内成像，表明，在开始或中断CART后的4周，外周血（PB）中观察到的变化主要与整体CD4库中的变化相关，而不是整个体体CD4池的变化，而不是在淋巴细胞中的变化。发现淋巴结组织重构的时机在同一宿主内的淋巴结簇中是随机的，淋巴结和淋巴结并未重构为健康对照中看到的相同水平。相比之下，在启动手推车和脾脏CD4池的4周之间，脾脏CD4+T细胞池的尺寸始终在统计学上显着增加，在经过治疗的，受感染的动物和健康对照组之间似乎相似。总体而言，我们的数据表明，仅在周围血液CD4计数中观察到的动力学近似近似于SIV感染的NHP中CD4+细胞池的动力学。在一项相关研究中，使用大脑的FDG PET成像，CART的停用与脑葡萄糖代谢增加有关，脊髓液中促炎性细胞因子的水平增加。