Immune Activation in Virologically Suppressed Indian HIV-infected Patients

描述（由申请人提供）：使用有效的新型联合抗逆转录病毒疗法（cART），HIV感染者的寿命一直在稳步延长，但通常因非AIDS合并症（如心血管疾病（CVD））的过早发作而变得复杂，这归因于免疫激活（IA）的持续性，尽管血浆病毒被抑制至不可检测的水平。持续性IA的一个机制是在HIV感染早期由HIV相关的肠道损伤引起的肠道微生物易位（MT），但肠道恢复延迟的原因尚不清楚。虽然已知HIV在感染早期建立储库，需要终身不间断治疗以防止病毒反弹，但我们的研究表明，尽管血浆病毒受到抑制，但LLVR实际上仍在发生，并且与IA相关。病毒宿主本身是否直接或间接驱动免疫激活尚不清楚。我们提议印度钦奈YRGCARE和美国迈阿密迈阿密大学的研究人员建立合作伙伴关系，以研究一种新的假设，即患有抑制性血浆病毒血症的cART患者继续存在持续的低水平病毒复制，从而驱动免疫激活和肠道损伤。此外，我们假设较低的CD 4最低值与较大的病毒库大小、免疫激活、共病和较差的免疫重建相关。目的1将确定接受抑制性ART的患者的CD 4 T细胞中病毒库的大小和残留病毒复制水平;将定量总的和未整合的HIV DNA，并评价CD 4 T细胞的体外HIV诱导。在目标2中，将通过炎性细胞因子、内皮活化标志物、MT和细胞表型的血浆测量来评估免疫活化水平。在目标3中，将研究最低CD 4对病毒储库、免疫激活、免疫重建和CVD证据的影响。为了这些目的，将在接受cART>48周、血浆VL<40拷贝且具有不同最低CD 4计数的患者中进行横断面研究。这项研究将在YRGCARE建立新的最先进的免疫学和病毒学检测方法，提供全球相关的初步数据，并为未来的合作研究做好准备，包括旨在消除水库和治愈艾滋病毒/艾滋病的研究。

DESCRIPTION (provided by applicant): With potent new combination antiretroviral therapies (cART), the life-span of HIV-infected persons has been steadily increasing, but is often complicated by premature onset of non-AIDS co-morbidities such as cardiovascular disease (CVD), attributed to persistence of immune activation (IA) despite suppression of plasma virus to undetectable levels. One mechanism of persistent IA is gut microbial translocation (MT) resulting from HIV-associated gut damage early in HIV infection, but why the gut recovery is delayed is unclear. While it is known that HIV establishes reservoirs early in infection necessitating life-long uninterrupted therapy to prevent virus rebound, our studies suggest that LLVR is in fact occurring despite plasma virus suppression and that it is associated with IA. Whether the virus reservoir per se is driving immune activation directly or indirectly is unknown. We are proposing a partnership between investigators in YRGCARE in Chennai, India and University of Miami, in Miami USA to examine a novel hypothesis that patients on cART with suppressed plasma viremia continue to have persistent low level virus replication that drives immune activation and gut damage. Further we hypothesize that lower nadir CD4 is associated with greater virus reservoir size, immune activation, co-morbidity and poorer immune reconstitution. Aim 1 will determine the size of virus reservoir and level of residual viral replication in CD4 T cells of patients on suppressive ART; total and unintegrated HIV DNA will be quantified and CD4 T cells evaluated for HIV induction ex-vivo. In aim 2, level of immune activation will be assessed by plasma measures of inflammatory cytokines, endothelial activation markers, MT, and cellular phenotyping. In aim 3, the impact of nadir CD4 on virus reservoirs, immune activation, immune reconstitution and evidence of CVD will be investigated. For these aims, a cross-sectional study in patients on cART for>48 weeks, plasma VL<40 copies with varying nadir CD4 counts will be conducted. This study will establish novel state of the art immunology and virology assays at YRGCARE, provide preliminary data of global relevance and prepare us for future collaborative research, including studies aimed at eradicating reservoirs and curing HIV/AIDS.