Immune Activation in Virologically Suppressed Indian HIV-infected Patients

描述（由申请人提供）：通过强有力的新型抗逆转录病毒联合疗法（cART），艾滋病毒感染者的寿命稳步增加，但往往因非艾滋病合并症的过早发作而复杂化，如心血管疾病（CVD），归因于持续的免疫激活（IA），尽管血浆病毒被抑制到无法检测到的水平。持续性IA的一种机制是在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在感染早期建立了储存库，需要终生不间断的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，LLVR实际上仍在发生，并且它与IA有关。病毒库本身是否直接或间接地驱动免疫激活尚不清楚。我们建议印度金奈的YRGCARE和美国迈阿密大学的研究人员建立合作伙伴关系，以检验一种新的假设，即cART抑制血浆病毒血症的患者继续具有持续的低水平病毒复制，从而驱动免疫激活和肠道损伤。进一步，我们假设较低的最低点CD4与较大的病毒库大小、免疫激活、合并症和较差的免疫重建有关。目的1将确定接受抑制性抗逆转录病毒治疗的患者CD4 T细胞中病毒库的大小和残留病毒复制水平；将对总HIV DNA和未整合HIV DNA进行定量，并对CD4 T细胞进行体外诱导HIV的评估。在目标2中，免疫激活水平将通过血浆测量炎症细胞因子、内皮细胞激活标志物、MT和细胞表型来评估。在目标3中，将调查最低CD4对病毒库、免疫激活、免疫重建和CVD证据的影响。为了达到这些目的，一项横断面研究将在接受cART治疗48周、血浆VL<40拷贝、CD4最低计数不同的患者中进行。这项研究将在YRGCARE建立最新的免疫学和病毒学检测方法，提供具有全球相关性的初步数据，并为我们未来的合作研究做好准备，包括旨在根除储存库和治愈艾滋病的研究。

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.