Immune Activation in Virologically Suppressed Indian HIV-infected Patients

描述(申请人提供)：有了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一直在稳步增加，但通常会因过早出现非艾滋病的并存疾病，如心血管疾病(CVD)而复杂化，这归因于免疫激活(IA)的持续，尽管血浆病毒被抑制到无法检测的水平。持续性IA的一个机制是肠道微生物易位(MT)，这是由于HIV感染早期与HIV相关的肠道损伤引起的，但为什么肠道恢复延迟尚不清楚。虽然我们知道HIV在感染早期就建立了宿主，需要终身不间断的治疗来防止病毒反弹，但我们的研究表明，尽管血浆病毒受到抑制，但LLVR实际上正在发生，而且它与IA有关。目前尚不清楚病毒库本身是否直接或间接地推动了免疫激活。我们建议印度金奈YRGCARE的研究人员和美国迈阿密大学的研究人员合作，以检验一项新的假设，即接受CART治疗的血浆病毒血症被抑制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。我们进一步假设，较低的CD4值与更大的病毒库大小、免疫激活、并存疾病和较差的免疫重建有关。目的1将确定ART抑制患者的CD4T细胞中病毒储存库的大小和残留病毒的复制水平；将量化总的和未整合的HIV DNA，并在体外评估CD4T细胞对HIV的诱导作用。在目标2中，免疫激活水平将通过血浆炎性细胞因子、内皮激活标志物、MT和细胞表型的测量来评估。在目标3中，将研究DEIR CD4对病毒库、免疫激活、免疫重建和心血管疾病证据的影响。为达到这些目的，将对服用CART 48周的患者进行横断面研究，其中40份血浆VL&lt；具有不同的最低CD4计数。这项研究将在YRGCARE建立新的最先进的免疫学和病毒学分析方法，提供具有全球相关性的初步数据，并为未来的合作研究做好准备，包括旨在根除宿主和治愈艾滋病毒/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.