Adipose Tissue is a significant reservoir for HIV

描述（由申请人提供）：细胞储库的持续存在是根除HIV感染的主要障碍。这项建议的目的是确定脂肪组织是否含有广泛的，但迄今未被怀疑的艾滋病毒水库。我们的假设是基于以下几点：1）T细胞和巨噬细胞在功能失调的脂肪组织中增加（如在HIV患者中）; 2）脂肪组织T细胞被激活，产生加速脂解的细胞因子，这增强了流入; 3）在功能失调的脂肪组织中，记忆T细胞增加，而T细胞减少; 4）脂肪细胞产生因子（IL 6和VLA-1配体）激活记忆性CD 4 + T细胞，增加HIV复制和存活力; 5）HIV DNA（不同的env序列）存在于血浆病毒载量检测不到的患者的脂肪组织的基质血管区室中; 6）脂肪细胞可以隔离亲脂性cART药物和HIV感染的细胞。 在R21阶段，提出了以下具体目的：1）在来自经治疗的HIV感染者的脂肪组织样品中鉴定：a）在基质血管区室中整合的HIV DNA、HIV mRNA和有复制能力的HIV; B）免疫细胞的功能; c）激活免疫细胞的脂肪细胞因子; 2）确定与来自SIV感染的恒河猴的外周血相比，在脂肪组织中的SIV RNA、SIV DNA的序列以及T细胞表型和应答; 3）确定当前药物在体外脂肪细胞和人脂肪样品中的渗透。 在R33阶段，我们将定义脂肪组织储库持久性的潜在机制，并通过以下具体目标测试靶向治疗以克服这一障碍：1）通过测量SIV RNA的水平、SIV DNA的序列和复制能力以及脂肪组织内的T细胞表型和应答，确定感染恒河猴后SIV接种的时间，2）在慢性SIV感染的恒河猴中，确定目前的cART药物是否在脂肪组织的脂肪细胞和基质血管区室中积累，并根除SIV; 3）确定绕过脂肪细胞隔离或克服脂肪细胞隔离的新药物是否是有效的。受感染免疫细胞的诱导存活力消除了该储库中的SIV。 在脂肪组织中的HIV储库的临床影响是相当大的，占多达1 - 5x 108个HIV感染的免疫细胞。我们的合作调查小组的专家在艾滋病毒免疫学，艾滋病毒相关的脂肪/脂质生物学，SIV/猕猴研究和艾滋病毒药理学将调查一个创新的假设高度响应TaPHIR。

DESCRIPTION (provided by applicant): Persistence of cellular reservoirs is a major obstacle to eradication of HIV infection. The goal of this proposal is to determine whether adipose tissue contains an extensive but hitherto unsuspected HIV reservoir. Our hypothesis is based on the following: 1) T cells and macrophages are increased in dysfunctional adipose tissues (as in HIV patients); 2) Adipose tissue T cells are activated, producing cytokines that accelerate lipolysis, which enhances influx; 3) Memory T cells are increased, whereas Tregs are reduced, in dysfunctional adipose tissue; 4) Adipocytes produce factors (IL6 and VLA-1 ligands) to activate memory CD4+ T cells with increased HIV replication and viability; 5) HIV DNA (distinct env sequences) is in the stromal vascular compartment of adipose tissues in patients with undetectable plasma viral load; 6) Adipocytes may sequester lipophilic cART drugs and to HIV-infected cells. In the R21 phase the following Specific Aims are proposed: 1) Identify, in adipose tissue samples from treated HIV-infected persons with undetectable plasma viral load: a) integrated HIV DNA, HIV mRNA and replication-competent HIV in the stromal vascular compartment; b) function of immune cells; c) adipocyte factors that activate immune cells; 2) Determine, in adipose tissues compared with peripheral blood from SIV-infected rhesus macaques, SIV RNA, sequences of SIV DNA, and T cell phenotypes and responses; 3) Determine penetration of current drugs in adipose cells in vitro and in human adipose samples. In the R33 phase, we will define mechanisms underlying persistence of the adipose tissue reservoir and test targeted therapies to overcome this barrier, through the following Specific Aims: 1) Determine the timing of seeding of SIV after infection of rhesus macaques by measuring levels of SIV RNA, sequences and replication competence of SIV DNA, and T cell phenotypes and responses within adipose tissues, associated lymph nodes and peripheral blood; 2) Determine, in chronically SIV-infected rhesus macaques, whether current cART drugs accumulate in the adipocyte and stromal vascular compartments of adipose tissues, and eradicate SIV; 3) Determine whether novel drugs that bypass adipocyte sequestration or overcome adipocyte-induced viability of infected immune cells eradicate SIV in this reservoir. The clinical impact of an HIV reservoir in adipose tissue is considerable, accounting for as many as 1 - 5 x 108 HIV-infected immune cells. Our collaborative investigative team of specialists in HIV immunology, HIV-related adipose/lipid biology, SIV/macaque research and HIV pharmacology will investigate an innovative hypothesis highly responsive to the TaPHIR.