Adipose Tissue is a significant reservoir for HIV

描述（由申请人提供）：细胞储存库的持久性是根除HIV感染的主要障碍。这项提议的目的是确定脂肪组织是否含有广泛但迄今未被怀疑的HIV储存库。我们的假设基于以下几点：1)T细胞和巨噬细胞在功能失调的脂肪组织中增加（如HIV患者）；2)脂肪组织T细胞被激活，产生加速脂肪分解的细胞因子，从而增强内流；3)功能失调脂肪组织中记忆T细胞增加，treg细胞减少；4)脂肪细胞产生因子（IL6和vla1配体）激活记忆性CD4+ T细胞，增加HIV复制和活力；5)在血浆病毒载量检测不到的患者中，HIV DNA（不同的环境序列）存在于脂肪组织的间质血管间室；6)脂肪细胞可以隔离亲脂性cART药物和hiv感染细胞。在R21阶段，提出了以下具体目标：1)在无法检测血浆病毒载量的治疗HIV感染者的脂肪组织样本中鉴定：a)在基质血管室中整合HIV DNA， HIV mRNA和复制能力HIV；B)免疫细胞功能；C)激活免疫细胞的脂肪细胞因子；2)测定与感染SIV的恒河猴外周血相比，脂肪组织中SIV RNA、SIV DNA序列和T细胞表型和反应；3)测定当前药物在体外脂肪细胞和人体脂肪样品中的渗透。在R33阶段，我们将明确脂肪组织储存库持续存在的机制，并通过以下具体目标来测试克服这一屏障的靶向治疗：1)通过测量SIV RNA水平、SIV DNA序列和复制能力，以及脂肪组织、相关淋巴结和外周血中的T细胞表型和反应，确定恒河猴感染后SIV的接种时间；2)在慢性SIV感染的恒河猴中，确定当前的cART药物是否在脂肪组织的脂肪细胞和间质血管室中积累，并根除SIV；3)确定绕过脂肪细胞隔离或克服脂肪细胞诱导的受感染免疫细胞活力的新药是否能根除该储存库中的SIV。脂肪组织中HIV储存库的临床影响是相当大的，占多达1 - 5 × 108个HIV感染的免疫细胞。我们在HIV免疫学、HIV相关脂肪/脂质生物学、SIV/猕猴研究和HIV药理学方面的专家合作调查团队将研究一个对TaPHIR高度敏感的创新假设。

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.