Adipose Tissue is a significant reservoir for HIV

描述(申请人提供)：细胞储存库的持久性是根除艾滋病毒感染的主要障碍。这项提议的目标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宿主。我们的假说基于下列情况：1)功能失调的脂肪组织中T细胞和巨噬细胞增加(与HIV患者一样)；2)脂肪组织的T细胞被激活，产生加速脂解的细胞因子，从而促进内流；3)在功能障碍的脂肪组织中，记忆T细胞增加，而Tregs减少；4)脂肪细胞产生因子(IL6和VLA-1配体)以激活记忆的CD4+T细胞，从而增加艾滋病毒的复制和活性；5)HIV DNA(不同的env序列)位于无法检测到血浆病毒载量的患者脂肪组织的间质血管中；6)脂肪细胞可能会隔离亲脂药物和对HIV感染的细胞。在R21阶段，建议了以下具体目标：1)在接受治疗但血浆病毒载量无法检测到的艾滋病毒感染者的脂肪组织样本中，确定：a)整合艾滋病毒DNA、艾滋病毒mRNA和具有复制能力的艾滋病毒在间质血管中的作用；b)免疫细胞的功能；c)激活免疫细胞的脂肪细胞因子；2)测定脂肪组织中SIV RNA、SIV DNA序列以及T细胞表型和反应；3)确定当前药物在体外脂肪细胞和人类脂肪样本中的渗透性。在R33阶段，我们将确定脂肪组织储存库持续存在的机制，并通过以下具体目标测试克服这一障碍的靶向治疗：1)通过测量SIV RNA水平、SIV DNA的序列和复制能力以及脂肪组织、相关淋巴结和外周血中T细胞的表型和反应，确定恒河猴感染SIV的时机；2)确定在慢性SIV感染的恒河猴体内，当前的CART药物是否在脂肪组织的脂肪细胞和间质血管中积累，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性的新药是否能根除这个储存库中的SIV。脂肪组织中的艾滋病毒蓄积物对临床的影响是相当大的，可产生多达1-5×108个艾滋病毒感染的免疫细胞。我们由HIV免疫学、HIV相关脂肪/脂质生物学、SIV/猕猴研究和HIV药理学专家组成的合作研究团队将研究一种对TaPHIR高度响应的创新假说。

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.