Adipose Tissue is a significant reservoir for HIV

脂肪组织是艾滋病毒的重要储存库

• 批准号: 8842411
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 25.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842411
• 关键词: Accounting; Adipocytes; Adipose tissue; Anti-Retroviral Agents; Antiviral Agents; B-Lymphocytes; Biology; Blood Vessels; Bypass; CD4 Positive T Lymphocytes; Cell Communication; Cells; Characteristics; Clinical; Competence; DNA; Dendritic Cells; Drug Formulations; Effectiveness; Fatty acid glycerol esters; Goals; Grant; HIV; HIV Infections; HIV-1; Human; IL6 gene; Immune; Immune system; Immunologist; Immunology; In Vitro; Infection; Lead; Ligands; Lipids; Lipolysis; Macaca; Macaca mulatta; Measures; Memory; Messenger RNA; Modeling; Monkeys; Natural Killer Cells; Nature; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Plasma; Prodrugs; RNA Sequences; Research; Research Personnel; SIV; Sampling; Specialist; System; T memory cell; T-Lymphocyte; Testing; Time; Tissue Sample; Tissues; Viral; Viral Load result; Virus; antiretroviral therapy; base; cytokine; immune function; improved; innovation; integrin alpha1beta1; lymph nodes; macrophage; memory CD4 T lymphocyte; novel; peripheral blood; prevent; public health relevance; response; time interval

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.

描述（由申请人提供）：细胞储存库的持续存在是根除 HIV 感染的主要障碍。该提案的目标是确定脂肪组织是否含有广泛但迄今为止未被怀疑的艾滋病毒储存库。我们的假设基于以下几点：1）功能失调的脂肪组织（如 HIV 患者）中 T 细胞和巨噬细胞增加； 2）脂肪组织T细胞被激活，产生加速脂肪分解的细胞因子，从而增强流入； 3) 在功能失调的脂肪组织中，记忆T细胞增加，而Treg细胞减少； 4) 脂肪细胞产生因子（IL6和VLA-1配体）来激活记忆CD4+ T细胞，从而增加HIV复制和活力； 5) HIV DNA（不同的 env 序列）存在于血浆病毒载量不可检测的患者的脂肪组织的基质血管区室中； 6) 脂肪细胞可能会隔离亲脂性 cART 药物和 HIV 感染细胞。 在 R21 阶段，提出了以下具体目标： 1) 在来自接受治疗的 HIV 感染者的脂肪组织样本中，鉴定血浆病毒载量不可检测的情况： a) 在基质血管区室中整合 HIV DNA、HIV mRNA 和具有复制能力的 HIV； b) 免疫细胞的功能； c) 激活免疫细胞的脂肪细胞因子； 2) 与感染SIV的恒河猴的外周血相比，确定脂肪组织中的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体脂肪样本中的渗透。 在 R33 阶段，我们将通过以下具体目标，定义脂肪组织储库持久性的潜在机制，并测试克服这一障碍的靶向治疗：1) 通过测量 SIV RNA 水平、SIV DNA 序列和复制能力以及脂肪组织内的 T 细胞表型和反应，确定恒河猴感染后 SIV 的接种时机，相关 淋巴结和外周血； 2) 确定在长期感染SIV的恒河猴中，当前的cART药物是否在脂肪组织的脂肪细胞和基质血管室中积聚，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能否根除该储存库中的 SIV。 脂肪组织中的 HIV 储存库的临床影响相当大，多达 1 - 5 x 108 个 HIV 感染的免疫细胞。我们的合作研究团队由 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，将研究对 TaPHIR 高度敏感的创新假设。