Tissue and Cell Reservoirs for HIV

HIV 的组织和细胞库

• 批准号: 7162104
• 负责人: SUZANNE GARTNER
• 金额: $ 48.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162104
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; Antiretroviral resistance; Attention; Biopsy; Biopsy Specimen; Blood; Blood Circulation; Bone Marrow; Brain; CD4 Positive T Lymphocytes; Cells; Cerebrospinal Fluid; Cervical lymph node group; Clinical; Code; Complement; Coupled; Data; Dementia; Dendritic Cells; Development; Disease; Disease Progression; Distant; Drug-sensitive; Event; Failure; Flow Cytometry; Follicular Dendritic Cells; Genes; Genetic; Genome; Genotype; HIV; HIV Infections; HIV drug resistance; Highly Active Antiretroviral Therapy; Immunohistochemistry; Immunologics; Impaired cognition; Incidence; Infection; Investigation; Lead; Left; Longevity; Lymphoid Tissue; Macrophage Activation; Marrow; Methods; Mononuclear; Mutation; Neuraxis; Numbers; Pathway interactions; Patients; Pattern; Plasma; Population; Protease Gene; Publishing; Quality of life; RNA-Directed DNA Polymerase; Reporting; Resistance; Route; Seeds; Site; Source; Specimen; Staging; Structure of germinal center of lymph node; T-Lymphocyte; Tissues; Venous; Viral; Virion; Withdrawal; arachnoid villi; base; bone; drug resistant virus; improved; latent infection; lymph nodes; macrophage; monocyte; particle; success; trafficking; transmission process

Success in treating HIV/AIDS is critically dependent upon a thorough and accurate understanding of occult infection---where and how HIV persistence is maintained. This proposal focuses on the macrophage and follicular dendritic cell (FDC) as cellular reservoirs for HIV, and bone marrow and brain as tissue reservoirs. Although they have received comparatively little attention, these cell and tissue compartments most probably represent HIV reservoirs of considerable significance. Importantly, each appears capable of serving as a sanctuary for latent HIV infection. We propose here to determine if, indeed, these cells and tissues can serve as latently-infected hosts able to yield infectious particles that can seed the body. We seek to identify patterns of HIV trafficking between lymphoid tissues and the Central Nervous System, and determine if the brain can reseed the periphery with HIV. We also seek to identify cell and tissue reservoirs for antiretroviral drug-sensitive, versus drug-resistant, HIV. For these studies, HIV genotyping will be performed using contemporaneously-collected ante-mortem bone marrow and excisional cervical lymph node biopsy specimens, in conjunction with patient-matched plasma, cerebrospinal fluid (CSF), and separated blood monocyte and T-lymphocyte specimens collected concomitantly, as well as prior to, and following biopsy. Two regions of the HIV genome will be examined, the V1-V4 region of the envelope gene, and a 1.2kb fragment which includes the protease gene and that portion of the reverse transcriptase gene which codes for most of the antiretroviral resistance mutations of significance. To optimally address the question of whether the brain can seed the periphery with HIV, we will evaluate the HIV species present not only within the lymph node (LN) CD4+ T-cell population, but also those associated with LN germinal center follicular dendritic cells (FDC). These investigations will be complemented with studies of post-mortem tissues. In addition, we seek to identify events in bone marrow associated with systemic virologic failure. Attention will be paid to HIV expression and monocyte/macrophage activation in marrow. Immunohistochemistry and flow cytometry methods will be used. These studies will yield important new information regarding HIV reservoirs, as well as the contributions of events in bone marrow to HIV immunopathogenesis and disease progression.

治疗艾滋病毒/艾滋病的成功关键取决于对神秘性的彻底和准确的理解。 感染--在哪里以及如何维持艾滋病毒的持久性。该提案的重点是巨噬细胞和 滤泡树突状细胞（FDC）作为HIV的细胞库，以及骨髓和脑作为组织库。 虽然它们受到的关注相对较少，但这些细胞和组织隔室很可能 代表着相当重要的艾滋病病毒储存库。重要的是，每一个似乎都能够作为一个 潜伏艾滋病毒感染者的避难所。我们在这里提出，以确定是否，确实，这些细胞和组织可以服务于 作为潜伏感染的宿主，能够产生感染性粒子，从而在身体中传播。我们试图找出 HIV在淋巴组织和中枢神经系统之间的运输模式，并确定 大脑可以将艾滋病毒植入大脑外围。我们还寻求确定抗逆转录病毒的细胞和组织储存库 对药物敏感的，对耐药的，艾滋病病毒。对于这些研究，将使用以下方法进行HIV基因分型： 同时收集死前骨髓和切除颈部淋巴结活检 标本，连同患者匹配血浆、脑脊液（CSF）和分离血液 同时、活检前后采集单核细胞和T淋巴细胞标本。 HIV基因组的两个区域将被检查，包膜基因的V1-V4区域，和一个1.2kb的区域。 该片段包括蛋白酶基因和逆转录酶基因的编码 对于大多数抗逆转录病毒的耐药突变的意义。为了最佳地解决 无论大脑是否能将艾滋病病毒植入外周，我们将评估不仅存在于大脑内部的艾滋病病毒种类， 淋巴结（LN）CD 4 + T细胞群，以及与LN生发中心滤泡相关的那些 树突状细胞（FDC）。这些调查将辅之以对死后组织的研究。在 此外，我们试图确定与全身病毒学失败相关的骨髓事件。注意力将 与骨髓中HIV表达和单核/巨噬细胞活化有关。免疫组化和流式 将使用细胞计数法。这些研究将产生关于艾滋病毒宿主的重要新信息， 以及骨髓中的事件对HIV免疫发病机制和疾病进展的贡献。