HOST SPECIFIC RESPONSES IN SIV-INDUCED HEMATOSUPPRESSION

SIV 引起的血细胞抑制的宿主特异性反应

• 批准号: 7562568
• 负责人: Silvija I Staprans
• 金额: $ 7.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562568
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Blood Platelets; Bone Marrow; Bone Marrow Cells; Bone Marrow Suppression; CD4 Positive T Lymphocytes; Cercocebus atys; Classification; Computer Retrieval of Information on Scientific Projects Database; Disease; Failure; Funding; Grant; HIV; HIV Infections; HIV-2; Homeostasis; Human; Immune; Immune response; Impairment; Infection; Institution; Intervention; Lead; Lymphopenia; Macaca mulatta; Modeling; Pathway interactions; Play; Research; Research Personnel; Resources; Role; SIV; Site; Source; Staging; T-Cell Proliferation; T-Lymphocyte; Testing; United States National Institutes of Health; Viremia; comparative; nonhuman primate; progenitor; reconstitution; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV disease is characterized by impairment of two key bone marrow (BM) functions: multilineage hemapoiesis and T cell homeostasis. Abnormal hemapoiesis leads to failure of diverse lineages (WBCs, RBCs, platelets, thymic progenitors), while compromised T cell homeostasis contributes to progressive CD4+ T cell loss. It is difficult to study HIV-induced BM suppression in humans, and there are no systematic analyses of the precise stages of hemapoiesis and T cell homeostasis that are altered. Direct HIV infection of BM cells does not appear to play a major role in suppression, pointing to indirect mechanisms of damage. These pathogenic mechanisms can be studied in SIV-infected non-human primates, in particular by comparing the divergent responses of natural and non-natural hosts to SIV infection, and by experimental manipulation to test hypotheses about disease mechanisms. Our studies of SIV-infected sooty mangabeys (SMs), the natural reservoir host from which HIV-2 arose, demonstrate that SMs avoid CD4+ T cell loss and BM suppression despite high viremia. In contrast, SIV infection of the non-natural rhesus macaque (RM) host, recapitulates the BM suppression and lymphopenia seen in human AIDS. In our studies, we also observed that the BM is a site of significant T cell proliferation in healthy, uninfected animals, suggesting a previously unappreciated role for the BM in the homeostasis of T cells. We have developed a comparative infection model, in which SMs and RMs can be infected with the same SIV strain, enabling study of the divergent host responses that lead to BM suppression in RMs, but not in SMs. We use this model to: 1) Identify the stages of hemapoiesis and T cell homeostasis suppressed by pathogenic SIV infection, 2) Identify candidate pathogenic mechanisms of BM suppression, and 3) Probe putative BM-suppressive pathways by specific interventions. Understanding HIV-induced BM suppression will be key for effective hematologic and immune reconstitution strategies.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 HIV疾病的特征在于两个关键骨髓（BM）功能受损：多肾脏hemapoiesis和T细胞稳态。异常的血脑异会导致多种谱系（WBC，RBC，血小板，胸腺祖细胞）的失败，而T细胞稳态受损会导致渐进的CD4+ T细胞损失。很难研究人类中的HIV诱导的BM抑制，并且没有对Hemapoiesis和T细胞稳态的精确阶段进行的系统分析。 BM细胞的直接HIV感染在抑制中似乎并不起主要作用，指出间接的损害机制。可以在SIV感染的非人类灵长类动物中研究这些致病机制，特别是通过将天然和非天然宿主与SIV感染的不同反应进行比较，并通过实验性操纵来测试有关疾病机制的假设。我们对HIV-2产生的天然储层宿主（SMS）的SIV感染烟草芒果（SMS）的研究表明，尽管病毒血症很高，SMS避免了CD4+ T细胞损失和BM抑制。相反，非天然恒河猴（RM）宿主的SIV感染概括了人类艾滋病中的BM抑制和淋巴细胞减少症。在我们的研究中，我们还观察到BM是健康，未感染的动物中显着T细胞增殖的部位，这表明BM在T细胞的稳态中的先前未欣赏的作用。我们已经开发了一种比较感染模型，其中可以用相同的SIV菌株感染SMS和RMS，从而可以研究导致RMS抑制BM但在SMS中抑制BM的不同宿主反应。我们使用此模型来：1）确定因致病性SIV感染抑制的hemapoiesis和T细胞体内平衡的阶段，2）确定BM抑制的候选病原机制，3）通过特定的干预措施探测BM抑制性途径。了解艾滋病毒引起的BM抑制将是有效的血液学和免疫重建策略的关键。