INTERACTIONS OF HUMAN RETROVIRUSES WITH HEMATOPOIETIC AND ADHERENT CELLS

人类逆转录病毒与造血细胞和贴壁细胞的相互作用

• 批准号: 3874507
• 负责人: F W RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874507
• 关键词: AIDS; B lymphocyte; HIV infections; gene expression; genetic enhancer element; genetic transcription; human T cell leukemia; human T cell lymphotropic virus type 1; human immunodeficiency virus 1; human tissue; latent virus infection; leukocyte activation /transformation; macrophage; messenger RNA; provirus; transcription factor; viral leukemogenesis; virus genetics; virus infection mechanism; virus receptors; virus replication

The human retroviruses, human immunodeficiency virus (HIV-I) and human tumor leukemia virus (HTLV-I), are involved in the pathogenesis of chronic, fatal human diseases. We have attempted to better understand the effects of host cell and other viruses on viral replication as well as the interaction between infected cells and the immune system. We have developed in vitro models of viral latency for both HTLV-I and HIV-I. In HTLV-I infected B cells from acute T cell leukemia (ATL) patients, no viral mRNAs are being transcribed, yet integrated provirus is functional and can be activated to transform other T and B cells. When the virus infects T cells, the virus is expressed; when it infects B cells, it is not expressed. Also, the macrophage, a reservoir of HIV-I infection in acquired immunodeficiency syndrome (AIDS) patients, was shown to be able to restrict HIV-I expression. THP-1, a macrophage cell line, was permissive for HIV-I expression. However, these infected cells become naturally non-productive for HIV 4-6 weeks after infection. Two classes of restricted HIV-I expression were seen: 1) low-level which can be regulated by factors in the nuclei of infected cells and 2) no expression which may be due to methylation of the LTR. Both viruses make proteins which act in trans to positively regulate viral transcription. In these latently infected cultures, transactivation of viral transcription is inhibited. This indicates that the host factors play a role in this transcription and these cells either are deficient in positive regulators or possess negative regulators of viral transcription. Understanding the mechanisms of action of negative regulators of viral expression can be useful in developing anti-viral therapies. For instance we have found that negative regulation of chronic expression in monocytes is mediated through inhibition of binding of the transcription factor, NF-kB to the HIV enhancer.

人类逆转录病毒、人类免疫缺陷病毒(HIV-I)和人类 肿瘤白血病病毒(HTLV-I)参与慢性粒细胞白血病的发病机制， 致命的人类疾病。我们试图更好地理解 宿主细胞和其他病毒对病毒复制以及相互作用的影响 在被感染的细胞和免疫系统之间。我们已经在体外培养出了 HTLV-I和HIV-I的病毒潜伏期模型在HTLV-I感染的B病毒中 来自急性T细胞白血病(ATL)患者的细胞，没有病毒mRNAs 转录的，但整合的前病毒具有功能，可以被激活 转化其他T和B细胞。当病毒感染T细胞时，病毒是 表达；当它感染B细胞时，它不表达。另外， 巨噬细胞，获得性免疫缺陷中HIV-I感染的储存库 综合症(艾滋病)患者，被证明能够限制HIV-I 表情。巨噬细胞系THP-1对HIV-I是允许的 表情。然而，这些被感染的细胞自然变得不能生产 在感染后4-6周进行HIV检测。两类限制性HIV-I 可以看到：1)低水平的，可以被因子调节的 和2)无表达，这可能是由于 LTR的甲基化。这两种病毒都会制造蛋白质，这些蛋白质可以反式作用于 正向调节病毒转录。在这些潜伏感染的人中 培养，病毒转录的反式激活被抑制。这 表明寄主因子在转录中起作用，这些 细胞要么缺乏正性调节因子，要么具有负性 病毒转录的调节者。理解作用机制 病毒表达的负调控因子在发展中可能是有用的 抗病毒疗法。例如，我们发现负面监管 在单核细胞中的慢性表达是通过抑制 转录因子核因子-kB与HIV增强子的结合。