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: 3853290
• 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/3853290
• 关键词: AIDS; B lymphocyte; HIV infections; T lymphocyte; gene expression; genetic transcription; human T cell leukemia; human T cell lymphotropic virus type 1; human immunodeficiency virus 1; human tissue; latent virus infection; macrophage; messenger RNA; provirus; transcription factor; virus RNA; virus genetics; virus infection mechanism; virus protein; virus replication

To better understand the effects of host cells 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, and restricted viral expression for both HTLV-I and HIV-I. In HTLV-I infected B cells from acute T cell leukemia (ATL) patients, very few 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 poorly expressed. Also, the macrophage, a reservoir of HIV-I infection in 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 these host 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.

为了更好地了解宿主细胞和其他病毒对 病毒复制以及感染细胞和病毒之间的相互作用 我们开发的免疫系统的病毒潜伏期的体外模型， 以及HTLV-I和HIV-I的限制性病毒表达。在HTLV-I中 来自急性T细胞白血病(ATL)患者的感染B细胞，非常少 病毒的mRNAs正在转录，但整合的前病毒是有功能的 并可被激活以转化其他T和B细胞。当病毒 感染T细胞，病毒被表达；当它感染B细胞时，它是 表达不佳。此外，巨噬细胞是HIV-I感染的蓄水池 在艾滋病患者中，被证明能够限制HIV-I的表达。 巨噬细胞株THP-1允许表达HIV-I。 然而，这些受感染的细胞自然不会产生艾滋病毒。 感染后4~6周。两类HIV-I限制性表达 可以看到：1)核内可受因子调节的低水平 2)没有表达，这可能是由于甲基化 LTR的。这两种病毒都会产生反式转正的蛋白质。 调节病毒转录。在这些潜伏感染的文化中， 病毒转录的反式激活被抑制。这表明 这些宿主细胞要么缺乏正性调节因子，要么 拥有病毒转录的负调控因子。了解 病毒表达的负调控因子的作用机制可以是 在开发抗病毒疗法方面很有用。例如，我们已经发现 单核细胞慢性表达的负性调节是由 通过抑制转录因子的结合，核因子-kB与 艾滋病毒增强剂。