VIRUS-CELL INTERACTIONS AND HOST FACTORS IN HIV PATHOGENESIS

HIV 发病过程中的病毒-细胞相互作用和宿主因素

• 批准号: 5200814
• 负责人: I K HEWLETT
• 金额: --
• 依托单位: BUREAU OF HEALTH PLANNING AND RESOURCES DEVELOPMENT
• 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/5200814
• 关键词: AIDS; HIV infections; RNA directed DNA polymerase; aflatoxins; benzopyrenes; biological signal transduction; cell cell interaction; cellular pathology; chemical carcinogen; cytokine; disease /disorder proneness /risk; environmental toxicology; host organism interaction; human immunodeficiency virus 1; human immunodeficiency virus 2; latent virus infection; macrophage; mutagens; nitrosamines; second messengers; tissue /cell culture; tumor necrosis factor alpha; virus antigen; virus replication

The activation of a latent HIV genome in the U1 cell line was used as a model to study cellular pathways involved in viral replication. Specifically, several chemical carcinogens and environmental mutagens were examined for their ability to induce virus from this cell line also with the objective of identifying risk factors of physiologic relevance that may affect disease progression in AIDS. Enhanced virus production, measured by RT, p24 and PCR analysis, was seen in cells treated with benzopyrene, NNK and aflatoxin B. Viral induction was accompanied by an increase in NF-KB activity and production of cytokines such as TNF-alpha. In the case of aflatoxin, virus induction appeared to be a TNF-a independent mechanism. We are investigating the effects of these agents on signal transduction pathways related to T cell function and activation i.e. phosphorylation, JAK-STAT kinases, and production of cytokines other than TNFa and IL-6 and apoptotic mechanisms that may enhance virus production. Future studies will focus on BP and NNK. The in vivo significance of these findings will be investigated using alveolar macrophages as a model system. In a separate effort, the phenomenon of viral interference will be studied with the goal of identifying cellular pathways using HIV-1 superinfection of HIV-2 infected cells and vice versa. From epidemiologic studies it is known that HIV-2 infection can confer some degree of protection against HIV-1 infection. It will be of interest to identify cellular pathways that may be common to both types of phenomena (i.e. induction and interference). These approaches should enhance our understanding of virus-cell interactions and their impact on viral replication. In vivo studies involving patients from various risk groups who are rapid (RP) or slow progressors (SPs) and some in the early phase of infection have been initiated where virus burden will be evaluated by quantitative PCR and culture. Virus isolated from some RPs, SPs and early seroconverters will be subject to nucleotide analysis in the LTR, gag(p24), RT and env regions. The tropism, pathogenicity and immunological profile of a few selected isolates from RP, SP and patients with primary HIV syndrome will be studied in vitro in T cells and monocytes and in a small animal model. These studies are expected to provide some insights into the biology of isolates in progressive vs. non progressive and in primary HIV infection (early seroconversion).

U1细胞系中潜伏的HIV基因组的激活被用作 用于研究病毒复制所涉及的细胞途径的模型。 具体来说，几种化学致癌物和环境诱变剂 检测了它们从该细胞系诱导病毒的能力， 目的是确定与生理相关的风险因素 这可能会影响艾滋病的病情发展。 增强病毒生产， 通过RT、p24和PCR分析测量，在用 苯并芘、NNK和黄曲霉毒素B。 病毒诱导伴随着 增加NF-κ B活性和细胞因子如TNF-α的产生。 在黄曲霉毒素的情况下，病毒诱导似乎是TNF-α 独立机制。 我们正在研究这些药剂的作用 与T细胞功能和活化相关的信号转导途径 即磷酸化、JAK-STAT激酶和细胞因子的产生 比TNF α和IL-6和凋亡机制，可能增强病毒 生产 未来的研究将集中在BP和NNK。 体内 这些发现的意义将使用肺泡 巨噬细胞作为模型系统。在另一项努力中， 将研究病毒干扰，目的是鉴定细胞 途径使用HIV-1重叠感染HIV-2感染的细胞， 亦然 流行病学研究表明，HIV-2感染可 对HIV-1感染具有一定程度的保护作用。 将具有 感兴趣的是识别可能是两种类型共同的细胞途径 现象（即感应和干扰）。 这些方法应 增强我们对病毒-细胞相互作用及其对 病毒复制 涉及来自不同风险组的患者的体内研究，这些患者快速 (RP)或缓慢进展者（SP）和一些处于感染早期的患者 已启动，将通过定量 PCR和培养。 从一些RP、SP和早期 血清转化者将在LTR中进行核苷酸分析， gag（p24）、RT和env区。 嗜性、致病性和 从RP、SP和患者中选择的几个分离株的免疫学特征 将在T细胞中进行体外研究， 单核细胞和小动物模型。 这些研究预计将 提供了一些关于进行性与非进行性中分离株生物学的见解。 进行性和原发性HIV感染（早期血清转化）。