VIRUS-CELL INTERACTIONS AND HOST FACTORS IN HIV PATHOGENESIS

U1细胞系中潜伏的HIV基因组的激活被用作 模型来研究病毒复制所涉及的细胞途径。 具体地说，几种化学致癌物和环境诱变剂 也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危险因素 这可能会影响艾滋病的疾病进展。增强了病毒的产生， 经RT、p24和聚合酶链式反应分析，在经 苯并[2]、NNK和黄曲霉毒素B的病毒诱导伴随有 增加核因子-kB的活性和细胞因子的产生，如肿瘤坏死因子-α。 在黄曲霉毒素的情况下，病毒的诱导似乎是一种肿瘤坏死因子-a 独立的机制。我们正在调查这些毒剂的影响 与T细胞功能和活化相关的信号转导途径 即磷酸化、JAK-STAT激酶和其他细胞因子的产生 比TNFa和IL-6和可能增强病毒的凋亡机制更重要 制作。未来的研究将集中在BP和NNK上。活体内 这些发现的意义将用肺泡进行调查。 巨噬细胞作为模型系统。在另一项努力中，这种现象 将研究病毒干扰，目的是识别细胞 利用HIV-1重叠感染HIV-2感染细胞和病毒的途径 反过来说。从流行病学研究中得知，艾滋病毒-2感染可以 提供一定程度的预防艾滋病毒-1感染的保护。它将是 有兴趣确定这两种类型可能共有的细胞通路 现象(即感应和干扰)。这些方法应该 加强我们对病毒-细胞相互作用及其影响的了解 病毒复制。 体内研究涉及来自不同风险组的患者，这些患者 (RP)或进展缓慢(SP)和一些处于感染早期的 已启动，其中病毒负荷将通过定量评估 聚合酶链式反应和培养。从一些RPS、SPS和早期分离的病毒 血清转化器将在LTR中接受核苷酸分析， Gag(P24)、RT和env区。嗜性、致病性和 几株RP、SP和患者分离株的免疫学特性 将在T细胞和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 提供对进展型与非进展型分离株生物学方面的一些见解 进行性和原发艾滋病毒感染(早期血清转换)。

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).