MOLECULAR INTERACTIONS BETWEEN HIV-1 AND HHV-8

卡波西肉瘤（KS）是艾滋病患者中最常见的肿瘤，影响约20%的HIV感染者。 虽然HIV-1对KS的发展既不是必要的，也不是充分的，但AIDS-KS被认为比其他形式的这种疾病更具侵略性，传播性和耐药性。 最近的研究已经确定了一种新的人类疱疹病毒，HHV-8，几乎100%的KS病变。 虽然HHV-8似乎对KS的发展至关重要，但目前还不清楚哪些其他辅助因子负责AIDS-KS的侵袭性。 通常认为，艾滋病中免疫抑制的诱导通过抑制抗病毒和免疫监视机制允许HHV-8的复制和KS的发展。 然而，单独的免疫抑制不能解释与其他免疫抑制患者人群相比，KS在AIDS患者中的压倒性患病率，几乎完全在HIV-1感染的患者中发生KS，而不是HIV-2，或者在免疫抑制发生之前在AIDS早期频繁发生KS。在这个提议中，我们假设HIV-1和HHV-8之间发生分子相互作用。 从HIV-1感染的细胞释放的HIV-1相关蛋白和/或细胞因子使HHV-8从潜伏期重新活化，导致病毒载量增加，并因此导致AIDS- KS的高频率和侵袭性。 拟定研究不仅将表征这两种病毒之间的相互作用，还将鉴定参与诱导病毒复制的病毒和/或细胞因子。 然后，我们将扩展这一体外数据，并在完全由人体成分组成的体内模型中研究HIV-1和HHV-8之间的病毒相互作用。 通过在未来三年内完成这三个目标，我们将获得对HHV-8和HIV-1病毒体外和体内复制调控的分子机制的新见解。确定HHV-8导致KS的关键辅因子，如HIV-1，也将促进实验动物模型的开发，以进一步研究这种疾病。 这种模型对于设计艾滋病- KS的新疗法特别有用。

Kaposi's Sarcoma (KS) is the most common neoplasm in AIDS patients affecting approximately 20 percent of HIV infected individuals. While HIV-1 is neither necessary nor sufficient for the development of KS, AIDS-KS is recognized as more aggressive, disseminated and resistant to treatment that other forms of this disease. Recent studies have identified a new human herpesvirus, HHV-8, in virtually 100 percent of KS lesions. While it appears that HHV-8 is essential to the development of KS, it is currently unclear what additional co-factors are responsible for the aggressive nature of AIDS-KS. It is often assumed that induction of immunosuppression in AIDS allows for the replication of HHV-8 and development of KS by suppression of anti-viral and immunosurveillance mechanisms. However, immunosuppression alone can not explain the overwhelming prevalence of KS in AIDS patients in comparison with other immunosuppressed patient populations, the almost exclusive development of KS in patients infected with HIV-1, but not HIV-2, or the frequent occurrence of KS early in AIDS prior to the development of immunosuppression. In this proposal, we hypothesize that a molecular interaction occurs between HIV-1 and HHV-8. HIV-1 related proteins and/or cytokines released from HIV-1 infected cells reactivate HHV-8 from latency resulting in an increased viral load and, therefore, contributing to the high frequency and aggressive nature of AIDS- KS. The proposed studies will not only characterize the interaction between these two viruses but also identify the viral and/or cellular factors involved in induction of viral replication. We will then extend this in vitro data and examine viral interactions between HIV-1 and HHV-8 in an in vivo model composed entirely of human constituents. By completing these three aims over the next three years, we will gain new insight into the molecular mechanisms governing regulation of HHV-8 and HIV-1 viral replication both in vitro and in vivo Determining essential co-factors that are critical for HHV-8 to cause KS, such as HIV-1, will also facilitate development of experimental animal models to further investigate this disease. Such models will be particularly useful for devising new therapies for AIDS- KS.