Immediate-Early Genes of KSHV

描述（由申请方提供）：卡波西肉瘤相关疱疹病毒（KSHV），也称为人疱疹病毒-8（HHV-8），与艾滋病患者中最常见的恶性肿瘤卡波西肉瘤（KS）和原发性渗出性淋巴瘤（PEL）密切相关。越来越多的证据表明，KSHV的裂解周期在KS和其他KSHV相关疾病的发展中起着关键作用。因此，病毒从潜伏期感染到裂解期感染的转变不仅对病毒的繁殖非常重要，而且对病毒的致病性也至关重要。KSHV在潜伏期和裂解性复制之间的转换由病毒的立即早期（IE）基因编码的一些调节蛋白控制。本实验室对KSHV的再激活机制及其在病毒致病性中的作用一直很感兴趣。在KSHV基因组中鉴定了几个IE基因，其中一些，包括ORF 50，K8和ORF 45，已在我们的实验室在过去的预算期间进行了表征。这一建议反映了我们继续研究KSHV立即早期基因在病毒生活周期和致病性中的功能作用的努力。在下一个预算期间，我们的研究将集中在立即早期蛋白ORF 45上。(1)发现ORF 45抑制IRF-7的活化和病毒介导的干扰素产生。然而，ORF 45功能的潜在机制仍然难以捉摸。提出了三个假设，并将进行审查。我们将确定ORF 45是否通过（i）抑制其构象变化，或（ii）干扰其在病毒感染细胞中的磷酸化，或（iii）阻断其与其他细胞蛋白的相互作用来阻断IRF-7活化。(2)我们的初步研究表明ORF 45可能在拮抗IFN相关的抗病毒反应中起作用，这种免疫逃避机制可能是成功的病毒感染和再激活所必需的。我们将确定ORF 45在阻断宿主细胞抗病毒反应和促进KSHV感染和再活化中的作用。此外，拟议研究的结果将评估靶向KSHV IE蛋白ORF 45是否可能成为KSHV相关疾病治疗干预的新策略。

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is closely associated with the most common malignancies in AIDS patients, Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Increasing evidence suggest that lytic cycle of KSHV plays critical roles in development of KS and other KSHV-associated diseases. Therefore, switch of the virus from latency to lytic cycle infection is not only important for viral propagation, but also crucial for viral pathogenicity. The switch of KSHV between latency and lytic replication is controlled by a few regulatory proteins encoded by immediate-early (IE) genes of the virus. Our laboratory has been interested in the mechanism of KSHV reactivation and its roles in viral pathogenicity. Several IE genes were identified in the KSHV genome and some, including ORF50, K8 and ORF45, have been characterized in our laboratory during the past budget period. This proposal reflects our effort to continue the investigation on functional roles of KSHV immediate-early genes in viral life cycle and pathogenicity. In the next budget period, our research will be focused on the immediate- early protein ORF45. (1) ORF45 was found to inhibit activation of IRF-7 and virus-mediated interferon production. However, the mechanism underlying the ORF45 function remains elusive. Three hypotheses are proposed and will be examined. We will determine whether ORF45 blocks IRF-7 activation through (i) inhibiting its conformational change, or (ii) interfering with its phosphorylation in viral infected cells, or (iii) blocking its interaction with other cellular protein(s). (2) Our preliminary studies suggested that ORF45 may function in antagonizing IFN-associated antiviral responses and this immune evasion mechanism may be necessary for a successful viral infection and reactivation. We will determine roles of ORF45 in blocking host cell antiviral responses and facilitating KSHV infection and reactivation. In addition, the results from the proposed studies will provide assessment of whether targeting KSHV IE proteins ORF45 could be new strategies for therapeutic intervention for KSHV-associated diseases.