Immediate-Early Genes of KSHV

描述(申请人提供)：卡波西肉瘤相关疱疹病毒(KSHV)，也称为人类疱疹病毒-8(HHV-8)，与艾滋病患者最常见的恶性肿瘤卡波西肉瘤(KS)和原发渗出性淋巴瘤(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相关疾病的发生发展中起着关键作用。因此，病毒从潜伏感染到裂解周期感染的转换不仅对病毒的繁殖很重要，而且对病毒的致病性也是至关重要的。KSHV在潜伏和裂解复制之间的转换是由病毒的即刻早期(IE)基因编码的少数调节蛋白控制的。我们实验室一直对KSHV重新激活的机制及其在病毒致病中的作用感兴趣。在KSHV基因组中发现了几个IE基因，其中一些基因，包括ORF50、K8和ORF45，在过去的预算期间已经在我们的实验室被鉴定。这一建议反映了我们继续研究KSHV即刻早期基因在病毒生命周期和致病性中的功能作用的努力。在下一个预算期，我们的研究将集中在即刻早期蛋白ORF45上。(1)ORF45可抑制IRF-7的激活和病毒介导的干扰素的产生。然而，ORF45功能的潜在机制仍然难以捉摸。提出了三个假设，并将对其进行检验。我们将确定ORF45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止irf-7的激活(S)。(2)我们的初步研究表明，ORF45可能具有拮抗干扰素相关的抗病毒反应的功能，这种免疫逃避机制可能是病毒成功感染和重新激活所必需的。我们将确定ORF45在阻断宿主细胞抗病毒反应和促进KSHV感染和再激活方面的作用。此外，拟议研究的结果将评估靶向KSHV IE蛋白ORF45是否可能成为治疗KSHV相关疾病的新策略。

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.