DETERMINANTS OF CHRONIC GAMMAHERPESVIRUS 68 INFECTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。γ疱疹病毒在宿主淋巴细胞中建立终身潜伏感染，在此期间，有限的病毒基因亚群促进病毒维持。ORF 73是一个保守的γ疱疹病毒基因，其产物被证明为卡波西？S肉瘤相关疱疹病毒将病毒基因组系在宿主染色体上，并干扰细胞内稳态调节途径。为了了解ORF 73在建立和维持？为了在体内观察HV 68潜伏感染，我们利用靶向突变体将ORF 73定义为鼻内接种后建立潜伏感染的关键。此外，ORF 73突变体在感染小鼠的肺中表现出严重的复制缺陷。在原代鼠胚胎成纤维细胞中的病毒复制的分析揭示了ORF 73突变病毒的裂解复制在培养物中受损。此外，这种复制缺陷与宿主翻译的抑制和感染细胞中细胞凋亡动力学的增加相关。这些研究结果表明，ORF 73在限制宿主细胞死亡，以促进有效的病毒复制和传播，促进建立？HV 68潜伏感染。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gammaherpesviruses establish life-long, latent infections in host lymphocytes during which a limited subset of viral genes facilitate viral maintenance. ORF73 is a conserved gammaherpesvirus gene whose product was demonstrated for Kaposi?s sarcoma-associated herpesvirus to tether viral genomes to host chromosomes and interfere with cellular homeostatic regulatory pathways. To understand the role of ORF73 in the establishment and maintenance of ?HV68 latent infection in vivo, we utilized targeted mutants to define ORF73 as critical to the establishment of a latent infection following intranasal inoculation. In addition, ORF73 mutants exhibited a severe replication defect in the lungs of infected mice. Analysis of viral replication in primary murine embryonic fibroblasts revealed that lytic replication of ORF73 mutant virus is impaired in culture. Further, this replication deficit correlates with inhibition of host translation and increased kinetics of apoptosis in infected cells. These findings suggest a role for ORF73 in limiting host-cell death to promote efficient viral replication and dissemination that facilitates the establishment of ?HV68 latent infection.