Human cytomegalovirus (HCMV) is an important cause of disease in the immunocompromised host, including the developmentally immature fetus. HCMV is largest human herpesviruses and can potentially encode over 200 proteins. Little is known about the envelopment and assembly of the infectious particle. Recent studies have shown that the envelope is acquired in a cytoplasmic compartment, which is in close proximity to the trans Golgi network (TGN). Our goal in this proposal is to gain a further understanding of the process of cytoplasmic virion assembly, particularly envelopment of the infectious particle. As an approach to this goal, we have proposed to study the role that the virion envelope glycoprotein complex, gM/gN, plays in the assembly of the infectious particle. Recent studies have demonstrated that gM is essential for the production of infectious HCMV. This glycoprotein complexes with gN in the ER and is transported to the site of virion assembly only after complex formation. Interestingly, neither gM nor gN traffics to the assembly site by itself, even though well-described targeting signals are present on at least the gM component of the complex. We believe that gM and gN are both essential for the production of infectious virus, but may have separable roles in that gM is required for particle formation whereas gN is required for assembly of an infectious particle. In this application we have outlined an experimental plan for the characterization of the structural features of gM and gN, which facilitate their interaction and intracellular transport. Definition of the trafficking of the gM/gN complex to the assembly compartment will lead to a more complete view of cytoplasmic envelopment and assembly of this complex virus. Furthermore, characterization of envelopment and the trafficking of structural proteins to the assembly centers will potentially identify new targets for the development of new classes of antiviral drugs.
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