Role of Rab GTPases in HSV-1 infection: Molecular understanding of viral maturation and egress.

Most enveloped viruses exploit complex cellular pathways for assembly and egress from the host cell, and the large DNA virus Herpes simplex virus 1 (HSV-1) makes no exception, hijacking several cellular transport pathways for its glycoprotein trafficking and maturation, as well as for viral morphogenesis and egress according to the envelopment, de-envelopment and re-envelopment model. Importantly Rab GTPases, widely distributed master regulators of intracellular membrane trafficking pathways, have recently being tightly implicated in such process. Indeed, siRNA-mediated genetic ablation of specific Rab proteins differently affected HSV-1 production, suggesting a complex role of different Rab proteins in HSV-1 life cycle. In this review, we discuss how different Rabs can regulate HSV-1 assembly/egress and the potential therapeutic applications of such findings for the management of HSV-1 infections.

Envelope-Fusion-Syncytium Formation in Microplitis bicoloratus bracovirus Maturation.

The viral envelope is essential for virus maturation. Virus-mediated syncytium formations are induced by viral envelope proteins that cause membrane fusion of the infected cells. Polydnaviridae (Polydnavirus) are enveloped viruses with multiple nucleocapsids, and virions mature in symbiotic parasitoid wasp ovaries. However, the mechanism governing the envelope packaging of multiple nucleocapsids remains unclear. In this study, we used transmission electron microscopy to examine the process whereby multiple nucleocapsids of Microplitis bicoloratus bracovirus are packaged into an envelope and observed envelope-fusion-syncytium formation in symbiotic wasp calyx cells during virus maturation. The virus maturation process in calyx cells comprised four stages: pre-virogenic stroma, virogenic stroma, assembly, and fusion. Each virus contained a single envelope with one nucleocapsid in the assembly stage; multiple envelopes then fused to form a viral envelope with multiple nucleocapsids (i.e., the envelope-fusion-syncytium) around the envelope fusion core in the fusion stage. The envelope-fusion-syncytium then stabilized the virions that were released into the lumen of the ovary across the calyx epithelial layer. The phagocytic calyx epithelial cells on the border of the calyx and ovary lumen cleared the majority of non-enveloped nucleocapsids. In contrast, non-phagocytic calyx epithelial cells with microvilli and a cuticular line between the ovary wall and the lumen remained intact in the ovary lumen. These results indicate that envelope-fusion-syncytium formation is important for packaging multiple nucleocapsids in bracovirus maturation.

Architecture of the herpesvirus genome-packaging complex and implications for DNA translocation.

Genome packaging is a fundamental process in a viral life cycle and a prime target of antiviral drugs. Herpesviruses use an ATP-driven packaging motor/terminase complex to translocate and cleave concatemeric dsDNA into procapsids but its molecular architecture and mechanism are unknown. We report atomic structures of a herpesvirus hexameric terminase complex in both the apo and ADP•BeF3-bound states. Each subunit of the hexameric ring comprises three components-the ATPase/terminase pUL15 and two regulator/fixer proteins, pUL28 and pUL33-unlike bacteriophage terminases. Distal to the nuclease domains, six ATPase domains form a central channel with conserved basic-patches conducive to DNA binding and trans-acting arginine fingers are essential to ATP hydrolysis and sequential DNA translocation. Rearrangement of the nuclease domains mediated by regulatory domains converts DNA translocation mode to cleavage mode. Our structures favor a sequential revolution model for DNA translocation and suggest mechanisms for concerted domain rearrangements leading to DNA cleavage.

How to package the RNA of HIV-1.

Interactions between viral RNA and the integrase enzyme are required for HIV-1 particles to become infectious, a process that can be disrupted through multiple mechanisms.