Virus strategies for passing the nuclear envelope barrier

Abstract

Viruses that replicate in the nucleus need to pass the nuclear envelope barrier during infection. Research in recent years indicates that the nuclear envelope is a major hurdle for many viruses. This review describes strategies to overcome this obstacle developed by seven virus families: herpesviridae, adenoviridae, orthomyxoviridae, lentiviruses (which are part of retroviridae), Hepadnaviridae, parvoviridae and polyomaviridae. Most viruses use the canonical nuclear pore complex (NPC) in order to get their genome into the nucleus. Viral capsids that are larger than the nuclear pore disassemble before or during passing through the NPC, thus allowing genome nuclear entry. Surprisingly, increasing evidence suggest that parvoviruses and polyomaviruses may bypass the nuclear pore by trafficking directly through the nuclear membrane. Additional studies are required for better understanding these processes. Since nuclear entry emerges as the limiting step in infection for many viruses, it may serve as an ideal target for antiviral drug development.

Figure 1. Schematic illustrations of the different strategies used by viral genomes for nuclear entry. The following color scheme is used through the figure: Viral DNA, black; host DNA, green; viral RNA, red; NPC, blue; Lamins, gray; viral capsid and capsid proteins, orange and other viral proteins are in different shades of purple. (A) The herpesvirus capsid arrives at the NPC with the internal tegument proteins attached. Following conformational change and opening the portal ring at the capsid vertex the DNA is ejected into the nucleus. (B) After release from the endosome the adenovirus capsid docks to the NPC, where molecular motors disrupt both the capsid and the NPC structure allowing the viral DNA to enter the nucleus. (C) Orthomyxovirus RNPs are released from the endosome into the cytoplasm after fusion of the viral envelope (enriched with viral glycoproteins) with the endosome membrane (shown as a blue line). The RNPs freely diffuse toward the NPC, where they are actively transported as karyopherin cargo into the nucleus. (D) Following uncoating in the cytoplasm, the lentivirus RNA genome is reverse-transcribed into a double stranded DNA. The PIC, containing the viral DNA and several viral proteins including CA, promotes nuclear entry by interaction with NPC proteins. After passing through the NPC the viral DNA integrates into the host chromosome. (E) Hepadnavirus capsids enter the NPC but are too big to pass intact through the basket and into the nucleus. Mature, DNA-containing capsids, disassemble in the basket, releasing the circular viral genome into the nucleoplasm. (F) Parvovirus particles enter the nucleus intact. The N-terminal domain of the minor capsid parvoviruses is extruded in the endosome, exposing phospholipase A activity that facilitates its release to the cytoplasm. Extrusion of the N-terminus also exposes four NLS domains that appear to function in nuclear entry through the NPC. An alternative model suggests direct nuclear entry from the cytoplasm through local disruptions in the NE. G. Polyomaviruses disassemble in the ER. The exposed genomes exit the ER via viroporins created by the internal capsid proteins by either of two proposed mechanism. One is directly from the ER lumen through the inner nuclear membrane, and the other is via the cytoplasm and the NPC.