Most DNA and few RNA viruses target their genome to the host nucleus. The crossing of nuclear membrane occurs in several ways 
:
-RNA virus, dsDNA virus and lentivirus genomes enter via the nuclear pore complex (NPC) through the cellular Importin transport.
-ssDNA virus capsid seems to be small enough to cross the NPC and enter the nucleus as an intact capsid.
-Hepadnaviridae capsid would enter the NPC pore, but remains attached to it and releases the viral genomic DNA into the nucleoplasm.
-Herpesvirales capsid is too large to enter the NPC pore, the viral genome is directly injected through the NPC on which the capsid docks.
-All retroviridae except lentivirus would enter the nucleus during mitosis, when the nuclear membrane temporarily disintegrates.
All these strategies to cross the nuclear envelope barrier are associated with various levels of capsid disassembly, since virus can pass intact (e.g. parvoviridae) or, in the case of injection, only the viral genome enters the nucleus (e.g. herpesviruses). Genome integration in the host genome may eventually follow
.
| Family | Virus | Viral protein | Host protein | Process | Reference |
|---|
| Herpesviridae | HSV-1 | capsid | Importin-beta | capsid docking at nuclear pore | |
| | capsid | Nup358 | capsid docking at nuclear pore | |
| | pUL25, capsid | Nup214 | capsid docking at nuclear pore; DNA release | |
| | pUL25 | hCG1 (NUPL-2) | binds free pUL25; might be involved in capsid docking at nuclear pore | |
| | pUL25 | unknown, likely NPC component | uncoating of DNA at the NPC; soluble pUL25 inhibited uncoating but not NPC docking | |
| Polyomaviridae | SV40 | VP1/2/3 | general nuclear transport machinery | capsid delivery to the nucleus; all VPs contain classical NLSs which likely use the importin-alpha/beta pathway | |
| | VP1 pentamer | caspase-6, Lamin A/C | disruption of nuclear lamins by caspase-6 in order for capsids to penetrate INM from ER; fluctuations in Lamin A/C levels and associated phosphorylation at an unidentified residue in quiescent cells | |
| Adenoviridae | Ad2/5 | | Crm1, Hsp70 | nuclear targeting of capsids | |
| Ad2 | | Nup214, Importin-beta and importin-7, Histone H1 | nuclear targeting of capsids via adapter protein histone H1 | |
| | hexon | Nup214/62/358 | capsids bind Nup214/88/358 to dock at the NPC; Nup358 recruits kinesin heavy chain Kif5c to promote capsid disintegration; simultaneously leads to NPC perturbation | |
| | pVII | Importin-alpha/beta, Importin-7, Transportin-1 | nuclear import of Ad genomic DNA post-docking | |
| | hexon | Importin-alpha/beta, Nups | nuclear docking of capsids | |
| Baculo-viridae | AcMNPV | | Importin-beta | nuclear delivery of capsids | |
| Parvo-viridae | MVM | | proteasome | nuclear delivery of capsids | |
| | | Caspase-3, lamin B2 | NE disruption (ONM) by digestion of lamin B2 | |
| | | | | |
| wtAAV2 | | unknown | (unknown mechanism but independent from trafficking through the NPC) | |
| recAAV2 | | Importin-beta, Importin-7, NPC | nuclear delivery of capsids | |
| H1 | | Nup62, Nup153, Nup214, Nup358, PKCa, Cdk1/2, Caspase-3, Lamins | binding to NPC via alternative mechanism leads to subsequent disruption of the ONM and INM via the mitotic kinase-protease axis | |
| Orthomyxoviridae | Influenza A | NP | Importin-a | nuclear import of vRNP | |
| | NP | Importin-a1 or 2 + Importin-beta | nuclear import of vRNP | |
| | NP | Transportin-3 | nuclear import of vRNP (RNAi) | |
| | | CSE1L, KPNB 1, NUP214,NUP153, TNPO3 | potentially nuclear import of vRNP (RNAi) | |
| | | Importin-beta, Crm1, Nup98, Nup205 | potentially nuclear import of vRNP (RNAi) | |
| | | Importin-5 | likely nuclear import of vRNP as delayed gene expression | |
| | PB1/2, NP, PA + NS1 | Importin-a4 | | |
| | PB1/2, NP, PA | Importin-a7 | | |
| Retroviridae | HIV-1 | Vpr | hCG1, Nup54, Importin-alpha/beta | NEBD if Vpr overexpressed; greatly improves docking of the PIC at the NPC by directly binding to nucleoporins; increased affinity of importin-alpha/beta to the PIC; Vpr at the NE promotes G2 arrest/apoptosis | |
| | Integrase | Nup62 | chromatin associated Nup62 to aid genome integration | |
| | Integrase | Importin-7 | nuclear transport of pre-integration complex (PIC) | |
| | Integrase | Nup98 | reduction of genome integration | |
| | Integrase | Importin-a1 | nuclear import of PIC | |
| | Integrase | Importin-a3 | nuclear import of PIC into T cell nuclei | |
| | Integrase, CA | Transportin-3 | nuclear import of PIC | |
| | CA | Nup153, Nup155 | nuclear import of PIC | |
| | CA | Nup358 | targeting of imported PIC and increased efficiency of integration in transcriptionally active areas | |
| | Matrix | | nuclear import of PIC into non-dividing cells | |
| MLV | CA protein | masking of receptor binding site | inhibits nuclear transport of PIC | |
| Hepadna-viridae | HBV | core protein | importin alpha/beta, Nup153 | capsid entry to the nucleus and capsid arrest at Nup153 acts as a maturity checkpoint (coupled potentially to phosphorylation state) | |
Source: Viruses and the nuclear envelope,Thomas Hennig, Peter O'Hare, Curr. Opin. Cell Biol. June 2015; 34: 113.121
Viruses and the nuclear envelope
Thomas Hennig, Peter O'Hare
Curr. Opin. Cell Biol. June 2015; 34: 113-121
Herpes simplex virus type 1 entry into host cells: reconstitution of capsid binding and uncoating at the nuclear pore complex in vitro
P. M. Ojala, B. Sodeik, M. W. Ebersold, U. Kutay, A. Helenius
Mol. Cell. Biol. July 2000; 20: 4922-4931
Herpesvirus capsid association with the nuclear pore complex and viral DNA release involve the nucleoporin CAN/Nup214 and the capsid protein pUL25
David Pasdeloup, Danielle Blondel, Anabela L. Isidro, Frazer J. Rixon
J. Virol. July 2009; 83: 6610-6623
Herpes simplex virus replication: roles of viral proteins and nucleoporins in capsid-nucleus attachment
Anna Maria Copeland, William W. Newcomb, Jay C. Brown
J. Virol. February 2009; 83: 1660?1668
Uncoupling uncoating of herpes simplex virus genomes from their nuclear import and gene expression
Kathrin Rode, Katinka D?hner, Anne Binz, Mandy Glass, Tanja Strive, Rudolf Bauerfeind, Beate Sodeik
J. Virol. May 2011; 85: 4271?4283
Import of simian virus 40 virions through nuclear pore complexes
J. Clever, M. Yamada, H. Kasamatsu
Proc. Natl. Acad. Sci. U.S.A. August 15, 1991; 88: 7333?7337
Simian virus 40 induces lamin A/C fluctuations and nuclear envelope deformation during cell entry
Veronika Butin-Israeli, Orly Ben-nun-Shaul, Idit Kopatz, Stephen A. Adam, Takeshi Shimi, Robert D. Goldman, Ariella Oppenheim
Nucleus August 2011; 2: 320?330
Nuclear targeting of adenovirus type 2 requires CRM1-mediated nuclear export
Sten Strunze, Lloyd C. Trotman, Karin Boucke, Urs F. Greber
Mol. Biol. Cell June 2005; 16: 2999?3009
Import of adenovirus DNA involves the nuclear pore complex receptor CAN/Nup214 and histone H1
L. C. Trotman, N. Mosberger, M. Fornerod, R. P. Stidwill, U. F. Greber
Nat. Cell Biol. December 2001; 3: 1092?1100
Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection
Sten Strunze, Martin F. Engelke, I.-Hsuan Wang, Daniel Puntener, Karin Boucke, Sibylle Schleich, Michael Way, Philipp Schoenenberger, Christoph J. Burckhardt, Urs F. Greber
Cell Host Microbe September 15, 2011; 10: 210?223
A role for transportin in the nuclear import of adenovirus core proteins and DNA
Clemence E. Hindley, Fiona J. Lawrence, David A. Matthews
Traffic October 2007; 8: 1313?1322
Nuclear import of adenovirus DNA in vitro involves the nuclear protein import pathway and hsc70
A. C. Saphire, T. Guan, E. C. Schirmer, G. R. Nemerow, L. Gerace
J. Biol. Chem. February 11, 2000; 275: 4298?4304
Baculovirus infection of nondividing mammalian cells: mechanisms of entry and nuclear transport of capsids
N. D. van Loo, E. Fortunati, E. Ehlert, M. Rabelink, F. Grosveld, B. J. Scholte
J. Virol. January 2001; 75: 961?970
Effect of viral infection on the nuclear envelope and nuclear pore complex
Sarah Cohen, Igor Etingov, Nelly Pant?
Int Rev Cell Mol Biol 2012; 299: 117?159
Adeno-associated virus type 2-mediated gene transfer: altered endocytic processing enhances transduction efficiency in murine fibroblasts
J. Hansen, K. Qing, A. Srivastava
J. Virol. May 2001; 75: 4080?4090
Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus
Sarah C. Nicolson, R. Jude Samulski
J. Virol. April 2014; 88: 4132?4144
Parvoviruses cause nuclear envelope breakdown by activating key enzymes of mitosis
Manvi Porwal, Sarah Cohen, Kenza Snoussi, Ruth Popa-Wagner, Fenja Anderson, Nathalie Dugot-Senant, Harald Wodrich, Christiane Dinsart, J?rgen A. Kleinschmidt, Nelly Pant?, Michael Kann
PLoS Pathog. October 2013; 9: e1003671
Contributions of two nuclear localization signals of influenza A virus nucleoprotein to viral replication
Makoto Ozawa, Ken Fujii, Yukiko Muramoto, Shinya Yamada, Seiya Yamayoshi, Ayato Takada, Hideo Goto, Taisuke Horimoto, Yoshihiro Kawaoka
J. Virol. January 2007; 81: 30?41
Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import
R. E. O?Neill, R. Jaskunas, G. Blobel, P. Palese, J. Moroianu
J. Biol. Chem. September 29, 1995; 270: 22701?22704
Human host factors required for influenza virus replication
Renate K?nig, Silke Stertz, Yingyao Zhou, Atsushi Inoue, H.-Heinrich Hoffmann, Suchita Bhattacharyya, Judith G. Alamares, Donna M. Tscherne, Mila B. Ortigoza, Yuhong Liang, Qinshan Gao, Shane E. Andrews, Sourav Bandyopadhyay, Paul De Jesus, Buu P. Tu, Lars Pache, Crystal Shih, Anthony Orth, Ghislain Bonamy, Loren Miraglia, Trey Ideker, Adolfo Garc?a-Sastre, John A. T. Young, Peter Palese, Megan L. Shaw, Sumit K. Chanda
Nature February 11, 2010; 463: 813?817
Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication
Alexander Karlas, Nikolaus Machuy, Yujin Shin, Klaus-Peter Pleissner, Anita Artarini, Dagmar Heuer, Daniel Becker, Hany Khalil, Lesley A. Ogilvie, Simone Hess, Andr? P. M?urer, Elke M?ller, Thorsten Wolff, Thomas Rudel, Thomas F. Meyer
Nature February 11, 2010; 463: 818?822
Role of ran binding protein 5 in nuclear import and assembly of the influenza virus RNA polymerase complex
Tao Deng, Othmar G. Engelhardt, Benjamin Thomas, Alexandre V. Akoulitchev, George G. Brownlee, Ervin Fodor
J. Virol. December 2006; 80: 11911?11919
A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection
Sagi D. Shapira, Irit Gat-Viks, Bennett O. V. Shum, Amelie Dricot, Marciela M. de Grace, Liguo Wu, Piyush B. Gupta, Tong Hao, Serena J. Silver, David E. Root, David E. Hill, Aviv Regev, Nir Hacohen
Cell December 24, 2009; 139: 1255?1267
Localization of HIV-1 Vpr to the nuclear envelope: impact on Vpr functions and virus replication in macrophages
Guillaume Jacquot, Erwann Le Rouzic, Annie David, Julie Mazzolini, J?r?me Bouchet, Serge Bouaziz, Florence Niedergang, Gianfranco Pancino, Serge Benichou
Retrovirology 2007; 4: 84
Contribution of host nucleoporin 62 in HIV-1 integrase chromatin association and viral DNA integration
Zhujun Ao, Kallesh Danappa Jayappa, Binchen Wang, Yingfeng Zheng, Xiaoxia Wang, Jinyu Peng, Xiaojian Yao
J. Biol. Chem. March 23, 2012; 287: 10544?10555
HIV-1 exploits importin 7 to maximize nuclear import of its DNA genome
Lyubov Zaitseva, Peter Cherepanov, Lada Leyens, Sam J. Wilson, Jane Rasaiyaah, Ariberto Fassati
Retrovirology 2009; 6: 11
Role of Nup98 in nuclear entry of human immunodeficiency virus type 1 cDNA
Hirotaka Ebina, Jun Aoki, Shunsuke Hatta, Takeshi Yoshida, Yoshio Koyanagi
Microbes Infect. July 2004; 6: 715?724
HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway
P. Gallay, T. Hope, D. Chin, D. Trono
Proc. Natl. Acad. Sci. U.S.A. September 2, 1997; 94: 9825?9830
Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication
Zhujun Ao, Kallesh Danappa Jayappa, Binchen Wang, Yingfeng Zheng, Sam Kung, Eric Rassart, Reinhard Depping, Matthias Kohler, Eric A. Cohen, Xiaojian Yao
J. Virol. September 2010; 84: 8650?8663
The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase
Lavanya Krishnan, Kenneth A. Matreyek, Ilker Oztop, Kyeongeun Lee, Christopher H. Tipper, Xiang Li, Mohd J. Dar, Vineet N. Kewalramani, Alan Engelman
J. Virol. January 2010; 84: 397?406
Flexible use of nuclear import pathways by HIV-1
KyeongEun Lee, Zandrea Ambrose, Thomas D. Martin, Ilker Oztop, Alok Mulky, John G. Julias, Nick Vandegraaff, Joerg G. Baumann, Rui Wang, Wendy Yuen, Taichiro Takemura, Kenneth Shelton, Ichiro Taniuchi, Yuan Li, Joseph Sodroski, Dan R. Littman, John M. Coffin, Stephen H. Hughes, Derya Unutmaz, Alan Engelman, Vineet N. KewalRamani
Cell Host Microbe March 18, 2010; 7: 221?233
HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency
Torsten Schaller, Karen E. Ocwieja, Jane Rasaiyaah, Amanda J. Price, Troy L. Brady, Shoshannah L. Roth, St?phane Hu?, Adam J. Fletcher, KyeongEun Lee, Vineet N. KewalRamani, Mahdad Noursadeghi, Richard G. Jenner, Leo C. James, Frederic D. Bushman, Greg J. Towers
PLoS Pathog. December 2011; 7: e1002439
Two nuclear localization signals in the HIV-1 matrix protein regulate nuclear import of the HIV-1 pre-integration complex
O. K. Haffar, S. Popov, L. Dubrovsky, I. Agostini, H. Tang, T. Pushkarsky, S. G. Nadler, M. Bukrinsky
J. Mol. Biol. June 2, 2000; 299: 359?368
Capsid is a dominant determinant of retrovirus infectivity in nondividing cells
Masahiro Yamashita, Michael Emerman
J. Virol. June 2004; 78: 5670?5678
Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket
Andr? Schmitz, Alexandra Schwarz, Michael Foss, Lixin Zhou, Birgit Rabe, Julia Hoellenriegel, Miriam Stoeber, Nelly Pant?, Michael Kann
PLoS Pathog. January 2010; 6: e1000741
