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Review
, 5 (10), 2483-511

Viral and Cellular Requirements for the Nuclear Entry of Retroviral Preintegration Nucleoprotein Complexes

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Review

Viral and Cellular Requirements for the Nuclear Entry of Retroviral Preintegration Nucleoprotein Complexes

Kenneth A Matreyek et al. Viruses.

Abstract

Retroviruses integrate their reverse transcribed genomes into host cell chromosomes as an obligate step in virus replication. The nuclear envelope separates the chromosomes from the cell cytoplasm during interphase, and different retroviral groups deal with this physical barrier in different ways. Gammaretroviruses are dependent on the passage of target cells through mitosis, where they are believed to access chromosomes when the nuclear envelope dissolves for cell division. Contrastingly, lentiviruses such as HIV-1 infect non-dividing cells, and are believed to enter the nucleus by passing through the nuclear pore complex. While numerous virally encoded elements have been proposed to be involved in HIV-1 nuclear import, recent evidence has highlighted the importance of HIV-1 capsid. Furthermore, capsid was found to be responsible for the viral requirement of various nuclear transport proteins, including transportin 3 and nucleoporins NUP153 and NUP358, during infection. In this review, we describe our current understanding of retroviral nuclear import, with emphasis on recent developments on the role of the HIV-1 capsid protein.

Figures

Figure 1
Figure 1
Schematic of the nuclear pore complex (NPC) and classical nuclear import pathway. (top) General NPC substructures and locations of nucleoporins (NUPs) that scored as potential HIV-1 co-factors in genome-wide RNA interference screens [17,18,19,20]. Asterisks denote NUPs that scored in more than one screen. (bottom) The Ran-based nuclear import cycle. Import protein cargo binds to a karyopherin (KPN) β protein, oftentimes bridged by a member of the KPN α protein family (KPN β1, which is also referred to as importin β1, and KPN α2 or importin α1, depicted, are canonical members of each protein family). KPN β1 ferries the complex through the NPC channel. The engagement of KPN β1 by Ran-GTP concentrated at the nuclear basket releases the KPN α-cargo complex into the nucleus. KPN β1 becomes free to bind additional import cargo after Ran dissociates from it upon RanBP1 binding and Ran-GTP hydrolysis, stimulated by RanGAP concentrated at the cytoplasmic filaments.
Figure 2
Figure 2
PCR-based methods for detection of post-entry to viral DNA integration steps of HIV-1 infection. (A) Generalized replication intermediates and byproducts leading up to integration. (B) Order of viral trafficking and RT and IN enzymatic steps. (C) Summary of viral DNA species that serve as markers for the various infection intermediates and byproducts.
Figure 3
Figure 3
Schematic of HIV-1 capsid (CA) and mutations described in the text. A single HIV-1 CA monomer (protein database code 3j34) is represented by a cartoon of the peptide backbone, as well as a semi-transparent surface representation: N-terminal domain (NTD), green; flexible linker, purple; C-terminal domain (CTD), red. A subset of CA residue side-chains that exhibit phenotypic differences in preintegrative steps of HIV-1 infection are shown as sticks and colored as follows: carbon, orange; nitrogen, blue; oxygen, red.
Figure 4
Figure 4
Model of the potential roles of the CA-dependent nuclear transport factors during HIV-1 infection. NUP358, NUP153, and CPSF6 at the nuclear pore most likely act on PIC-associated CA to aid HIV-1 infection. TNPO3 is required to localize CPSF6 to the nucleus; premature cytoplasmic CPSF6 binding to CA prevents nuclear import. TNPO3 may affect integration by interacting with IN within the nucleus. CypA modulates CA uncoating, altering dependencies on NUP358, NUP153, and TNPO3. Perturbation of this pathway by CA mutation or TNPO3, NUP153, or NUP358 knockdown results in altered integration site selection away from gene-dense regions of chromatin.

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