The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase.

Abstract

Recent genome-wide screens have highlighted an important role for transportin 3 in human immunodeficiency virus type 1 (HIV-1) infection and preintegration complex (PIC) nuclear import. Moreover, HIV-1 integrase interacted with recombinant transportin 3 protein under conditions whereby Moloney murine leukemia virus (MLV) integrase failed to do so, suggesting that integrase-transportin 3 interactions might underscore active retroviral PIC nuclear import. Here we correlate infectivity defects in transportin 3 knockdown cells with in vitro protein binding affinities for an expanded set of retroviruses that include simian immunodeficiency virus (SIV), bovine immunodeficiency virus (BIV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), and Rous sarcoma virus (RSV) to critically address the role of integrase-transportin 3 interactions in viral infection. Lentiviruses, with the exception of FIV, display a requirement for transportin 3 in comparison to MLV and RSV, yielding an infection-based dependency ranking of SIV > HIV-1 > BIV and EIAV > MLV, RSV, and FIV. In vitro pulldown and surface plasmon resonance assays, in contrast, define a notably different integrase-transportin 3 binding hierarchy: FIV, HIV-1, and BIV > SIV and MLV > EIAV. Our results therefore fail to support a critical role for integrase binding in dictating transportin 3 dependency during retrovirus infection. In addition to integrase, capsid has been highlighted as a retroviral nuclear import determinant. Accordingly, MLV/HIV-1 chimera viruses pinpoint the genetic determinant of sensitization to transportin 3 knockdown to the HIV-1 capsid protein. We therefore conclude that capsid, not integrase, is the dominant viral factor that dictates transportin 3 dependency during HIV-1 infection.

• Authors: Lavanya Krishnan, Kenneth A Matreyek, Ilker Oztop, Kyeongeun Lee, Christopher H Tipper, Xiang Li, Mohd J Dar, Vineet N Kewalramani, Alan Engelman
• Journal: Journal of virology (J Virol) Vol. 84 Issue 1 Pg. 397-406 (Jan 2010) ISSN: 1098-5514 [Electronic] United States
• PMID: 19846519 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Human Immunodeficiency Virus Proteins
• Karyopherins
• TNPO3 protein, human
• beta Karyopherins
• Integrases

Topics

• Animals
• Capsid (metabolism, physiology)
• Cell Line
• HIV Infections (etiology)
• HIV-1 (pathogenicity)
• Human Immunodeficiency Virus Proteins (metabolism, physiology)
• Humans
• Integrases (metabolism, physiology)
• Karyopherins (deficiency, genetics, metabolism, physiology)
• Lentivirus (pathogenicity)
• Leukemia Virus, Murine
• Protein Binding
• beta Karyopherins (genetics, metabolism, physiology)