HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 13, 12355-12362, March 26, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/13/12355    most recent M312426200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akari, H. Articles by Strebel, K. Search for Related Content PubMed PubMed Citation Articles by Akari, H. Articles by Strebel, K. Social Bookmarking                      What's this?

High Level Expression of Human Immunodeficiency Virus Type-1 Vif Inhibits Viral Infectivity by Modulating Proteolytic Processing of the Gag Precursor at the p2/Nucleocapsid Processing Site^*

Hirofumi Akari, Mikako Fujita¶, Sandra Kao, Mohammad A. Khan, Miranda Shehu-Xhilaga, Akio Adachi¶, and Klaus Strebel||

From the Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, Tsukuba Primate Center for Medical Science, The National Institute of Infectious Diseases, Ibaraki 305-0843, Japan, and the ^¶Department of Virology, The University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan

The human immunodeficiency virus type-1 Vif protein has a crucial role in regulating viral infectivity. However, we found that newly synthesized Vif is rapidly degraded by cellular proteases. We tested the dose dependence of Vif in non-permissive H9 cells and found that Vif, when expressed at low levels, increased virus infectivity in a dose-dependent manner. Surprisingly, however, the range of Vif required for optimal virus infectivity was narrow, and further increases in Vif severely reduced viral infectivity. Inhibition of viral infectivity at higher levels of Vif was cell type-independent and was associated with an accumulation of Gag-processing intermediates. Vif did not act as a general protease inhibitor but selectively inhibited Gag processing at the capsid and nucleocapsid (NC) boundary. Identification of Vif variants that were efficiently packaged but were unable to modulate Gag processing suggests that Vif packaging was necessary but insufficient for the production of 33- and 34-kDa processing intermediates. Interestingly, these processing intermediates, like Vif, associated with viral nucleoprotein complexes more rigidly than mature capsid and NC. We conclude that virus-associated Vif inhibits processing of a subset of Gag precursor molecules at the p2/NC primary cleavage site. Modulation of processing of a small subset of Gag molecules by physiological levels of Vif may be important for virus maturation. However, the accumulation of such processing intermediates at high levels of Vif is inhibitory. Thus, rapid intracellular degradation of Vif may have evolved as a mechanism to prevent such inhibitory effects of Vif.

Received for publication, November 12, 2003 , and in revised form, January 6, 2004.

^* This work was supported in part by a grant from the National Institutes of Health Intramural AIDS Targeted Antiviral Program (to K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: NIAID, National Institutes of Health, 4/312, 4 Center Dr., MSC 0460, Bethesda, MD 20892-0460. Tel.: 301-496-3132; Fax: 301-402-0226; E-mail: kstrebel{at}nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Henriet, G. Mercenne, S. Bernacchi, J.-C. Paillart, and R. Marquet Tumultuous Relationship between the Human Immunodeficiency Virus Type 1 Viral Infectivity Factor (Vif) and the Human APOBEC-3G and APOBEC-3F Restriction Factors Microbiol. Mol. Biol. Rev., June 1, 2009; 73(2): 211 - 232. [Abstract] [Full Text] [PDF]

				S. Porcellini, L. Alberici, F. Gubinelli, R. Lupo, C. Olgiati, G.-P. Rizzardi, and C. Bovolenta The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration Blood, April 9, 2009; 113(15): 3443 - 3452. [Abstract] [Full Text] [PDF]

				Y. Dang, L. M. Siew, and Y.-H. Zheng APOBEC3G Is Degraded by the Proteasomal Pathway in a Vif-dependent Manner without Being Polyubiquitylated J. Biol. Chem., May 9, 2008; 283(19): 13124 - 13131. [Abstract] [Full Text] [PDF]

				C. M. Exline, Z. Feng, and C. M. Stoltzfus Negative and Positive mRNA Splicing Elements Act Competitively To Regulate Human Immunodeficiency Virus Type 1 Vif Gene Expression J. Virol., April 15, 2008; 82(8): 3921 - 3931. [Abstract] [Full Text] [PDF]

				D. Mandal, Z. Feng, and C. M. Stoltzfus Gag-Processing Defect of Human Immunodeficiency Virus Type 1 Integrase E246 and G247 Mutants Is Caused by Activation of an Overlapping 5' Splice Site J. Virol., February 1, 2008; 82(3): 1600 - 1604. [Abstract] [Full Text] [PDF]

				E. Miyagi, S. Opi, H. Takeuchi, M. Khan, R. Goila-Gaur, S. Kao, and K. Strebel Enzymatically Active APOBEC3G Is Required for Efficient Inhibition of Human Immunodeficiency Virus Type 1 J. Virol., December 15, 2007; 81(24): 13346 - 13353. [Abstract] [Full Text] [PDF]

				H. Takeuchi, A. Buckler-White, R. Goila-Gaur, E. Miyagi, M. A. Khan, S. Opi, S. Kao, E. Sokolskaja, T. Pertel, J. Luban, et al. Vif Counteracts a Cyclophilin A-Imposed Inhibition of Simian Immunodeficiency Viruses in Human Cells J. Virol., August 1, 2007; 81(15): 8080 - 8090. [Abstract] [Full Text] [PDF]

				S. Henriet, L. Sinck, G. Bec, R. J. Gorelick, R. Marquet, and J.-C. Paillart Vif is a RNA chaperone that could temporally regulate RNA dimerization and the early steps of HIV-1 reverse transcription Nucleic Acids Res., August 1, 2007; 35(15): 5141 - 5153. [Abstract] [Full Text] [PDF]

				S. Opi, H. Takeuchi, S. Kao, M. A. Khan, E. Miyagi, R. Goila-Gaur, Y. Iwatani, J. G. Levin, and K. Strebel Monomeric APOBEC3G Is Catalytically Active and Has Antiviral Activity. J. Virol., May 1, 2006; 80(10): 4673 - 4682. [Abstract] [Full Text] [PDF]

				M. J. Wichroski, K. Ichiyama, and T. M. Rana Analysis of HIV-1 Viral Infectivity Factor-mediated Proteasome-dependent Depletion of APOBEC3G: CORRELATING FUNCTION AND SUBCELLULAR LOCALIZATION J. Biol. Chem., March 4, 2005; 280(9): 8387 - 8396. [Abstract] [Full Text] [PDF]

				F. Feng, A. Davis, J.-A. Lake, J. Carr, W. Xia, C. Burrell, and P. Li Ring Finger Protein ZIN Interacts with Human Immunodeficiency Virus Type 1 Vif J. Virol., October 1, 2004; 78(19): 10574 - 10581. [Abstract] [Full Text] [PDF]