Previous Article | Next Article 
Journal of Virology, August 2007, p. 8201-8210, Vol. 81, No. 15
0022-538X/07/$08.00+0 doi:10.1128/JVI.00395-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Identification of Two Distinct Human Immunodeficiency Virus Type 1 Vif Determinants Critical for Interactions with Human APOBEC3G and APOBEC3F
Rebecca A. Russell and
Vinay K. Pathak*
Viral Mutation Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702
Received 23 February 2007/
Accepted 14 May 2007
Human cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) inhibit replication of Vif-deficient human immunodeficiency virus type 1 (HIV-1). HIV-1 Vif overcomes these host restriction factors by binding to them and inducing their proteasomal degradation. The Vif-A3G and Vif-A3F interactions are attractive targets for antiviral drug development because inhibiting the interactions could allow the host defense mechanism to control HIV-1 replication. It was recently reported that the Vif amino acids D14RMR17 are important for functional interaction and degradation of the previously identified Vif-resistant mutant of A3G (D128K-A3G). However, the Vif determinants important for functional interaction with A3G and A3F have not been fully characterized. To identify these determinants, we performed an extensive mutational analysis of HIV-1 Vif. Our analysis revealed two distinct Vif determinants, amino acids Y40RHHY44 and D14RMR17, which are essential for binding to A3G and A3F, respectively. Interestingly, mutation of the A3G-binding region increased Vif's ability to suppress A3F. Vif binding to D128K-A3G was also dependent on the Y40RHHY44 region but not the D14RMR17 region. Consistent with previous observations, subsequent neutralization of the D128K-A3G antiviral activity required substitution of Vif determinant D14RMR17 with SEMQ, similar to the SERQ amino acids in simian immunodeficiency virus SIVAGM Vif, which is capable of neutralizing D128K-A3G. These studies are the first to clearly identify two distinct regions of Vif that are critical for independent interactions with A3G and A3F. Pharmacological interference with the Vif-A3G or Vif-A3F interactions could result in potent inhibition of HIV-1 replication by the APOBEC3 proteins.
* Corresponding author. Mailing address: HIV Drug Resistance Program, National Cancer InstituteFrederick, P.O. Box B, Bldg. 535, Rm. 334, Frederick, MD 21702-1201. Phone: (301) 846-1710. Fax: (301) 846-6013. E-mail:
vpathak{at}ncifcrf.gov
Published ahead of print on 23 May 2007.
Journal of Virology, August 2007, p. 8201-8210, Vol. 81, No. 15
0022-538X/07/$08.00+0 doi:10.1128/JVI.00395-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
This article has been cited by other articles:
-
Chen, G., He, Z., Wang, T., Xu, R., Yu, X.-F.
(2009). A Patch of Positively Charged Amino Acids Surrounding the Human Immunodeficiency Virus Type 1 Vif SLVx4Yx9Y Motif Influences Its Interaction with APOBEC3G. J. Virol.
83: 8674-8682
[Abstract]
[Full Text]
-
Dang, Y., Wang, X., Zhou, T., York, I. A., Zheng, Y.-H.
(2009). Identification of a Novel WxSLVK Motif in the N Terminus of Human Immunodeficiency Virus and Simian Immunodeficiency Virus Vif That Is Critical for APOBEC3G and APOBEC3F Neutralization. J. Virol.
83: 8544-8552
[Abstract]
[Full Text]
-
Henriet, S., Mercenne, G., Bernacchi, S., Paillart, J.-C., Marquet, R.
(2009). 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.
73: 211-232
[Abstract]
[Full Text]
-
Kataropoulou, A., Bovolenta, C., Belfiore, A., Trabatti, S., Garbelli, A., Porcellini, S., Lupo, R., Maga, G.
(2009). Mutational analysis of the HIV-1 auxiliary protein Vif identifies independent domains important for the physical and functional interaction with HIV-1 reverse transcriptase. Nucleic Acids Res
37: 3660-3669
[Abstract]
[Full Text]
-
Malim, M. H
(2009). APOBEC proteins and intrinsic resistance to HIV-1 infection. Phil Trans R Soc B
364: 675-687
[Abstract]
[Full Text]
-
Pery, E., Rajendran, K. S., Brazier, A. J., Gabuzda, D.
(2009). Regulation of APOBEC3 Proteins by a Novel YXXL Motif in Human Immunodeficiency Virus Type 1 Vif and Simian Immunodeficiency Virus SIVagm Vif. J. Virol.
83: 2374-2381
[Abstract]
[Full Text]
-
Perkovic, M., Schmidt, S., Marino, D., Russell, R. A., Stauch, B., Hofmann, H., Kopietz, F., Kloke, B.-P., Zielonka, J., Strover, H., Hermle, J., Lindemann, D., Pathak, V. K., Schneider, G., Lochelt, M., Cichutek, K., Munk, C.
(2009). Species-specific Inhibition of APOBEC3C by the Prototype Foamy Virus Protein Bet. J. Biol. Chem.
284: 5819-5826
[Abstract]
[Full Text]
-
Russell, R. A., Smith, J., Barr, R., Bhattacharyya, D., Pathak, V. K.
(2009). Distinct Domains within APOBEC3G and APOBEC3F Interact with Separate Regions of Human Immunodeficiency Virus Type 1 Vif. J. Virol.
83: 1992-2003
[Abstract]
[Full Text]
-
Tan, L., Sarkis, P. T. N., Wang, T., Tian, C., Yu, X.-F.
(2009). Sole copy of Z2-type human cytidine deaminase APOBEC3H has inhibitory activity against retrotransposons and HIV-1. FASEB J.
23: 279-287
[Abstract]
[Full Text]
-
Bennett, R. P., Salter, J. D., Liu, X., Wedekind, J. E., Smith, H. C.
(2008). APOBEC3G Subunits Self-associate via the C-terminal Deaminase Domain. J. Biol. Chem.
283: 33329-33336
[Abstract]
[Full Text]
-
Watashi, K., Khan, M., Yedavalli, V. R. K., Yeung, M. L., Strebel, K., Jeang, K.-T.
(2008). Human Immunodeficiency Virus Type 1 Replication and Regulation of APOBEC3G by Peptidyl Prolyl Isomerase Pin1. J. Virol.
82: 9928-9936
[Abstract]
[Full Text]
-
DeHart, J. L., Bosque, A., Harris, R. S., Planelles, V.
(2008). Human Immunodeficiency Virus Type 1 Vif Induces Cell Cycle Delay via Recruitment of the Same E3 Ubiquitin Ligase Complex That Targets APOBEC3 Proteins for Degradation. J. Virol.
82: 9265-9272
[Abstract]
[Full Text]
-
Land, A. M., Ball, T. B., Luo, M., Pilon, R., Sandstrom, P., Embree, J. E., Wachihi, C., Kimani, J., Plummer, F. A.
(2008). Human Immunodeficiency Virus (HIV) Type 1 Proviral Hypermutation Correlates with CD4 Count in HIV-Infected Women from Kenya. J. Virol.
82: 8172-8182
[Abstract]
[Full Text]
-
Gallois-Montbrun, S., Holmes, R. K., Swanson, C. M., Fernandez-Ocana, M., Byers, H. L., Ward, M. A., Malim, M. H.
(2008). Comparison of Cellular Ribonucleoprotein Complexes Associated with the APOBEC3F and APOBEC3G Antiviral Proteins. J. Virol.
82: 5636-5642
[Abstract]
[Full Text]
-
Mulder, L. C. F., Harari, A., Simon, V.
(2008). Cytidine deamination induced HIV-1 drug resistance. Proc. Natl. Acad. Sci. USA
105: 5501-5506
[Abstract]
[Full Text]
-
Gandhi, S. K., Siliciano, J. D., Bailey, J. R., Siliciano, R. F., Blankson, J. N.
(2008). Role of APOBEC3G/F-Mediated Hypermutation in the Control of Human Immunodeficiency Virus Type 1 in Elite Suppressors. J. Virol.
82: 3125-3130
[Abstract]
[Full Text]
-
Virgen, C. A., Hatziioannou, T.
(2007). Antiretroviral Activity and Vif Sensitivity of Rhesus Macaque APOBEC3 Proteins. J. Virol.
81: 13932-13937
[Abstract]
[Full Text]
-
Mehle, A., Wilson, H., Zhang, C., Brazier, A. J., McPike, M., Pery, E., Gabuzda, D.
(2007). Identification of an APOBEC3G Binding Site in Human Immunodeficiency Virus Type 1 Vif and Inhibitors of Vif-APOBEC3G Binding. J. Virol.
81: 13235-13241
[Abstract]
[Full Text]