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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{triangledown}

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 Institute—Frederick, 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

{triangledown} 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.



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