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Journal of Virology, April 2007, p. 3807-3815, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02795-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of Amino Acid Residues in APOBEC3G Required for Regulation by Human Immunodeficiency Virus Type 1 Vif and Virion Encapsidation{triangledown}

Hendrik Huthoff and Michael H. Malim*

Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom

Received 19 December 2006/ Accepted 19 January 2007

The human immunodeficiency virus type-1 (HIV-1) accessory protein Vif serves to neutralize the human antiviral proteins apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G [A3G]) and A3F. As such, the therapeutic blockade of Vif function represents a logical objective for rational drug design. To facilitate such endeavors, we have employed molecular genetics to define features of A3G that are required for its interaction with Vif. Using alanine-scanning mutations and multiple different substitutions at key residues, we confirm the central role played by the aspartic acid at position 128 and identify proline 129 and aspartic acid 130 as important contributory residues. The overall negative charge of this 3-amino-acid motif appears critical for recognition by Vif, as single lysine substitutions are particularly deleterious and a double alanine substitution at positions 128 and 130 is far more inhibitory than single-residue mutations at either position. Our analyses also reveal that the immediately adjacent 4 amino acids, residues 124 to 127, are important for the packaging of A3G into HIV-1 particles. Most important are tyrosine 124 and tryptophan 127, and mutations at these positions can ablate virion incorporation, as well as the capacity to inhibit virus infection. Thus, while pharmacologic agents that target the acidic motif at residues 128 to 130 have the potential to rescue A3G expression by occluding recognition by Vif, care will have to be taken not to perturb the contributions of the neighboring 124-to-127 region to packaging if such agents are to have therapeutic benefit by promoting A3G incorporation into progeny virions.

* Corresponding author. Mailing address: Department of Infectious Diseases, King's College London School of Medicine, 2nd Floor, New Guy's House, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom. Phone: 44 0 20 7188 0149. Fax: 44 0 20 7188 0147. E-mail: michael.malim{at}kcl.ac.uk

{triangledown} Published ahead of print on 31 January 2007.

Journal of Virology, April 2007, p. 3807-3815, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02795-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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