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J. Virol. doi:10.1128/JVI.02795-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of amino acid residues in APOBEC3G required for regulation by HIV-1 Vif and virion encapsidation

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

^* To whom correspondence should be addressed. Email: michael.malim{at}kcl.ac.uk.

	Abstract

The human immunodeficiency virus type-1 (HIV-1) accessory protein Vif serves to neutralise the human antiviral proteins APOBEC3G (A3G) and APOBEC3F (A3F). As such, the therapeutic blockade of Vif function represents a logical objective for rational drug design. To facilitate such endeavours, 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 three 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 four amino acids, residues 124 to 127, are important for the packaging of A3G into HIV-1 virus 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 neighbouring 124 to 127 region to packaging if such agents are to have therapeutic benefit by promoting A3G incorporation into progeny virions.

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