AEGiS-12IAC: Coreceptor utilization by divergent human immunodeficiency viruses involves a highly conserved envelope residue.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

Coreceptor utilization by divergent human immunodeficiency viruses involves a highly conserved envelope residue.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:5 (abstract no. 11115)

Wang WK, Dudek T, Zhao YJ, Brumblay HG, Essex M, Lee TH
Harvard School of Health, Boston, MA, USA.

BACKGROUND: Several seven-transmembrane chemokine receptors were recently found to double as a coreceptor for a genetically diverse family of human and non-human primate lentiviruses. Paradoxically, the main region believed to be involved in coreceptor utilization was mapped to the hypervariable region 3, or V3, of gp120. The question of whether functional convergence in coreceptor utilization is mediated by some V3 residues that are highly conserved among HIV-1, HIV-2, and SIV was addressed.

METHODS: Site-directed mutagenesis was carried out to introduce substitutions to highly conserved V3 residues in infectious molecular clones of HIV-1. The effect of substitution on envelope expression, processing and incorporation into virions was examined by Western blot. The effect on coreceptor utilization was monitored by the ability of the mutant viruses to infect cell lines stably transfected with various chemokine coreceptors.

RESULTS: A highly conserved arginine residue at position 298, Arg298, in the V3 of gp120 was found to have an important role in coreceptor utilization. The inability of Arg298 mutants to use chemokine coreceptors was not attributed to global alteration of gp120 conformation. Neither the expression, processing, and incorporation of mutant envelope proteins into virions, nor CD4 binding were significantly affected by the mutations. Substitutions introduced to adjacent V3 residues that are not as highly conserved as Arg298 had no discernible effect on coreceptor utilization.

CONCLUSIONS: Functional convergence in chemokine coreceptor utilization by genotypically divergent HIV-1 involves at least one highly conserved residue in the V3. Such highly conserved residues may represent a new class of targets for future anti-viral designs aimed at blocking interaction between HIV-1 and chemokine coreceptors.

Keywords: AEGIS, HIV-1, HIV-2, Antigens, CD4, SIV, Receptors, Chemokine, Virion, Mutagenesis, Site-Directed, Cell Line, Complementarity Determining Regions, Human, immunology, ICA12
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