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J. Biol. Chem., Vol. 278, Issue 43, 42149-42160, October 24, 2003

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Functional Evolution of the HIV-1 Envelope Glycoprotein 120 Association Site of Glycoprotein 41^*

Pantelis Poumbourios, Anne L. Maerz, and Heidi E. Drummer

From the St. Vincent's Institute of Medical Research, Fitzroy Victoria 3065, Australia

Protein-protein interaction surfaces can exhibit structural plasticity, a mechanism whereby an interface adapts to mutations as binding partners coevolve. The HIV-1 envelope glycoprotein gp120-gp41 complex, which is responsible for receptor attachment and membrane fusion, represents an extreme example of a coevolving complex as up to 35% amino acid sequence divergence has been observed in these proteins among HIV-1 isolates. In this study, the function of conserved gp120 contact residues, Leu⁵⁹³, Trp⁵⁹⁶, Gly⁵⁹⁷, Lys⁶⁰¹, and Trp⁶¹⁰ within the disulfide-bonded region of gp41, was examined in envelope glycoproteins derived from diverse HIV-1 isolates. We found that the gp120-gp41 association function of the disulfide-bonded region is conserved. However, the contribution of individual residues to gp41 folding and/or stability, gp120-gp41 association, membrane fusion function, and viral entry varied from isolate to isolate. In gp120-gp41 derived from the dual-tropic isolate, HIV-1_89.6, the importance of Trp⁵⁹⁶ for fusion function was dependent on the chemokine receptor utilized as a fusion cofactor. Thus, the engagement of alternative chemokine receptors may evoke distinct fusion-activation signals involving the site of gp120-gp41 association. An examination of chimeric glycoproteins revealed that the isolate-specific functional contributions of particular gp120-contact residues are influenced by the sequence of gp120 hypervariable regions 1, 2, and 3. These data indicate that the gp120-gp41 association site is structurally and functionally adaptable, perhaps to maintain a functional glycoprotein complex in a setting of host selective pressures driving the rapid coevolution of gp120 and gp41.

Received for publication, May 19, 2003 , and in revised form, August 8, 2003.

^* This work was supported by National Health and Medical Research Council Project Grants 205306 and 156714. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Virology Unit, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. Tel.: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail: apoum{at}ariel.its.unimelb.edu.au.

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