Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding

Authors

Andrés Finzi, Department of Cancer Immunology and AIDS, Dana-Farber Cancer InstituteFollow
Beatriz Pacheco, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
Shi-Hua Xiang, University of Nebraska-LincolnFollow
Marie Pancera, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Alon Herschhorn, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
Liping Wang, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,
Xing Zeng, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,
Anik Desormeaux, Université de Montréal, Montréal
Peter D. Kwong, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Joseph Sodroski, Department of Cancer Immunology and AIDS, Dana-Farber Cancer InstituteFollow

Date of this Version

2012

Citation

Journal of Virology p. 8974–8986 September 2012 Volume 86 Number 17

Comments

Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Abstract

Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain β-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding.