Transitions to and from the CD4-Bound Conformation Are Modulated by a Single-Residue Change in the Human Immunodeficiency Virus Type 1 gp120 Inner Domain

Authors

• Aemro Kassa, Harvard Medical School
• Navid Madani, Harvard Medical School
• Arne Schön, Johns Hopkins University
• Hillel Haim, Harvard Medical School
• Andrés Finzi, Harvard Medical SchoolFollow
• Shi-Hua Xiang, University of Nebraska-LincolnFollow
• Liping Wang, Harvard Medical School
• Amy Princiotto, Harvard Medical School
• Marie Pancera, National Institutes of Health, Bethesda, Maryland
• Joel Courter, University of Pennsylvania
• Amos B. Smith III, University of Pennsylvania
• Ernesto Freire, Johns Hopkins University
• Peter D. Kwong, National Institutes of Health, Bethesda, Maryland
• Joseph Sodroski, Harvard Medical SchoolFollow

Document Type

Article

Date of this Version

9-2009

Comments

Published in JOURNAL OF VIROLOGY, Sept. 2009, p. 8364–8378 Vol. 83, No. 17 Copyright © 2009, American Society for Microbiology. Used by permission

Abstract

Binding to the primary receptor CD4 induces conformational changes in the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein that allow binding to the coreceptor (CCR5 or CXCR4) and ultimately trigger viral membrane-cell membrane fusion mediated by the gp41 transmembrane envelope glycoprotein. Here we report the derivation of an HIV-1 gp120 variant, H66N, that confers envelope glycoprotein resistance to temperature extremes. The H66N change decreases the spontaneous sampling of the CD4-bound conformation by the HIV-1 envelope glycoproteins, thus diminishing CD4-independent infection. The H66N change also stabilizes the HIV-1 envelope glycoprotein complex once the CD4-bound state is achieved, decreasing the probability of CD4-induced inactivation and revealing the enhancing effects of soluble CD4 binding on HIV-1 infection. In the CD4-bound conformation, the highly conserved histidine 66 is located between the receptor-binding and gp41-interactive surfaces of gp120. Thus, a single amino acid change in this strategically positioned gp120 inner domain residue influences the propensity of the HIV-1 envelope glycoproteins to negotiate conformational transitions to and from the CD4-bound state.