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.