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Journal of Virology, September 2009, p. 8364-8378, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00594-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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 ^,

Aemro Kassa,¹ Navid Madani,¹ Arne Schön,² Hillel Haim,¹ Andrés Finzi,¹ Shi-Hua Xiang,¹ Liping Wang,¹ Amy Princiotto,¹ Marie Pancera,³ Joel Courter,⁴ Amos B. Smith III,⁴ Ernesto Freire,² Peter D. Kwong,³ and Joseph Sodroski^1,5*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115,¹ Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218,² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,³ Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104,⁴ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115⁵

Received 23 March 2009/ Accepted 8 June 2009

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.

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* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Center for Life Science Building, Room 1009, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-3371. Fax: (671) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu

Published ahead of print on 17 June 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, September 2009, p. 8364-8378, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00594-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.