title: 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.
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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Aemro
authors.initials: A
authors.lastname: Kassa
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Hillel
authors.initials: H
authors.lastname: Haim
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Amy
authors.initials: A
authors.lastname: Princiotto
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.forename: Joel
authors.initials: J
authors.lastname: Courter
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D019943:Amino Acid Substitution; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D053585:Virus Attachment
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1