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.
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.
Kassa
Aemro
A
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
Madani
Navid
N
Schön
Arne
A
Haim
Hillel
H
Finzi
Andrés
A
Xiang
Shi-Hua
SH
Wang
Liping
L
Princiotto
Amy
A
Pancera
Marie
M
Courter
Joel
J
Smith
Amos B
AB
Freire
Ernesto
E
Kwong
Peter D
PD
Sodroski
Joseph
J
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
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1