Mutation at a single position in the V2 domain of the HIV-1 envelope protein confers neutralization sensitivity to a highly neutralization-resistant virus.
Understanding the determinants of neutralization sensitivity and resistance is important for the development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. In these studies, we have made use of the swarm of closely related envelope protein variants (quasispecies) from an extremely neutralization-resistant clinical isolate in order to identify mutations that conferred neutralization sensitivity to antibodies in sera from HIV-1-infected individuals. Here, we describe a virus with a rare mutation at position 179 in the V2 domain of gp120, where replacement of aspartic acid (D) by asparagine (N) converts a virus that is highly resistant to neutralization by multiple polyclonal and monoclonal antibodies, as well as antiviral entry inhibitors, to one that is sensitive to neutralization. Although the V2 domain sequence is highly variable, D at position 179 is highly conserved in HIV-1 and simian immunodeficiency virus (SIV) and is located within the LDI/V recognition motif of the recently described α4β7 receptor binding site. Our results suggest that the D179N mutation induces a conformational change that exposes epitopes in both the gp120 and the gp41 portions of the envelope protein, such as the CD4 binding site and the MPER, that are normally concealed by conformational masking. Our results suggest that D179 plays a central role in maintaining the conformation and infectivity of HIV-1 as well as mediating binding to α4β7.
O'Rourke
Sara M
SM
Department of Biomolecular Engineering, Baskin School of Engineering, University of California, Santa Cruz, 1156 High Street, MS-SOE2, Santa Cruz, CA 95064, USA.
Schweighardt
Becky
B
Phung
Pham
P
Fonseca
Dora P A J
DP
Terry
Karianne
K
Wrin
Terri
T
Sinangil
Faruk
F
Berman
Phillip W
PW
D000914:Antibodies, Viral / Q000494:pharmacology*; D000937:Antigen-Antibody Reactions; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D020125:Mutation, Missense; D009500:Neutralization Tests; D011487:Protein Conformation / Q000187:drug effects
D000914:Antibodies, Viral; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D016023:Integrins; C071777:integrin alpha4beta7