title: Maturation-induced cloaking of neutralization epitopes on HIV-1 particles.
abstract: To become infectious, HIV-1 particles undergo a maturation process involving proteolytic cleavage of the Gag and Gag-Pol polyproteins. Immature particles contain a highly stable spherical Gag lattice and are impaired for fusion with target cells. The fusion impairment is relieved by truncation of the gp41 cytoplasmic tail (CT), indicating that an interaction between the immature viral core and gp41 within the particle represses HIV-1 fusion by an unknown mechanism. We hypothesized that the conformation of Env on the viral surface is regulated allosterically by interactions with the HIV-1 core during particle maturation. To test this, we quantified the binding of a panel of monoclonal antibodies to mature and immature HIV-1 particles by immunofluorescence imaging. Surprisingly, immature particles exhibited markedly enhanced binding of several gp41-specific antibodies, including two that recognize the membrane proximal external region (MPER) and neutralize diverse HIV-1 strains. Several of the differences in epitope exposure on mature and immature particles were abolished by truncation of the gp41 CT, thus linking the immature HIV-1 fusion defect with altered Env conformation. Our results suggest that perturbation of fusion-dependent Env conformational changes contributes to the impaired fusion of immature particles. Masking of neutralization-sensitive epitopes during particle maturation may contribute to HIV-1 immune evasion and has practical implications for vaccine strategies targeting the gp41 MPER.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Joyner
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Willis
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology*; D005455:Fluorescent Antibody Technique / Q000379:methods; D015967:Gene Expression Regulation, Viral; D015752:Genes, env; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D015151:Immunoblotting; D009500:Neutralization Tests; D014771:Virion / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41