title: Neutralization resistance of virological synapse-mediated HIV-1 Infection is regulated by the gp41 cytoplasmic tail.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection can spread efficiently from infected to uninfected T cells through adhesive contacts called virological synapses (VSs). In this process, cell-surface envelope glycoprotein (Env) initiates adhesion and viral transfer into an uninfected recipient cell. Previous studies have found some HIV-1-neutralizing patient sera to be less effective at blocking VS-mediated infection than infection with cell-free virus. Here we employ sensitive flow cytometry-based infection assays to measure the inhibitory potency of HIV-1-neutralizing monoclonal antibodies (MAb) and HIV-1-neutralizing patient sera against cell-free and VS-mediated infection. To various degrees, anti-Env MAbs exhibited significantly higher 50% inhibitory concentration (IC(50)s) against VS-mediated infection than cell-free infection. Notably, the MAb 17b, which binds a CD4-induced (CD4i) epitope on gp120, displayed a 72-fold reduced efficacy against VS-mediated inocula compared to cell-free inocula. A mutant with truncation mutation in the gp41 cytoplasmic tail (CT) which is unable to modulate Env fusogenicity in response to virus particle maturation but which can still engage in cell-to-cell infection was tested for the ability to resist neutralizing antibodies. The ΔCT mutation increased cell surface staining by neutralizing antibodies, significantly enhanced neutralization of VS-mediated infection, and had reduced or no effect on cell-free infection, depending upon the antibody. Our results suggest that the gp41 CT regulates the exposure of key neutralizing epitopes during cell-to-cell infection and plays an important role in immune evasion. Vaccine strategies should consider immunogens that reflect Env conformations exposed on the infected cell surface to enhance protection against VS-mediated HIV-1 spread.
authors.affiliation: Microbiology Graduate School Training Program, Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Natasha D
authors.initials: ND
authors.lastname: Durham
authors.forename: Alice W
authors.initials: AW
authors.lastname: Yewdall
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lee
authors.forename: Chati
authors.initials: C
authors.lastname: Zony
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D009154:Mutation; D053585:Virus Attachment
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514787:gp41 protein, Human immunodeficiency virus 1