Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs.
Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4+T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cell-associated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis.IMPORTANCEIn recent years, isolation of new-generation HIV-1 bNAbs has invigorated HIV vaccine research. These bNAbs display remarkable potency and breadth of coverage against cell-free virus; however, they exhibit a diminished ability to block HIV-1 cell-to-cell transmission. The mechanism(s) by which HIV-1 resists neutralization when transmitting through VS remains uncertain. We examined a panel of bNAbs for their ability to neutralize HIV-1 T/F viruses in cell-to-cell infection assays. We found that some antibodies exhibit not only reduced potency but also decreased maximum neutralization capacity orin vitroefficacy against cell-to-cell infection of HIV-1 with T/F Envs compared to cell-free infection of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif YXXL as a determinant that can affect the incomplete neutralization phenotype of these T/F clones. When the maximum neutralization capacity falls short of 100%, this can have a major impact on the ability of antibodies to halt viral replication.
Microbiology Graduate School Training Program, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Division of Infectious Disease, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Hongru
H
Li
Microbiology Graduate School Training Program, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Division of Infectious Disease, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Chati
C
Zony
Division of Infectious Disease, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ping
P
Chen
Microbiology Graduate School Training Program, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA ben.chen@mssm.edu.|Division of Infectious Disease, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Benjamin K
BK
Chen
D057134:Antibodies, Neutralizing / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D009500:Neutralization Tests; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus
HIV-1 envelope (Env); broadly neutralizing antibodies (bNAbs); cell-to-cell infection; efficacy; human immunodeficiency virus subtype 1 (HIV-1); incomplete neutralization; maximum neutralization; potency; tyrosine-based sorting motif; virological synapse (VS)