Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein.

Valentine U Chukwuma,Spyros A Kalams,Katherine J Nicholas,Donald N Forthal,Amanda Joyner,Gary Landucci,Xuemin Chen,Mark D Hicar,James E Crowe,Paul W Spearman,Nicholas J Mantis

doi:10.1371/journal.pone.0133509

Valentine U Chukwuma, Spyros A Kalams + Show 9 more

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https://doi.org/10.1371/journal.pone.0133509

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Abstract

The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.

Highlights

The emergence of neutralizing antibody responses to HIV-1 in naturally infected humans is delayed compared to the induction of comparable antibodies following most other viral infections
We describe the isolation and characterization of a panel of monoclonal antibodies (mAbs) from an HIV-1 infected subject that reacted to Gag-only virus-like particles (VLPs) that were not expressing envelope
Through binding analysis of B cell supernates to HIV antigens, we identified a subset of six B cells that showed binding to HIV VLPs, but not to purified HIV Env proteins

Summary

Introduction

The emergence of neutralizing antibody responses to HIV-1 in naturally infected humans is delayed compared to the induction of comparable antibodies following most other viral infections. The basis for the slow kinetics of this HIV-1 neutralizing response is understood incompletely [1] One contributor to this delayed neutralizing response is the large number of highly antigenic epitopes that induce high titers of binding antibodies that are unable to neutralize infectious virus [2]. Many of these binding antibody epitopes are found in variable loops on the HIV-1 envelope (Env) glycoprotein, or on conformationally altered or incomplete forms of the glycoprotein [3]. By interacting with B cells and triggering intracellular signaling pathways, p17 protein has been shown to play a role in AIDS-associated lymphoma [13]

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