Different Pattern of Immunoglobulin Gene Usage by HIV-1 Compared to Non-HIV-1 Antibodies Derived from the Same Infected Subject

Liuzhe Li,Xuemin Chen,Michael S Seaman,Constance Williams,Diana Virland,Miroslaw K Gorny,Susan Zolla-Pazner,Barbara Volsky,Paul Spearman,Sagarika Banerjee,Xiao-Hong Wang,Arthur Nadas,Yoshihiko Hoshino

doi:10.1371/journal.pone.0039534

Abstract

A biased usage of immunoglobulin (Ig) genes is observed in human anti-HIV-1 monoclonal antibodies (mAbs) resulting probably from compensation to reduced usage of the VH3 family genes, while the other alternative suggests that this bias usage is due to antigen requirements. If the antigen structure is responsible for the preferential usage of particular Ig genes, it may have certain implications for HIV vaccine development by the targeting of particular Ig gene-encoded B cell receptors to induce neutralizing anti-HIV-1 antibodies. To address this issue, we have produced HIV-1 specific and non-HIV-1 mAbs from an infected individual and analyzed the Ig gene usage. Green-fluorescence labeled virus-like particles (VLP) expressing HIV-1 envelope (Env) proteins of JRFL and BaL and control VLPs (without Env) were used to select single B cells for the production of 68 recombinant mAbs. Ten of these mAbs were HIV-1 Env specific with neutralizing activity against V3 and the CD4 binding site, as well as non-neutralizing mAbs to gp41. The remaining 58 mAbs were non-HIV-1 Env mAbs with undefined specificities. Analysis revealed that biased usage of Ig genes was restricted only to anti-HIV-1 but not to non-HIV-1 mAbs. The VH1 family genes were dominantly used, followed by VH3, VH4, and VH5 among anti-HIV-1 mAbs, while non-HIV-1 specific mAbs preferentially used VH3 family genes, followed by VH4, VH1 and VH5 families in a pattern identical to Abs derived from healthy individuals. This observation suggests that the biased usage of Ig genes by anti-HIV-1 mAbs is driven by structural requirements of the virus antigens rather than by compensation to any depletion of VH3 B cells due to autoreactive mechanisms, according to the gp120 superantigen hypothesis.

Highlights

Neutralizing antibodies (Abs) are critical elements in vaccine development as they form the first line of defense against pathogens and are associated with protection against virus infection [1]
Ig variable genes coding for heavy chains are used by human anti-HIV-1 monoclonal antibodies (mAbs) with different frequencies compared to Abs from healthy individuals
PBMCs were purified from the blood sample of one NYU IRB-approved HIV-1 infected volunteer

Summary

Introduction

Neutralizing antibodies (Abs) are critical elements in vaccine development as they form the first line of defense against pathogens and are associated with protection against virus infection [1]. We have shown that anti-V3 mAbs preferentially use the VH5-51 gene segment [9,15]. This suggests that biased usage of Ig genes may depend on antigen requirements and that only certain Ig geneencoded Abs fit well and with high initial affinity to Env antigens. If this hypothesis is correct, targeting such Ig genes may trigger Abs with enhanced affinity maturation to the HIV-1 epitopes

Methods

Results

Conclusion