IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria.

Kwan‐Ki Hwang ,Nicholas Chiorazzi,Shi-Mao Xia,Minyue Wang,Charles C Chu,Garnett Kelsoe,Kevin Wiehe,Dawn J Marshall,Abby J Cooper,Ashley M Trama,Munir Alam,Rosa Catera,Daniel M Kozink,Georgia D Tomaras,Barton F Haynes,Xi Chen,John F Whitesides ,R Kanti ,Jane A Mckeating ,Sheila Allen ,Xiao‐Jie Yan ,Hua‐Xin Liao

doi:10.1371/journal.pone.0090725

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) patients expressing unmutated immunoglobulin heavy variable regions (IGHVs) use the IGHV1-69 B cell receptor (BCR) in 25% of cases. Since HIV-1 envelope gp41 antibodies also frequently use IGHV1-69 gene segments, we hypothesized that IGHV1-69 B-CLL precursors may contribute to the gp41 B cell response during HIV-1 infection. To test this hypothesis, we rescued 5 IGHV1-69 unmutated antibodies as heterohybridoma IgM paraproteins and as recombinant IgG1 antibodies from B-CLL patients, determined their antigenic specificities and analyzed BCR sequences. IGHV1-69 B-CLL antibodies were enriched for reactivity with HIV-1 envelope gp41, influenza, hepatitis C virus E2 protein and intestinal commensal bacteria. These IGHV1-69 B-CLL antibodies preferentially used IGHD3 and IGHJ6 gene segments and had long heavy chain complementary determining region 3s (HCDR3s) (≥21 aa). IGHV1-69 B-CLL BCRs exhibited a phenylalanine at position 54 (F54) of the HCDR2 as do rare HIV-1 gp41 and influenza hemagglutinin stem neutralizing antibodies, while IGHV1-69 gp41 antibodies induced by HIV-1 infection predominantly used leucine (L54) allelic variants. These results demonstrate that the B-CLL cell population is an expansion of members of the innate polyreactive B cell repertoire with reactivity to a number of infectious agent antigens including intestinal commensal bacteria. The B-CLL IGHV1-69 B cell usage of F54 allelic variants strongly suggests that IGHV1-69 B-CLL gp41 antibodies derive from a restricted B cell pool that also produces rare HIV-1 gp41 and influenza hemagglutinin stem antibodies.

Highlights

The initial B cell responses to HIV-1 envelope (Env) gp41 are non-neutralizing [1] and are polyreactive with human intestinal commensal bacterial antigens [2]
We have demonstrated that one third of IGHV1-69 B chronic lymphocytic leukemia (B-CLL) B cell receptor (BCR) are polyreactive for infectious agent or commensal bacterial antigens (Figure S1 and Figure 1)
While IGHV1-69 B-CLL BCRs predominantly used F54 allelic variants, IGHV1-69 HIV-1 Env gp41 antibodies from HIV-1 infected patients predominantly used L54 (Table 1)

Summary

Introduction

The initial B cell responses to HIV-1 envelope (Env) gp are non-neutralizing [1] and are polyreactive with human intestinal commensal bacterial antigens [2]. It has been proposed that B-CLL cells derive from human B-1-like cells, marginal zone (MZ) innate B cells, or transitional B cells, based on cell surface phenotype and molecular and functional characteristics [11]. In this regard, recent studies identified a human equivalent of murine B-1 cells (CD20+, CD27+, CD43+, CD702) [12] and circulating CD5+ human B cells [13] as the precursors of CLL B cells. Anti-viral innate antibodies have been reported to be derived from B-1/MZ B cells [15,16,17]

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