An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1
Mattia Bonsignori, … , John R. Mascola, Barton F. Haynes
Mattia Bonsignori, … , John R. Mascola, Barton F. Haynes
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1835-1843. https://doi.org/10.1172/JCI73441.
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An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1

Abstract

Broadly HIV-1–neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1–infected individuals with autoimmune disease and defective immune tolerance mechanisms may produce BnAbs more readily than those without autoimmune diseases. In this study, we identified an HIV-1–infected individual with SLE who exhibited controlled viral load (<5,000 copies/ml) in the absence of controlling HLA phenotypes and developed plasma HIV-1 neutralization breadth. We collected memory B cells from this individual and isolated a BnAb, CH98, that targets the CD4 binding site (CD4bs) of HIV-1 envelope glycoprotein 120 (gp120). CH98 bound to human antigens including dsDNA, which is specifically associated with SLE. Anti-dsDNA reactivity was also present in the patient’s plasma. CH98 had a mutation frequency of 25% and 15% nt somatic mutations in the heavy and light chain variable domains, respectively, a long HCDR3, and a deletion in the light chain CDR1. The occurrence of anti-dsDNA reactivity by a HIV-1 CD4bs BnAb in an individual with SLE raises the possibility that some BnAbs and SLE-associated autoantibodies arise from similar pools of B cells.

Authors

Mattia Bonsignori, Kevin Wiehe, Sebastian K. Grimm, Rebecca Lynch, Guang Yang, Daniel M. Kozink, Florence Perrin, Abby J. Cooper, Kwan-Ki Hwang, Xi Chen, Mengfei Liu, Krisha McKee, Robert J. Parks, Joshua Eudailey, Minyue Wang, Megan Clowse, Lisa G. Criscione-Schreiber, M. Anthony Moody, Margaret E. Ackerman, Scott D. Boyd, Feng Gao, Garnett Kelsoe, Laurent Verkoczy, Georgia D. Tomaras, Hua-Xin Liao, Thomas B. Kepler, David C. Montefiori, John R. Mascola, Barton F. Haynes

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Figure 1

Identification of neutralizing CD4bs antibodies in CH5329 serum.

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Identification of neutralizing CD4bs antibodies in CH5329 serum. (A) CH5...
(A) CH5329 plasma and mAb CH98 neutralization profiles, measured as ID50 and IC50,respectively, in TZM-bl assay. Transmitted/founder HIV-1 isolates are italicized. For plasma neutralization: red, ID50 >1,000; orange, ID50 100 to 1,000; yellow, ID50 >20 and <100; white, ID50 <20 (absence of neutralization). For CH98 BnAb: red, IC50 <1 μg/ml; orange, IC50 1 to 50 μg/ml; white, IC50 >50 μg/ml (absence of neutralization). (B) Differential binding by CH5329 serum to the RSC3 protein and the CD4bs knockout RSC3Δ371I/P363N, graphed as ELISA endpoint titer (final reciprocal serum dilution with background-corrected OD ≥0.1). (C) CD4bs-directed neutralizing activity in CH5329 serum, shown as percent reduction in ID80 in the presence of RSC3 compared with the knockout RSC3Δ371I/P363N against HIV-1 JRFL and HxB2 strains. Values for the BnAbs VRC01 and 2F5 are included as positive and negative control, respectively. In B and C, error bars represent SEM from 2 independent experiments.