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Maturational characteristics of HIV-specific antibodies in viremic individuals
Eric Meffre, … , Anthony S. Fauci, Susan Moir
Eric Meffre, … , Anthony S. Fauci, Susan Moir
Published March 17, 2016
Citation Information: JCI Insight. 2016;1(3):e84610. https://doi.org/10.1172/jci.insight.84610.
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Research Article AIDS/HIV Immunology

Maturational characteristics of HIV-specific antibodies in viremic individuals

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Abstract

Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4–binding site–sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs–specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.

Authors

Eric Meffre, Aaron Louie, Jason Bannock, Leo J.Y. Kim, Jason Ho, Cody C. Frear, Lela Kardava, Wei Wang, Clarisa M. Buckner, Yimeng Wang, Olivia R. Fankuchen, Kathleen R. Gittens, Tae-Wook Chun, Yuxing Li, Anthony S. Fauci, Susan Moir

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Figure 6

CD4bs mAbs derived from TLM B cells have lower HIV-neutralizing capacity than do those from RM B cells.

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CD4bs mAbs derived from TLM B cells have lower HIV-neutralizing capacity...
(A) HIV-neutralizing activities of the CD4bs mAbs (n = 110) were evaluated in TZM-bl cells with JRFL-enveloped HIV pseudotype virus. (B) HIV-neutralizing activities of the CD4bs mAbs were correlated between HXB2- and JRFL-enveloped pseudoviruses. Percentage of neutralization at maximum concentration of mAb (40 μg/ml) of the titration curve was used for the comparisons. Neutralization of JRFL was correlated with SHM percentages in variable segments of heavy (C) and light (D) chains of the corresponding mAbs. Horizontal bars represent median values, and symbols in correlations are the same as those used for the group analyses. *P < 0.05, by Mann-Whitney U test. CD4bs, CD4 binding site; Max, maximum; RM, resting memory; SHM, somatic hypermutation; TLM, tissue-like memory.

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