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

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 1

Reduced SHMs among Ig heavy chains of TLM B cells despite higher KREC levels.

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Reduced SHMs among Ig heavy chains of TLM B cells despite higher KREC le...
(A) KREC analysis of B cell populations sorted from the peripheral blood of HIV-infected chronically viremic patients (n = 9–19 per population). Differences between naive and IM and all other populations were significant, although P values are not shown. (B) B cell populations were sorted from the peripheral blood of 3 patients (each identified by a different symbol) from A, and variable regions within the Ig heavy chains (VH) were amplified and sequenced. Mutation frequencies were calculated from nucleotide sequences and the number of clones sequenced per family ranged by population from 62 to 78 for VH1/7, 48 to 65 for VH3, and 45 to 60 for VH4. (C) R/S ratios were determined from the sequences in B. Horizontal bars represent the median values. P values were determined using Friedman/Wilcoxon signed-rank (A) and Kruskal-Wallis and Mann-Whitney U (B) tests. AM, activated memory; IM, intermediate memory; KREC, κ-deleting recombination excision circles; PB, plasmablast; RM, resting memory; R/S, replacement-to-silent; TLM, tissue-like memory.