title: 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.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Louie
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Bannock
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Leo J Y
authors.initials: LJ
authors.lastname: Kim
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ho
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Cody C
authors.initials: CC
authors.lastname: Frear
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Clarisa M
authors.initials: CM
authors.lastname: Buckner
authors.affiliation: Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Fankuchen
authors.affiliation: Critical Care Medicine Department, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Gittens
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.affiliation: Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA; Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Moir