title: Decreased mutation frequencies among immunoglobulin G variable region genes during viremic HIV-1 infection.
abstract: OBJECTIVE
  HIV-1 infection is complicated by high rates of opportunistic infections against which specific antibodies contribute to immune defense. Antibody function depends on somatic hypermutation (SHM) of variable regions of immunoglobulin heavy chain genes (VH-D-J). We characterized the frequency of SHM in expressed IgG mRNA immunoglobulin transcripts from control and HIV-1-infected patients.
  
  
  METHODS
  We compared utilization of genes in the most prominent VH family (VH3) and mutation frequencies and patterns of cDNA from VH3-IgG genes from 10 seronegative control subjects and 21 patients with HIV-1 infection (6 without and 15 patients with detectable plasma viremia).
  
  
  METHODS
  Unique IgG VH3 family cDNA sequences (n = 1,565) were PCR amplified, cloned, and sequenced from blood. Sequences were analyzed using online (Vbase) and in-house immunoglobulin alignment resources.
  
  
  RESULTS
  Mutation frequencies in the antigen-binding hypervariable complementarity determining regions (CDR1/2) of IgG class-switched B cells were lower among viremic HIV-1-infected patients vs. controls for nucleotides (CDR1/2: 10±5% vs. 13.5±6%, p = 0.03) and amino acids (CDR: 20%±10 vs. 25%±12, p = 0.02) and in structural framework regions. Mutation patterns were similar among groups. The most common VH3 gene, VH3-23, was utilized less frequently among viremic HIV-1-infected patients (p = 0.03), and overall, mutation frequencies were decreased in nearly all VH3 genes compared with controls.
  
  
  CONCLUSIONS
  B cells from HIV-1-infected patients show decreased mutation frequencies, especially in antigen-binding VH3 CDR genes, and selective defects in gene utilization. Similar mutation patterns suggest defects in the quantity, but not quality, of mutator activity. Lower levels of SHM in IgG class-switched B cells from HIV-1-infected patients may contribute to the increased risk of opportunistic infections and impaired humoral responses to preventative vaccines.
authors.affiliation: Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, Colorado, United States of America ; Infectious Disease Division, University of Colorado Denver, Aurora, Colorado, United States of America ; Department of Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America ; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bowers
authors.affiliation: Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Scamurra
authors.affiliation: Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Asrani
authors.affiliation: GIMAP EA 3064, Faculté de Médecine, Université Jean Monnet, Saint Etienne, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Beniguel
authors.affiliation: Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, Colorado, United States of America ; Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.affiliation: Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, Colorado, United States of America ; Infectious Disease Division, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Kathryne M
authors.initials: KM
authors.lastname: Keays
authors.affiliation: Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Thurn
authors.affiliation: Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, Colorado, United States of America ; Infectious Disease Division, University of Colorado Denver, Aurora, Colorado, United States of America ; Department of Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America ; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Janoff
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D022801:Complementarity Determining Regions / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D014766:Viremia; D055815:Young Adult
chemical_list: D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region