title: Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users.
abstract: BACKGROUND
  Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated.
  
  
  OBJECTIVE
  We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia.
  
  
  METHODS
  We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals.
  
  
  RESULTS
  As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion.
  
  
  CONCLUSIONS
  Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Costin
authors.initials: C
authors.lastname: Tomescu
authors.forename: Fuh-Mei
authors.initials: FM
authors.lastname: Duh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lanier
authors.forename: Angela
authors.initials: A
authors.lastname: Kapalko
authors.forename: Karam C
authors.initials: KC
authors.lastname: Mounzer
authors.forename: Maureen P
authors.initials: MP
authors.lastname: Martin
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: David S
authors.initials: DS
authors.lastname: Metzger
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D000328:Adult; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D018023:HIV Seronegativity; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D015143:Philadelphia; D015819:Substance Abuse, Intravenous / Q000276:immunology*