title: Innate activation of MDC and NK cells in high-risk HIV-1-exposed seronegative IV-drug users who share needles when compared with low-risk nonsharing IV-drug user controls.
abstract: BACKGROUND
  Previous studies have described increased innate immune activation in HIV-1-exposed seronegative intravenous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation.
  
  
  METHODS
  In this study, we investigated innate [natural killer (NK) cells and dendritic cells] and adaptive (HIV-specific antibody and CD8 T cell) immune parameters among a high-risk cohort of needle-sharing HESN-IDU subjects and compared them with low-risk nonsharing IDU subjects (NS-IDU) and non-drug-user controls.
  
  
  RESULTS
  We observed that HIV-specific antibody and CD8 T-cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and myeloid dendritic cells (CD40 and CD83 upregulation) when compared with NS-IDU subjects or non-drug-user controls (P < 0.01 and P < 0.05, respectively). HESN-IDU subjects maintained strong NK-cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha, and MIP-1 beta) production after target cell incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (ρ = 0.5073, P = 0.0059, n = 28).
  
  
  CONCLUSIONS
  Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (ie, exposure to pathogens or heterologous cells among donor blood).
authors.affiliation: *HIV Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA; †Duke Human Vaccine Institute, Duke University, Durham, NC; and ‡HIV Prevention Division, Department of Psychiatry, The University of Pennsylvania, Philadelphia, PA.
authors.forename: Costin
authors.initials: C
authors.lastname: Tomescu
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Seaton
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Mack
authors.initials: M
authors.lastname: Taylor
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.forename: David S
authors.initials: DS
authors.lastname: Metzger
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood; D015488:HIV Antigens / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016485:Needle Sharing; D015819:Substance Abuse, Intravenous
chemical_list: D015483:HIV Antibodies; D015488:HIV Antigens