title: A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy.
abstract: BACKGROUND
  Immune activation is a strong predictor of disease progression in HIV infection. Combinatorial plasma biomarker signatures that represent surrogate markers of immune activation in both viremic and aviremic HIV patients on combination antiretroviral therapy (cART) have not been defined. Here, we identify a plasma inflammatory biomarker signature that distinguishes between both viremic and aviremic HIV patients on cART and healthy controls and examine relationships of this signature to markers of disease progression.
  
  
  METHODS
  Multiplex profiling and ELISA were used to detect 15 cytokines/chemokines, soluble IL-2R (sIL-2R), and soluble CD14 (sCD14) in plasma from 57 HIV patients with CD4 nadir <300 cells/µl and 29 healthy controls. Supervised and unsupervised analyses were used to identify biomarkers explaining variance between groups defined by HIV status or drug abuse. Relationships between biomarkers and disease markers were examined by Spearman correlation.
  
  
  RESULTS
  The majority (91%) of HIV subjects were on cART, with 38% having undetectable viral loads (VL). Hierarchical clustering identified a biomarker cluster in plasma consisting of two interferon-stimulated gene products (CXCL9 and CXCL10), T cell activation marker (sIL-2R), and monocyte activation marker (sCD14) that distinguished both viremic and aviremic HIV patients on cART from controls (p<0.0001) and were top-ranked in variables important in projection plots. IL-12 and CCL4 were also elevated in viremic and aviremic patients compared to controls (p<0.05). IL-12 correlated with IFNα, IFNγ, CXCL9, and sIL-2R (p<0.05). CXCL10 correlated positively with plasma VL and percentage of CD16+ monocytes, and inversely with CD4 count (p = 0.001, <0.0001, and 0.04, respectively).
  
  
  CONCLUSIONS
  A plasma inflammatory biomarker signature consisting of CXCL9, CXCL10, sIL-2R, and sCD14 may be useful as a surrogate marker to monitor immune activation in both viremic and aviremic HIV patients on cART during disease progression and therapeutic responses.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Anupa
authors.initials: A
authors.lastname: Kamat
authors.forename: Vikas
authors.initials: V
authors.lastname: Misra
authors.forename: Edana
authors.initials: E
authors.lastname: Cassol
authors.forename: Petronela
authors.initials: P
authors.lastname: Ancuta
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yan
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000097:blood; D054370:Chemokine CXCL9 / Q000097:blood; D015331:Cohort Studies; D003710:Demography; D016002:Discriminant Analysis; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications; D007372:Interferons / Q000378:metabolism; D016018:Least-Squares Analysis; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000097:blood; D019966:Substance-Related Disorders / Q000097:blood / Q000150:complications; D019562:Viral Load
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018950:Lipopolysaccharide Receptors; D015375:Receptors, Interleukin-2; D007372:Interferons