title: Type I interferon-dependent gene MxA in perinatal HIV-infected patients under antiretroviral therapy as marker for therapy failure and blood plasmacytoid dendritic cells depletion.
abstract: BACKGROUND
  To determine the role of interferon-alpha in controlling HIV infection we phenotypically and functionally analyzed circulating plasmacytoid dendritic cells (pDC), which are known to be the highest interferon-alpha producing cells, in 33 perinatally infected HIV+ patients undergoing standard antiretroviral therapy.
  
  
  METHODS
  Circulating pDC were identified by flow cytometry using anti-BDCA-2 monoclonal antibody and by measuring BDCA-2 mRNA by real-time PCR, while tissue-resident pDC were identified by immunohistochemistry. mRNA for interferon-alpha and MxA, a gene that is specifically induced by interferon-alpha, was quantified in peripheral blood cells by real-time PCR, while serum interferon-alpha protein was measured by ELISA.
  
  
  RESULTS
  While median values of pDC, both in terms of percentage and absolute number, were not statistically different from age-matched controls, interferon-alpha mRNA was increased in HIV-infected patients. However, in a group of patients with long disease duration, having a low number of both pDC and CD4+ lymphocytes and a significant increase of serum interferon-alpha, MxA mRNA was produced at high level and its expression directly correlated with HIV RNA copy numbers. Furthermore in patients displaying a low CD4+ blood cell count, a severe depletion of pDC in the tonsils could be documented.
  
  
  CONCLUSIONS
  HIV replication unresponsive to antiretroviral treatment in perinatal-infected patients with advanced disease and pDC depletion may lead to interferon-alpha expression and subsequent induction of MxA mRNA. Thus, the latter measurement may represent a valuable marker to monitor the clinical response to therapy in HIV patients.
authors.affiliation: Istituto di Medicina Molecolare Angelo Nocivelli, Department of Pediatrics, University of Brescia, Brescia 25123, Italy. badolato@med.unibs.it
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
authors.forename: Claudia
authors.initials: C
authors.lastname: Ghidini
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Federico
authors.initials: F
authors.lastname: Serana
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sottini
authors.forename: Marco
authors.initials: M
authors.lastname: Chiarini
authors.forename: Elena
authors.initials: E
authors.lastname: Spinelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Luigi
authors.initials: L
authors.lastname: Caimi
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000473:pathology* / Q000821:virology; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D008221:Lymphoid Tissue / Q000473:pathology / Q000821:virology; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017211:Treatment Failure
chemical_list: D015415:Biomarkers; D007370:Interferon Type I; D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D019204:GTP-Binding Proteins
references.citation: J Am Soc Nephrol. 1998 Dec;9(12):2344-8
references.pmid: 9848789
references.citation: J Gen Virol. 2000 Sep;81(Pt 9):2215-2218
references.pmid: 10950979
references.citation: HIV Med. 2004 Jul;5 Suppl 2:61-86
references.pmid: 15239717
references.citation: AIDS Res Hum Retroviruses. 2006 Sep;22(9):893-6
references.pmid: 16989615
references.citation: J Virol. 2004 May;78(10):5223-32
references.pmid: 15113904
references.citation: AIDS Res Hum Retroviruses. 1991 Apr;7(4):375-80
references.pmid: 1906289
references.citation: Antivir Ther. 2002 Dec;7(4):293-303
references.pmid: 12553485
references.citation: J Immunol. 2006 May 1;176(9):5644-51
references.pmid: 16622034
references.citation: Semin Immunol. 2005 Aug;17(4):253-61
references.pmid: 15990333
references.citation: Immunol Lett. 2006 Nov 15;107(2):89-92
references.pmid: 16963128
references.citation: J Neuroimmunol. 2007 Sep;189(1-2):102-10
references.pmid: 17619058
references.citation: Haematologica. 2004 Apr;89(4):450-61
references.pmid: 15075079
references.citation: Blood. 1997 Nov 1;90(9):3245-87
references.pmid: 9345009
references.citation: J Acquir Immune Defic Syndr. 2008 May 1;48(1):1-12
references.pmid: 18300699
references.citation: Pediatr Infect Dis J. 2005 Aug;24(8):747-9
references.pmid: 16094240
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: Clin Immunol. 2008 May;127(2):252-64
references.pmid: 18342575
references.citation: J Virol. 2005 Jan;79(1):17-27
references.pmid: 15596797
references.citation: Clin Pharmacokinet. 1990 Nov;19(5):390-9
references.pmid: 1702693
references.citation: Nat Immunol. 2004 Dec;5(12):1219-26
references.pmid: 15549123
references.citation: J Infect Dis. 2005 May 1;191(9):1451-9
references.pmid: 15809903
references.citation: Annu Rev Immunol. 2005;23:275-306
references.pmid: 15771572
references.citation: J Infect Dis. 2003 Jan 1;187(1):26-37
references.pmid: 12508143
references.citation: AIDS. 2005 Feb 18;19(3):261-71
references.pmid: 15718836
references.citation: Curr Opin Pediatr. 2004 Feb;16(1):76-9
references.pmid: 14758118
references.citation: Cell Mol Biol Lett. 2004;9(3):497-509
references.pmid: 15332126
references.citation: Blood. 2007 May 15;109(10):4272-9
references.pmid: 17289812
references.citation: Eur J Immunol. 1990 Sep;20(9):2015-9
references.pmid: 2120071
references.citation: Clin Immunol. 2001 Nov;101(2):201-10
references.pmid: 11683579
references.citation: Hepatology. 1994 Apr;19(4):857-65
references.pmid: 8138257
references.citation: Proc Soc Exp Biol Med. 1985 Mar;178(3):407-11
references.pmid: 3919398
references.citation: Science. 1999 Jun 11;284(5421):1835-7
references.pmid: 10364556
references.citation: Blood. 2001 Oct 15;98(8):2574-6
references.pmid: 11588058
references.citation: Clin Immunol. 2007 May;123(2):121-8
references.pmid: 17112786
references.citation: Mol Cell Biol. 1989 Nov;9(11):5062-72
references.pmid: 2481229
references.citation: J Infect Dis. 2002 Aug 1;186(3):312-20
references.pmid: 12134227
references.citation: Nat Med. 1999 Nov;5(11):1232-3
references.pmid: 10545981
references.citation: J Virol Methods. 1998 Feb;70(2):183-91
references.pmid: 9562412
references.citation: Mol Diagn. 2003;7(1):17-25
references.pmid: 14529316
references.citation: J Immunol. 2004 Dec 15;173(12):7269-76
references.pmid: 15585849
references.citation: Scand J Immunol. 2002 May;55(5):453-7
references.pmid: 11975756
references.citation: Blood. 2001 Aug 15;98(4):906-12
references.pmid: 11493432
references.citation: J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Apr 15;20(5):468-73
references.pmid: 10225229
references.citation: Lancet. 1987 Nov 7;2(8567):1092-3
references.pmid: 2890005
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3851-6
references.pmid: 9520456
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7000-5
references.pmid: 16632604
references.citation: J Exp Med. 2001 Dec 17;194(12):1823-34
references.pmid: 11748283
references.citation: Blood. 2001 Nov 15;98(10):3016-21
references.pmid: 11698285
references.citation: J Immunol. 2002 May 1;168(9):4796-801
references.pmid: 11971031
references.citation: Blood. 2003 Dec 1;102(12):4099-106
references.pmid: 12893749
references.citation: Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S67-71
references.pmid: 7551417