Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy.
BACKGROUND
To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)-6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART).


METHODS
A case-control study of subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, who were matched according to the CD4 cell count and plasma viral load at baseline, was performed using conditional logistic regression.


RESULTS
Higher pretreatment concentrations of sTNFR-1, sCD27, sCD40L, and plasma IL-6 were associated with a new AIDS-defining illness or death in separate models adjusted for age, sex, hemoglobin, and the latest CD4 cell counts. In additional models that excluded case patients with opportunistic infections, sTNFR-1, sCD27, and sCD40L were each associated with a new AIDS-defining malignancy or death that developed at a median of 51 weeks after initiation of HAART, by which time the majority of subjects had a CD4 cell count of >200 cells/cm(3) and had achieved a plasma viral load of <50 copies/mL.


CONCLUSIONS
These data are compatible with a model in which these soluble inflammatory markers identify pathways that may contribute to the pathogenesis of HIV disease progression, pathways that might not be a direct consequence of ongoing HIV type 1 replication.
Kalayjian
Robert C
RC
MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109-1998, USA. rkalayjian@metrohealth.org
Machekano
Rhoderick N
RN
Rizk
Nesrine
N
Robbins
Gregory K
GK
Gandhi
Rajesh T
RT
Rodriguez
Benigno A
BA
Pollard
Richard B
RB
Lederman
Michael M
MM
Landay
Alan
A
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D019562:Viral Load
D019380:Anti-HIV Agents; D015415:Biomarkers; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor
J Infect Dis. 2005 Mar 1;191(5):694-701
15688282
J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):426-34
16810109
Clin Immunol. 1999 Sep;92(3):293-9
10479534
J Immunol. 2009 Apr 1;182(7):4237-43
19299722
J Infect Dis. 2009 Apr 15;199(8):1177-85
19265479
J Gerontol A Biol Sci Med Sci. 1997 Mar;52(2):B93-7
9060965
J Infect Dis. 2008 Apr 15;197(8):1145-55
18476293
AIDS. 2009 Jan 28;23(3):335-42
19114870
Clin Diagn Lab Immunol. 2002 May;9(3):558-61
11986259
J Infect Dis. 2009 Sep 15;200(6):973-83
19678756
J Infect Dis. 2002 Feb 15;185(4):456-62
11865397
Clin Diagn Lab Immunol. 1998 Sep;5(5):597-603
9729522
N Engl J Med. 2003 Dec 11;349(24):2304-15
14668456
Nat Med. 2006 Dec;12(12):1365-71
17115046
Blood. 2009 Jan 8;113(2):377-88
18824599
J Immunol. 1991 Jul 1;147(1):29-35
1646845
PLoS Med. 2008 Oct 21;5(10):e203
18942885
N Engl J Med. 2009 Apr 30;360(18):1815-26
19339714
N Engl J Med. 2004 Dec 16;351(25):2599-610
15602020
J Infect Dis. 1994 Apr;169(4):739-45
7907641
Cell. 1995 Dec 1;83(5):793-802
8521496
Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1694-9
17114246
Nat Med. 2009 Aug;15(8):955-9
19597505
J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Sep 1;19(1):29-33
9732065
Trends Immunol. 2008 Feb;29(2):61-7
18178131
FEBS Lett. 2002 Mar 27;515(1-3):119-26
11943206
J Biol Chem. 1994 Jan 28;269(4):2834-40
8300617
Clin Immunol. 2009 Jan;130(1):27-33
18845487
Immunity. 2004 Oct;21(4):461-5
15485624
J Infect Dis. 2003 Jun 15;187(12):1924-33
12792869
J Exp Med. 2006 Sep 4;203(9):2145-55
16923852
J Acquir Immune Defic Syndr. 2002 Apr 1;29(4):346-55
11917238
Lancet. 2002 Jul 13;360(9327):119-29
12126821
J Pathol. 2008 Jan;214(2):231-41
18161758
Blood. 1992 Jul 15;80(2):498-504
1320956
Blood. 2009 Jan 8;113(2):269-70
19131556
AIDS. 2007 Nov 12;21(17):2283-91
18090276
Clin Immunol. 2001 Feb;98(2):212-9
11161977
Clin Immunol. 1999 Nov;93(2):114-23
10527687
Clin Infect Dis. 2005 Mar 15;40(6):853-8
15736019
J Exp Med. 1999 Apr 5;189(7):1025-31
10190893
Curr Med Chem. 2004 Aug;11(16):2205-12
15279559
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):570-5
9435233
Lancet. 1998 Nov 7;352(9139):1510-4
9820299
Retrovirology. 2007 Sep 21;4:65
17888148
J Infect Dis. 2006 Oct 15;194(8):1098-107
16991084
AIDS. 2003 Sep 5;17(13):1881-8
12960820
J Infect Dis. 1997 Nov;176(5):1161-7
9359714
J Immunol. 1999 Feb 15;162(4):2154-61
9973490