1054 
Severity of Liver Disease Associated with IL-10 DNA Polymorphisms in Patients Co-infected with HIV and HCV
Marion Peters*1, J Andersen2, K Sherman3, R Chung4, C Graham5, M Koziel5, and ACTG 5071 team
1Univ of California, San Francisco, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Cincinnati, OH, US; 4Massachusetts Gen Hosp, Harvard Med Sch, Boston, US; and 5Beth Israel Deaconess Med Ctr, Harvard Med Sch, Boston, MA, US
Background: The relationship of the immune responses
to liver injury in hepatitis C virus (HCV) is poorly understood. Defining these
interactions may be critical to understanding the pathogenesis of liver damage
and improving treatment outcomes in HIV/HCV co-infection. Interleukin (IL) -10 is
thought to modulate protective immune responses and may have an important
pathogenic role in HCV outcomes. Our aim was to assess the association between
allelic variation in IL-10, and IL-10 secretion in response to HCV proteins on
the histologic severity of liver disease.
Methods: AIDS Clinical Trials Group (ACTG) 5071 was
a 134-subject randomized trial to determine the efficacy of HCV therapy in HCV/HIV
co-infection. Liver biopsy was required within 48 weeks of study entry. DNA was
obtained from 81 A5071 subjects who consented to human genetic analysis. Single
nucleotide polymorphisms (SNP) were tested and reported as homozygous for wild
type (Wt), variant (V), or heterozygous (Wt/V) for IL-10, IL-1a, and complement factor 5 (C5). Enzyme-linked
immunosorbent spot (ELISpot) assays were performed on peripheral blood
mononuclear cells (PBMC) for IL-10 using HCV antigens Core, NS3, and NS5. Averaged
numbers of spot-forming cells (SFC) in control wells were subtracted from stimulated
wells to correct for spontaneous cytokine production and reported as
SFC/million PBMC. Data were analyzed using nonparametric methods. Recursive
partitioning (CART) was employed to identify predictors of fibrosis (HAI-E
score).
Results: Of 81subjects, 31 (41%) had advanced fibrosis
(HAI-E score 3-6); 71% with Wt IL-10 alleles and variant C5 alleles had advanced
fibrosis compared with 18% among those who had variant IL-10 and Wt IL-1a alleles. Of those 59 subjects with data on
both DNA polymorphisms and PBMC analysis, there was a non-significant trend
towards lower IL-10 production in Wt/Wt and V/V individuals (p = 0.27)
compared to Wt/V individuals.
Conclusions: This preliminary analysis shows that
allelic variations in IL-10, C5, and IL-1a,
proteins critical to the inflammatory response, are associated with severity of
chronic HCV disease. Further studies should address whether allelic variations
in IL-10 alter production of IL-10 and investigate the association of IL-10
with severity of liver fibrosis.
|
