Effects and mechanisms of interleukin-10 promoter polymorphisms on HIV-1 susceptibility and pathogenesis.
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Date
2012
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Abstract
HIV infection has risen to pandemic proportions. Interleukin-10 (IL-10), a potent antiinflammatory
cytokine has been shown to enhance the establishment and persistence of
chronic viral infections through inactivation of effector antiviral immune responses and it
may also directly influence HIV-1 replication in cells of diverse lineages. IL-10 promoter
polymorphisms have been shown to affect HIV-1 susceptibility and pathogenesis. However,
the underlying mechanisms are poorly understood. We investigated the relationship between
IL-10 promoter variants, plasma IL-10 levels, and markers of disease outcome in chronically
HIV-1-infected individuals. To investigate the mechanistic role of IL-10 and its genetic
variants on HIV pathogenesis, we studied markers of activation on B cells, CD4+ and CD8+ T
cells, and assessed effects on CD4+ T cell proliferation with and without blockade of the IL-
10 pathway.
We used Taqman genotyping assays to genotype three IL-10 promoter single nucleotide
polymorphisms (SNPs) in our study cohort. Baseline plasma IL-10 levels were measured
using Luminex technology for 112 individuals. Viral load, CD4+ T cell counts and cytotoxic
T lymphocyte (CTL) immune responses were measured at baseline. The rate of CD4+ T cell
decrease was calculated in 300 individuals with a median follow-up of 25 months. CD38,
CD95, Ki67, IgG and PD-1, markers of activation or exhaustion were measured on B cells,
and CD38, CD95, Ki67, HLA-DR and PD-1 were measured on CD4+ and CD8+ T cells in a
subset of 63 individuals. CD4+ T cell proliferation was measured using Carboxyfluorescein
succinimidyl ester (CFSE) assays, following IL-10 receptor blockade in a subset of 31
individuals.
The IL-10 -1082G, -592A and -3575 variants were observed at frequencies of 0.3, 0.34 and
0.23 respectively, in our study cohort. Plasma IL-10 levels were significantly higher in the -
1082GG group than in the combined AA/AG group (p=0.0006). There was a significant
association between the 592AA genotype and a greater breadth of CTL responses compared
to the CC and CA (p= 0.002 and 0.004 respectively). The -592AA genotype associated
significantly with an attenuated loss of CD4 cells (p= 0.0496), with -592AA having the least
change in CD4 cells per year. The median expression of HLA-DR, a marker of T cell
activation was significantly higher in the-1082AA group for CD8 cells (p= 0.047), and the -
592AA group for CD4 T cells (p= 0.01). The median expression of IgG on the surface of B
cells was significantly higher in the -1082GG genotype and the -592CC genotype (p=0.0183
and 0.0659 respectively). Overall, IL-10 variants correlated with IL-10 expression and CD4
decline during chronic HIV-1 infection. IL-10 promoter variants may influence the rate of
HIV-1 disease progression by regulating IL-10 levels, which in-turn, may affect the breadth
of CTL responses. Furthermore, the increased expression of HLA-DR and PD-1 on CD8+ and
CD4+ T cells, indicates that lower IL-10 levels are associated with increased immune
activation and immune exhaustion. The increased expression of IgG on B cells, suggests that
in a setting of lower IL-10, there is possibly a bias towards a Th2 immune response. These
data suggest a significant role for IL-10 genetic variants and IL-10 in HIV pathogenesis.
Further studies to determine whether and how the IL-10 pathway may be manipulated for
therapeutic or vaccine strategies for HIV are warranted.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.
Keywords
Interleukin-10., HIV infections--Alternative treatment., Pathogenic bacteria--Inactivation., Theses--Immunology.