Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents

Abstract

Background: Immunological and clinical outcomes can vary considerably at the individual and population levels during both treated and untreated HIV-1 infection. Cytokines encoded by the interleukin-10 gene (IL10) family have broad immunomodulatory function in viral persistence, and several SNPs in the IL10 promoter sequence have been reported to influence pathogenesis or acquisition of HIV-1 infection.

Methodology/principal findings: We examined 104 informative SNPs in IL10, IL19, IL20, IL24, IL10RA and IL10RB among 250 HIV-1 seropositive and 106 high-risk seronegative African American adolescents in the REACH cohort. In subsequent evaluation of five different immunological and virological outcomes related to HIV-1 infection, 25 SNPs were associated with a single outcome and three were associated with two different outcomes. One SNP, rs2243191 in the IL19 open reading frame (Ser to Phe substitution) was associated with CD4(+) T-cell increase during treatment. Another SNP rs2244305 in IL10RB (in strong linkage disequilibrium with rs443498) was associated with an initial decrease in CD4(+) T-cell by 23 ± 9% and 29 ± 9% every 3 months (for AA and AG genotypes, respectively, compared with GG) during ART-free period. These associations were reversed during treatment, as CD4(+) T-cell increased by 31 ± 0.9% and 17 ± 8% every 3 months for AA and AG genotype, respectively.

Conclusions/significance: In African Americans, variants in IL10 and related genes might influence multiple outcomes of HIV-1 infection, especially immunological response to HAART. Fine mapping coupled with analysis of gene expression and function should help reveal the immunological importance of the IL10 gene family to HIV-1/AIDS.

Figure 1. SNPs in IL10 gene family associated with the combined immunological and virological control of HIV infection.

Genotype frequencies are compared for all “controllers” (CLs), “intermediate controllers” (IntCL) and “non-controllers” (NCL) as defined by virological and immunological markers. Two SNPs in IL20 (rs1518108 and rs11808752) are in LD (r ² = 0.90) and data is presented for rs1518108 with more complete data; rs4845147, rs6540701 and rs1856748 in IL24 are in LD (r ² = 0.91) and data are presented for rs4845147 with more complete data; p-value is presented for all individuals including and excluding 12 HLA-B57+ individuals.