Polymorphisms in the interleukin-4 receptor α chain gene influence susceptibility to HIV-1 infection and its progression to AIDS

Abstract

Interleukin (IL) 4 is a key T helper-2 cytokine that downregulates and upregulates CCR5 and CXCR4, respectively, the main coreceptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 receptor alpha chain gene (IL4RA) affect HIV infection and its progression to AIDS. The I50V SNP in exon 5 and the haplotypes of six SNPs in exon 12 (E375A, C406R, S411L, S478P, Q551R, and V554I) were studied by polymerase chain reaction and sequencing in 30 HIV+ long-term nonprogressors (LTNP), 36 HIV+ typical progressors (TP), 55 highly exposed but uninfected individuals (EU), 25 EU-sexuals (EU-Sex; mostly women) and 30 EU-hemophiliacs (EU-Hem; hepatitis C virus+), and 97 healthy controls (HC), all Caucasians and lacking CCR5Delta32 homozygosity. V50 homozygosity was increased in LTNP (44%) compared with the other groups [p = 0.005; relative risk ratio = 3.4, 95% confidence interval (CI) = 1.12-10.6, p = 0.03]. The most common (C) exon 12 haplotype, ECSSQV, predominated in all groups, but uncommon (U) haplotypes were increased in HIV+ individuals (n = 64), especially in those (51 of 64) infected via parenteral exposure (35.3%) compared with HC (20.4%) and EU-Hem (18.4%) [p = 0.01; odds ratio (OR) = 2.14, 95% CI = 1.25-3.67, p = 0.01]. EU-Sex also had an increased frequency of U-haplotypes (34.8%) (OR = 2.10, 95% CI = 1.03-4.21, p = 0.01) as well as an increased frequency of CU + UU genotypes (60.9%) compared with HC (38.2%) and EU-Hem (26.6%) (p = 0.043). Distributions of genotypes fitted Hardy-Weinberg equilibrium. Data suggest that V50 homozygosity associates with slow progression and that exon 12 U-haplotypes might be associated with both susceptibility to infection via parenteral route and resistance to infection via sexual exposure. Further studies are required to confirm these findings.

Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer

“…44 These polymorphisms are also of interest in other diseases influenced by the immune response. For I75V it is suggested that homozygosity for the V-allele associates with slow progression from HIV-1 to AIDS 45 and that the V-allele increases the risk of erosive disease in rheumatoid arthritis. 46 The Q576R polymorphism is suggested to have implications for susceptibility to HIV-1 infection 47 and multiple sclerosis 48,49 and IL-4R haplotypes have shown association with Type 1 diabetes.…”

Favorable impact of the interleukin-4 receptor allelic variant I75 on the survival of diffuse large B-cell lymphoma patients demonstrated in a large prospective clinical trial

“…Cervical cancer is related to human papillomavirus infection and Th1 immune responses are essential for viral clearance. The IL4R I75V polymorphism was also related to other viral diseases like acquired immunodeficiency syndrome or Rous sarcoma virus bronchiolitis and thus may alter the Th1/Th2 balance [27,28]. An altered host-tumor interaction by an imbalance of Th1/Th2 cytokine expression or an altered response to these cytokines may lead to harmful processes in DLBCL patients and thereby affect the clinical course in the way shown here for the IL4R I75V gene variation.…”

The Role of Genetic Polymorphisms in the Chemokine and their Receptors and Cytokines in the Human Immunodeficiency Virus Type 1 (HIV-1) Infection

“…The IL4-R alpha I50V polymorphism in exon 5 of IL-4R gene affects the functional responsiveness of the gene (Risma et al, 2002). The SNP I50V was found to be associated with slow progression to AIDS in HIV-1 infected individuals (Soriano et al, 2005). However, another study suggested an association of IL-4R alpha I50V allele with increased likelihood of HIV-1 infection in North Indian population ).…”