Interleukin‐18 and interferon‐gamma polymorphisms are implicated on proviral load and susceptibility to human T‐lymphotropic virus type 1 infection

Abstract

Interleukin-18 (IL-18) and interferon-gamma (IFN-γ) exert important functions in both innate and adaptive immune responses against intracellular pathogens and viruses. Previous studies suggested that host genetic factors, including cytokines gene polymorphisms, could be involved in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Thus, we analyzed -137C/G and -607A/C of the IL-18 promoter and +874T/A of the IFN-γ in DNA samples from 98 HTLV-1-infected individuals exhibiting or not clinical symptoms and 150 healthy control individuals. The IL-18 promoter -607CC genotype was significantly lower in HTLV-1 asymptomatic carriers (HAC) and HTLV-1-infected individuals (HAC + HAM/TSP) than healthy control group. In contrast, the -607AC genotype was significantly higher in HAC and HTLV-1-infected individuals group compared to the healthy control group. The -137G/-607A IL-18 haplotype was higher in infected group than healthy control group, and the -137C/-607C IL-18 haplotype was increased in the healthy control group compared to the others. Finally, the IFN-γ polymorphism analysis showed that the HTLV-1-infected individuals with +874AT genotype presented higher proviral load than +874AA genotype. These data indicate that the IL-18-607AC genotype and -137G/-607A haplotype could be a risk factor for HTLV-1 infection, whereas the protective effect could be conferred by -607CC genotype and -137C/-607C haplotype. Also, the IFN-γ could be implicated on the proviral load levels.

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients

“…However, we strongly believe that this discrepancy regarding -137GG genotype distribution between Kim’s study and ours may be due to racial differences in genotype constitution of the two studied population. Furthermore, the frequency of -137 GG, GC and CC genotypes in other Brazilian cohorts of healthy subjects are similar to those shown in our study, suggesting that the distribution of -137GG genotype in our control group is representative of the Brazilian population (Segat et al , 2006, Castelar et al , 2010, Rocha-Júnior et al , 2012). Importantly, this observation gives support to the idea that, although the Brazilian population is genetically heterogeneous when compared to other population, such as the Korean studied by Kim and collaborators, it seems to be homogeneous when intra-population comparisons are done.…”

“…Similarly, this haplotype was higher in patients with HTLV-1 infection than in healthy subjects, indicating this haplotype as a risk factor for the HTLV-1 infection. On the other hand, protection against HTLV-1 infection was conferred by the -137C/-607C haplotype, since it was increased in healthy controls (Rocha-Júnior et al , 2012). Furthermore, it was shown in studies involving HIV-1 infection that the haplotype -137G/-607C was related to susceptibility to this virus (Segat et al , 2006), and the same genotype was associated with protection against lipodystrophy syndrome development in HIV-1 infection (Castelar et al , 2010).…”

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

“…Virus-induced MAIT cell activation was dependent on the IL-18 pathway and could synergize with IL-12, IL-15 and IFNα/β. Little is known regarding IL-18 levels in HTLV-1 infection but polymorphisms in the IL-18 promoter have been associated with susceptibility to infection[42]. IL-12 secretion by neutrophils was found to be elevated in asymptomatic and symptomatic HTLV-1 carriers[43].…”

Human Genetic Determinants of Viral Diseases

“…Conversely, a Caribbean study that examined SNPs in 38 gene candidates found that SNPs in the coding regions of IL13 (A98G) and VCAM1 (G149A)—both of which are known to be upregulated in HTLV-1-infected T cells—were associated with decreased risk for ATL development (161). In HAM/TSP patients, expansions of a CA repeat polymorphism in the MMP9 gene correlate with development of disease (78), and individual SNPs in the immunity-related cytokine genes IL18, IFNG, IL28B, and IL10 have each been associated with higher proviral load (5, 127, 128). Such findings further highlight the genetic complexity underlying HTLV-1-mediated disease.…”