IL-18 GENE PROMOTER REGION 607C/A POLYMORPHISM IN HIV-1 INFECTED NORTH INDIAN POPULATION
Sobti RC1,*, Sharma VL2, Abitew AM2, Berhane N1, Mahdi SA1, Askari M1, Kuttiat VS3, Wanchu A3
*Corresponding Author: Ranbir C. Sobti, Department of Biotechnology, Panjab University, Chandigarh 160 014 India; Tel.: +172-2534087; +94-1-704-4523; Fax: +172-25341409; E-mail: rcsobti@ pu.ac.in
page: 41

DISCUSSION

Cytokines are important immunomodulatory molecules in immune response against pathogenic microorganisms and also have an important role in the setting of disorders affecting the immune system. Cytokine genes are highly polymorphic and genetic variations that can alter the expression of cytokine genes could have evident pathological consequences, potentially leading to a number of chronic diseases, increased risk of infection, and altered outcome of acute disorders [8,10]. With regard to HIV-1, cytokines have been identified as important tools toward better understanding of the profound interactions occurring between HIV-1 and the human immune system. Moreover, cytokine genes have been implicated to influence the rate of disease progression in HIV-1 seropositive patients either positively or negatively [6,7,26,27]. Interleukin-18 is a pleiotropic proinflammatory cytokine that is recognized as an important regulator of innate and acquired immune responses [28]. It is mainly produced by monocytes/macrophages and many other immune and non immune cells [17,29]. By virtue of its nature, IL-18 plays a key role in induction of both Th1 and Th2 cytokines and, thereby, modulates their immune responses. Interleukin-18 possesses broad and potent immunomodulatory properties. It is therefore not surprising that it appears essential to host defenses against a variety of infections. The involvement of IL-18 has been identified in several inflammatory and autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases [16,17]. Furthermore, it has been reported that IL-18 is not only one of several inflammatory markers that increases during HIV-1 infection, but may also be involved in the immunopathogenesis of this disease [22]. The expression of the IL-18 gene seems to be regulated at the transcriptional level by the two SNPs at positions 607C>A and 137G>C in the promoter of this gene. The C>A substitution at position 607 disrupts the binding site of a potential cAMP-responsive element binding protein and the G>C substitution at position 137 abolishes the H4TF-1 nuclear factorbinding site. The 607C and 137G alleles have been associated with higher transcription activity than the 607A and 137C alleles, respectively [15]. Moreover, investigations carried out to determine the association of SNPs in the IL-18 gene and various types of diseases have also shown the influence of the 607C/A promoter polymorphism on quantitative expression of the IL-18 protein. According to these studies, subjects with 607C/C and C/A genotypes have had significantly higher IL-18 concentrations than those with the 607A/A genotype [23,24]. Taking into account the findings of Giedraitis et al. [15], Sakai et al. [23] and Xu et al. [24], 500 HIV-1 patients and an equal number of healthy control subjects were studied for the IL-18 607C>A gene promoter polymorphism to assess its possible association with the risk of HIV-1 infection. Analysis of the present data demonstrated an association between the IL-18 607C/A polymorphism and risk of HIV-1 infection in North Indians. In the present study, statistically significant reduced risk of HIV-1 infection was observed with the 607A/A genotype, as compared to healthy controls (OR = 0.57, 95% CI = 0.33-0.98, p = 0.040). On the other hand, a statistically insignificant reduced risk of HIV-1 infection was observed with the heterozygous 607C/A genotype (OR = 0.87, 95% CI = 0.66-1.14, p = 0.321). As to the effect on HIV-1 infection, increased IL- 18 concentrations in HIV-1 patients are likely to play an important role in the disease progression and related clinical conditions [30]. Interleukin-18 has also been shown to induce HIV-1 replication in acutely or chronically infected human monocytic and T cell lines, suggesting its pathogenic role in HIV-1 pathogenesis [18,19,31]. Furthermore, Stylianou et al. [22] suggested the involvement of IL-18 in augmenting the expression of the HIV-1 co-receptor CXCR4 in peripheral blood monocytic cells (PBMCs) from HIV- 1-infected patients. Such up-regulation of CXCR4 by IL-18 seems to facilitate viral entry and replication, indicating a further role of the cytokine in the disease progression. Moreover, Wiercinska-Drapalo et al. [21] demonstrated the presence of an association between plasma level of IL-18 with viral load and disease progression in HIV-1-infected patients. In another instance, Song et al. [32] demonstrated the presence of overall positive correlation between serum IL-18 and HIV-1 viral load accompanied by negative correlation between serum IL-18 and CD4+-T cell count. The allelic variants of the IL-18 gene 607C>A promoter polymorphism have been shown to influence the transcriptional activity and subsequently a level of IL-18 production. The IL-18 607C/C and C/A genotypes represent the potential to produce high levels of IL-18, while, the A/A genotype is associated with low transcription activity and low production of this proinflammatory cytokine [23,24]. In connection with HIV- 1/AIDS, Segat et al. [33] demonstrated the association between the IL-18 gene 607C>A promoter polymorphism and risk of HIV-1 infection in seropositive Brazilian children. Moreover, high concentrations of circulating IL-18 have been correlated with enhanced HIV-1 replication and accelerated progression of the HIV-1 infection towards AIDS [21,30]. The results of the current study revealed the occurrence of the 607 A/A genotype at statistically significant lower frequency in the HIV-1 patients than healthy controls (p = 0.040). This suggests that subjects possessing the 607 A/A genotype may be at reduced risk of HIV-1 infection. Furthermore, the existence of the A allele in the heterozygous 607 C/A genotype may also confer reduced risk against disease progression. However, as the IL-18 gene 607 C>A promoter polymorphism was the only SNP examined in this study, we cannot rule out the possibility that genetic variants from other promoter positions of this gene may also be participating in disease progression of HIV-1 infection. The findings of the present study provide additional evidence regarding the possible involvement of host genetic variations in the immunopathogenesis of HIV-1 infection. It was found that the 607 A allele in the promoter of IL-18 gene may be playing a protective role against the progression of HIV-1 infection to AIDS. The 607 A allele is assumed to results in attenuated transcription activity and lower IL-18 cytokine production that in turn may be involved in slowing down viral replication. As a result, HIV-1 patients with the 607 A/A and C/A genotypes may progress to AIDS at slower rate than those with the C/C genotype. However, the results of this study need to be further evaluated by undertaking investigations correlating IL-18 gene promoter polymorphisms with serum levels of IL-18 in HIV-1/AIDS patients for precise determination of the role IL-18 plays in HIV-1 infection. Likewise, how the 607 A allele interacts with other possible genetic factors in influencing the pathogenesis of HIV-1 infection requires further study.



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