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
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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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