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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INTRODUCTION
Human immunodeficiency virus type 1 (HIV-1)
infection results in progressive deterioration of the immune
system and in acquired immune deficiency syndrome
(AIDS). However, the rate at which the HIV-1
infection progresses to AIDS varies considerably between
individuals, some progressing rapidly after primary
infection, while others remain asymptomatic with
no evidence of immune dysfunction for over 15 years
[1,2]. The reasons for the variation are multifactorial
and may involve genetic, virological or immunological
factors that function in different ways [3]. The role of
host genetic variations has been intensively examined
in different populations and in all major risk groups.
These have revealed that genetic polymorphisms in
genes for chemokine receptors or in those of their
natural ligands are likely to influence susceptibility or
resistance to HIV-1 infection as well as the subsequent
rate of disease progression [3,4]. Genes for human
leukocyte antigens (HLA) that regulate host immune
response to infection have also been correlated with
the clinical course of HIV-1 infection [5]. So far, in addition to polymorphic variants in genes encoding for
HIV-1 co-receptors and their ligands and those of HLA
alleles, some T helper type 1 (Th1) and type 2 (Th2)
cytokine genes have also been implicated to influence
the rate of disease progression in HIV-1 seropositive
patients either positively or negatively [6,7].
Cytokines play a crucial role in regulation of the
balance between Th1 and Th2 immune responsiveness.
The Th1 cytokines promote cell-mediated immunity to
intracellular pathogens including viruses and other intracellular
pathogens, whereas Th2 cytokines enhance
humoral immunity by up-regulating antibody production
against extracellular pathogens [8,9]. Furthermore,
several cytokine related studies confirmed their key
immunomodulatory role within the immune system
and cytokine genes have been targeted for association
studies of susceptibility and development of several
immune-related and infectious diseases [10-13].
The interleukin-18 (IL-18) gene encoding human
IL-18 cytokine is located at chromosome 11q22.2-
22.3 [14,15]. Three single nucleotide polymorphisms
(SNPs) (–656G>T, –607C>A, –137G>C) within the
IL-18 gene promoter have been localized. Of these,
those at positions –137 and –607 influence the quantitative
expression of the IL-18 protein. The –607C>A
disrupts a potential cyclic adenosine monophosphate
(cAMP) responsive element-binding protein (CREB)
binding site and –137G>C abolishes the human histone
4 transcription factor-1 (H4TF-1)-binding site , reducing
its transcription. Thus, these two polymorphisms
and their haplotypes seem to account for differential
IL-18 expression and changes in the production of this
cytokine [15].
The multiple biological functions of the IL-18
gene are associated with a wide variety of allergic,
inflammatory, autoimmune, cancerous and infectious
diseases [16,17]. In the context of HIV-1 infection, the
IL-18 cytokine also plays a pathogenic role by enhancing
viral replication in monocytic cells and in T cells
[18,19]. Moreover, clinical studies have demonstrated
the involvement of IL-18 in the immunopathogenesis
of HIV-1 infection [20-22]. However, most of these
studies focused primarily on the association of the levels
of IL-18 and the pathogenesis of HIV-1 infection.
Several studies have examined the association of SNPs
in the IL-18 gene with various other diseases [23,24],
but that with the HIV-1 infection has not been fully
explored. For this reason, we have evaluated the association
of the IL-18 gene promoter polymorphism
–607C>A with the HIV-1/AIDS infections. To the best
of our knowledge, this is the first association study of
the IL-18 gene polymorphism in North Indian HIV-1/
AIDS patients.
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