Polymorphism in the CCR5 Gene Promoter and HIV-1 Infection in North Indians
Introduction
Individuals infected with human immunodeficiency virus–1 (HIV-1) show extreme heterogeneity in immune responsiveness, leading to variable degrees of susceptibility and rates of progression to acquired immunodeficiency syndrome (AIDS). This variability is governed to a large extent by multiple host genetic factors including chemokine receptors, their ligands, MHC molecules, cytokines and their receptors [1, 2, 3, 4, 5].
Chemokine receptor CCR5 acts as a major coreceptor for entry of M-tropic, non syncytium inducing HIV-1 virions (R5 isolates) that generally initiate infection. The receptor is expressed on the surface of monocytes/ macrophages, dendritic cells, microglial cells and activated T cells. A number of polymorphisms exist in the CCR5 gene that have been associated with resistance to HIV-1 infection and with rapid or slow rate of progression to AIDS [5, 6, 7, 8, 9, 10]. The CCR5 Δ32 is a naturally occurring knockout deletion variant that introduces a premature stop codon and results in truncation of the protein synthesized. The truncated CCR5 protein is not expressed on the cell surface, leading to effectively restricted HIV-1 cell entry in homozygous people [11, 12, 13, 14] and delayed AIDS progression in heterozygotes [15, 16]. Distribution of the protective Δ32 allele is however restricted to Northern Europe, where it occurs at a frequency of 10%–16% [17, 18] and its frequency decreases in a Southeast cline toward the Mediterranean and gradually disappears toward the African and Asian populations [19].
Additional polymorphisms in the 5′cis-regulatory region of CCR5 have been defined [20] that affect susceptibility to HIV-1 infection and development of AIDS. Based on a unique constellation of single nucleotide polymorphisms, predominantly in the promoter region of CCR5, the gene has been organized into a number of haplotypes. A schematic organization of CCR5 haplotypes reported by other investigators and those identified in this study is shown in Figure 1. A set of seven evolutionarily distinct CCR5 human haplotypes, namely, HHA, HHB, HHC, HHD, HHE, HHF (F*1, F*2), and HHG (G*1, G*2), have been defined by Gonzalez et al. 1999 [21]. This organization differs from that reported earlier by Martin et al. 1998 [8], in which 10 CCR5 promoter alleles (i.e., P1– P10) have been described based on genotypic data from a region +208 to +811. These promoter alleles represent only a subset of the HHA–HHG haplotypes. The P1 allele is a composite of at least three haplotypes that share 303A and 627C (i.e., HHE, HHF*1, and HHG*1). P2, P3, and P4 correspond to HHA, HHD, and HHC, respectively. The additional alleles defined by P5–P10 are members of HHA, -B, -C, or -D.
A number of studies have shown that CCR5 promoter haplotypes are associated with susceptibility to HIV infection and progression to AIDS [16, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]. It has been reported that persons who are homozygous for allele CCR5*59029G may progress to AIDS more slowly than those who are homozygous for the CCR5*59029A allele [7]. Homozygosity for CCR5*59356 T allele, a polymorphism that occurs more frequently in African American persons than in Caucasian or Hispanic persons, has been associated with increased perinatal transmission [6]. In Caucasian individuals, the homozygous haplogroup HHE has been associated with both increased likelihood and an accelerated course of infection [21, 23, 24] but not among African Americans [9]. HHE has also been associated with perinatal infection in the Argentinean children [25]. Similarly, it has been reported to be associated with acquisition of HIV-1 infection, accelerated CD4 decline, and disease progression in Thai HEPS individuals [26] and Thai IDUs [27]. In the African population, homozygosity of HHD has been reported to be associated with increased perinatal infection [6] and with more rapid disease progression [28]. Furthermore, HHC has been associated with faster disease progression among African Americans [21], although in the Thai population, this haplotype is reported with slower disease progression [27]. A late onset of AIDS has also been reported among the Japanese hemophiliac individuals with HHC [29]. The CCR5 haplogroups HHG*2 and HHF*2 have been associated with slower HIV disease progression among Caucasian and African-American individuals, respectively, possibly because of the protective effects of Δ32 and CCR2 64I respectively [21].
Because distributions of CCR5 polymorphisms vary greatly among different populations, it is hypothesised that these polymorphisms influence HIV-1 transmission and disease progression differentially according to their distribution in a race-specific manner. Although distribution of CCR5 promoter variations has been reported in a representative study on uninfected individuals from southern India [31], it has not been investigated in details in the HIV-infected Asian Indian population. This study was carried out to determine the influence of CCR5 polymorphisms on HIV-1 infection among the Asian northern Indian population.
Section snippets
Subjects
A total of 119 unrelated healthy individuals and 180 HIV-1 seropositive subjects of thte same ethnicity from northern India (particularly Delhi and its immediate surrounding areas) were enrolled in the study. The healthy individuals were randomly selected from among the hospital staff and students. The HIV-1–infected cohort was collected from the AIDS clinic at the Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi. The patient cohort consisted of chronically
Absence of CCR5 32 bp deletion
No mutant CCR5 Δ32 allele was observed in any of the subjects tested, irrespective of HIV-1 infection status. All subjects included in the study carried the wild-type CCR5 alleles.
CCR5 promoter alleles and genotypes
The percent allele frequencies corresponding to five SNPs in the promoter region of CCR5 at positions 59029, 59353, 59356, 59402, and 59653 in the HIV-1–infected individuals and healthy controls are shown in Table 3. The frequency of allele CCR5*59402A was increased in the HIV-positive cohort (66.4%) compared with
Discussion
In this study, the protective CCR5Δ32 allele was not found in any of the subjects tested. A rare occurrence of this allele in the Asian Indian population has also been reported in earlier studies [36, 37]. The homozygous CCR5 promoter genotype 59402AA was found at a higher frequency in the HIV-positive individuals and in the patients classified as CDC stage C. This suggests that the CCR5*59402A allele might favor the likelihood of acquisition of HIV-1 infection and development of AIDS.
To date,
Acknowledgments
This study was supported by a research grant from the Department of Biotechnology (DBT), Ministry of Science and Technology and the Indian Council of Medical Research (ICMR) Government of India. The authors thank Shekhar Neolia for providing technical assistance.
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