Adverse effect of the CCR5 promoter -2459A allele on HIV-1 disease progression

HIV positive individuals heterozygous for a 32 basepair deletion in the CCR5 encoding gene (CCR5 Delta32) have a reduced number of CCR5 receptors on the cell surface and a slower progression towards AIDS and death. Other human polymorphisms, such as the CCR2 64I and the CCR5 promoter -2459 A/G transition that has been discovered recently, have also been shown to influence HIV progression. Since genetic linkages make these polymorphisms interdependent variables, the aim of the present study was to isolate and evaluate the effect on HIV disease progression for each of these mutations independently. Genotypes were determined in 119 individuals enrolled in the Copenhagen AIDS Cohort. When including the concurrent effects of the CCR5 Delta32 and CCR2 64I mutations, homozygous carriers of the CCR5 promoter -2459A allele had a significantly faster progression towards death than heterozygous A/G individuals (P = 0.03), whereas this adverse effect was not significant when comparing A/A and G/G individuals. However, independent analysis revealed a significant adverse effect of the CCR5 promoter -2459A allele. Homozygous carriers of the -2459A allele that lack the protective effects of the CCR5 Delta32 and CCR2 64I mutations were found to have a median survival of 6.0 years, whereas carriers of the -2459G allele had a median survival of 9.4 years (P < 0.01).     

CCR5-Delta32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Delta32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsing-remitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Delta32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (+/-SD) age at disease onset among the carriers and non-carriers of the CCR5-Delta32 allele was 31.7 (+/-11.1) and 36.6 (+/-12.0) years, respectively (p=0.1312). The duration (+/-SD) of the disease was 11.2 (+/-12.9) and 7.7 (+/- 5.6) years among the CCR5-Delta32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (+/-SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Delta32 allele was 2.4+/-1.2 and 2.67+/-2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Delta32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Delta32, and CCR5-Delta32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Delta32 involvement in the specific process of MS pathology and pathogenesis.     

Impact of Chemokine Receptor CCR2 and CCR5 Gene Polymorphism on Allograft Outcome in North Indian Renal Transplant Recipients

The CC chemokine receptors, CCR2 and CCR5, contribute to the trafficking of leucocytes into the sites of the immune response in transplanted kidney. Therefore, the inter-individual differences in CCR2 and CCR5 gene expression, due to single-nucleotide polymorphism, have the potential to influence various immune responses within the graft, eventually deciding the allograft outcome. In this study, we genotyped 296 North Indian renal transplant recipients and 277 healthy controls for CCR2V64I and CCR5-Δ32 polymorphisms by sequence-specific primers and restriction fragment length polymorphism and examined their association with allograft outcome. The frequency of CCR2 +/64I (heterozygous) and CCR2 -64I/64I (homozygous mutant) genotype were comparatively higher in non-rejecters when compared with transplant recipients experiencing one or more than one rejection episode (20.4% versus 8.2%), thereby resulting in a significantly reduced risk of allograft rejection (OR = 0.331, P  = 0.026). The Kaplan–Meier curve also suggested higher mean time for the first rejection episode in CCR2- 64I allele carriers (32.83 ± 1.36 months) when compared with CCR2 +/+ recipients (28.09 ± 0.93 months, log  P  = 0.027). The CCR5-Δ32 variant had no profound effect on allograft outcome. In conclusion, our study confirmed CCR2- 64I allele to be associated with reduced risk for allograft rejection in North Indian transplant recipients influencing allograft outcome.     

Lack of association of human chemokine receptor gene polymorphisms CCR2-64I and CCR5-Delta32 with autoimmune Addison's disease.

The attraction of leukocytes to tissues is essential for inflammation and the initiation of the autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytokines. We investigated whether human chemokine receptor gene polymorphisms, namely CCR5-Delta32 and CCR2-64I, are associated with susceptibility to autoimmune Addison's disease. Genotyping was performed in 56 patients and 127 healthy controls by a new method using pyrosequencing for CCR2-64I and by polymerase chain reaction and detecting gel for CCR5-Delta32. None of the CCR2 or CCR5 alleles was found to be associated, either positively or negatively, with disease risk. Our results indicate that the CCR2-64I and CCR5-Delta32 gene polymorphisms do not play a major role in conferring genetic risk for, and/or protection against, autoimmune Addison's disease.     

Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.     

The frequency of CCR5Delta32 and CCR2-64I in southern Iranian normal population

Host genetic control of HIV infection involves certain polymorphisms of some chemokine receptor genes that are associated with susceptibility and progression of HIV-1 infection. Recent data suggest that two important polymorphisms in CCR2 and CCR5 chemokine receptors, CCR5Delta32 and CCR2-64I, prevent HIV transmission and delay disease progression. In this study allele and haplotype frequencies of the CCR5Delta32 and CCR2-64I mutations were determined in southern Iranian normal population using PCR and PCR restriction fragment length polymorphism (PCR-RFLP) assays. Allele frequencies and the fit to the Hardy-Weinberg equilibrium (HWE) were evaluated by Arlequin population genetic software. Frequencies of CCR5Delta32 and CCR2-64I alleles were 0.0146 and 0.1221, respectively. Moreover, higher and lower haplotype frequencies in 341 normal individuals were CCR2/CCR5 (0.8636) and CCR5/CCR2-64I (0.1217), respectively. Only one case with CCR5Delta32/CCR2-64I haplotype was found among the studied normal population. This data is the first finding on the frequencies of CCR5Delta32 and CCR2-64I alleles in Iranian population. Results of the present study suggest that low frequency of CCR5Delta32 allele may be related to higher genetic susceptibility to the HIV-1 infection in Iranians. Results also suggest that the CCR2-64I mutation is sufficiently common in Iranians and may be associated with slower HIV infection progression in Iran.     

Homozygous and heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV infection

OBJECTIVE: To investigate evidence for resistance to HIV-1 infection associated with the heterozygous genotype CCR5-+/Delta32 and with the homozygous genotype CCR5-Delta32/Delta32, which results in a nonfunctional CCR5 receptor. DESIGN: Cohort study of initially HIV-seronegative high-risk individuals from eight different cities. Enrollment data were analyzed to investigate the association of demographic factors and risk behaviors with CCR5 genotypes on the assumption that increased genotype prevalence among persons with histories of longer or more intensive exposure to HIV would indicate HIV resistance associated with that genotype. Longitudinal data were analyzed to investigate the association of HIV seroincidence with CCR5 genotypes. The cohort of 2996 individuals included 1892 men who have sex with men (MSM), 474 male injection drug users (IDUs), 347 women at heterosexual risk, and 283 female IDUs. MEASUREMENTS: CCR5 genotype, HIV serostatus, demographic factors, and risk behaviors during the 6 months before enrollment, followed by measurement of HIV seroincidence during the subsequent 18 months (for men) and 24 months (for women). RESULTS: Forty (1.3%) subjects were homozygous CCR5-Delta32/Delta32 and 387 (12.9%) were heterozygous CCR5-+/Delta32. All but 1 CCR5-Delta32/Delta32 individuals and 51 CCR5-+/Delta32 individuals were Caucasian. Among 1531 Caucasian MSM, CCR5-+/Delta32 individuals were present more frequently (22.3%) among those reporting unprotected receptive anal intercourse than among those not reporting this risk (15.9%) (p =.002), suggesting a selective advantage of the heterozygous genotype. CCR5-+/Delta32 individuals also had a significantly reduced relative risk of HIV seroconversion adjusted for unprotected receptive anal intercourse compared with CCR5-/+ individuals (relative risk = 0.30, 95% confidence interval [CI]: 0.08-0.97). CCR5-Delta32/Delta32 prevalence among Caucasian MSM was significantly associated with age among subjects recruited from high HIV seroprevalence cities (New York City and San Francisco) (odds ratio [OR] for each decade increase in age = 2.57, CI: 1.56-4.21) but not among those recruited from lower HIV prevalence sites (Boston, Chicago, Philadelphia, Seattle, and Providence/Pawtucket, Rhode Island) (OR = 1.20, CI: 0.75-1.89). CONCLUSIONS: Cross-sectional and longitudinal analyses indicated that among high-risk HIV seronegative MSM, CCR5-+/Delta32 and CCR5-Delta32/Delta32 are associated with protection against HIV infection. These findings imply that strategies aimed at reducing susceptibility to HIV infection by blocking CCR5 receptor sites need not seek blockage of all receptor sites to achieve an imperfect but substantial degree of protection.     

Genotypes of CCR2 and CCR5 chemokine receptors in human myasthenia gravis

The aim of this study was to examine the association of human autoimmune myasthenia gravis (MG) with two DNA polymorphisms of the chemokine receptors CCR5-Delta 32 and CCR2-64I. CCR2 and CCR5 interact primarily with the human CC family ligands CCL2 (formerly called monocyte chemoattractant protein; MCP-1), CCL3 and CCL4 (macrophage inflammatory protein-1 alpha and -1 beta; MIP-1 alpha/beta), and their main function is to recruit leukocytes from circulation into the tissues, thus playing an important role in human inflammatory disorders. A PCR-based genotyping method was used to determine the genetic variation at the CCR5 gene and an automated real-time Pyrosequencing technology was employed for the analysis of G right curved arrow A point mutation at the CCR2 gene. Results obtained from 158 patients and 272 healthy controls demonstrate no evidence of association between genetic variants of CCR2 and CCR5 with MG and its clinical manifestations. CCR2-64I and CCR5-Delta 32 genotypes are thus unlikely to be involved in protection or predisposition to MG.     

The 32-base pair deletion of the chemokine receptor 5 gene (CCR5-Delta32) is not associated with primary sclerosing cholangitis in 363 Scandinavian patients

CCR5 is a chemokine receptor expressed on T-cells and macrophages. A 32-base pair deletion in the chemokine receptor 5 gene (CCR5-Delta32) leads to a non-functional receptor. Conflicting evidence exists whether this deletion is associated with primary sclerosing cholangitis (PSC). We genotyped the CCR5-Delta32 variant in 363 PSC patients and 366 controls. No significant increase in the Delta32 allele frequency was detected in the PSC patients compared to controls (12.7% vs 10.7% OR = 1.22, 95% CI [0.88, 1.68], P = 0.23). Survival analysis did not reveal any significant effects from CCR5-Delta32 genotypes on disease progression. Thus, in this study (power > 90%, given OR = 2, alpha = 0.05), we were unable to replicate previous findings and our results do not support an involvement of CCR5-Delta32 in either PSC susceptibility or progression.     

Lack of association of CCR2-64I and CCR5-Delta 32 with type 1 diabetes and latent autoimmune diabetes in adults

It is well known that type 1 diabetes mellitus (T1DM) is a complex genetic disease resulting from the autoimmune destruction of pancreatic beta cells. Several genes have been associated with susceptibility and/or protection for T1DM, but the disease risk is mostly influenced by genes located in the class II region of the major histocompatibility complex. The attraction of leukocytes to tissues is essential for inflammation and the beginning of autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytolines. Some studies have shown that CCR2-64I and CCR5-Delta 32 might be important for protection of susceptibility to some immunologically-mediated disorders. In the present study, we demonstrate the lack of association between CCR2-64I and CCR5-Delta 32 gene polymorphism and TIDM and we describe a new method for a simple and more precise genotyping of the CCR2 gene.     

The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer's disease

Chronic local inflammatory reaction involving reactive microglia is one of the major pathological events in Alzheimer's disease (AD). There is growing evidence that the chemokine receptor CCR5 is up-regulated in AD brain and plays a role in the recruitment and accumulation of microglia in senile plaques. A 32-base pair deletion in the CCR5 gene (CCR5-Delta32 mutant allele) confers resistance to HIV-1 infection by preventing expression of the receptor on the cell surface. Several other reports have shown a similar protective effect of CCR5-Delta32 mutation towards certain chronic inflammatory diseases. Given the potential importance of CCR5 in brain inflammation, we hypothesized that individuals carrying the CCR5-Delta32 allele would show a reduced risk of AD. So, we performed a case-control study in 376 Spanish AD patients and 369 healthy controls. The frequency of the CCR5-Delta32 allele in our AD sample was 7.8%, not significantly different from our control sample group (5.8%). The present study indicates that the CCR5-Delta32 allele is not a preventive factor for AD.     

Protective effect of CCR2-64I and not of CCR5-delta32 and SDF1-3'A in pediatric HIV-1 infection

The effects of chemokine and chemokine receptor genetic polymorphisms such as stromal derived factor 1 (SDF1-3'A), CCR2-64I, and CCR5-delta32 associated with HIV-1 transmission and/or rate of disease progression in infected study subjects remain highly controversial and have been analyzed primarily only in adults. We have investigated whether these polymorphisms may provide similar beneficial effects in children exposed to HIV-1 perinatally. The prevalence of CCR2-64I allele was significantly increased (p = .03) and the CCR2-64I genotype distribution was not in Hardy-Weinberg equilibrium, among HIV-1-exposed uninfected infants. Moreover, in the HIV-1-infected group, a delay to AIDS progression was observed among carriers of CCR2-64I allele. This is the first report that suggests a protective role of CCR2-64I allele in mother-to-infant HIV-1 transmission and documents a delay in disease progression, after the child has been infected with HIV-1. However, SDFI-3'A and CCR5-delta32 alleles did not modify the rate of HIV-1 transmission or disease progression in HIV-1-infected children.     

Distribution of CCR2-64I and SDF1-3'A alleles and HIV status in 7 ethnic populations of Cameroon

Limited information is available on the prevalence among rural Africans of host genetic polymorphisms conferring resistance to HIV-1 infection or slowing HIV disease progression. We report the allelic frequencies of the AIDS-related polymorphisms CCR2-64I, SDF1-3'A, and CCR5-Delta32 in 321 volunteers from 7 ethnic groups in Cameroon. Allelic frequencies differed among the 7 ethnic groups, ranging from 10.8% to 31.3% for CCR2-64I and 0.0% to 7.1% for SDF1-3'A. No CCR5-Delta32 alleles were found. HIV seroprevalence was 6.9% in the total population and peaked at younger ages in girls and women than in boys and men. Among 15- to 54-year-olds, HIV seroprevalence varied from 2.0% to 11.1% among the village populations. Conditional logistic regression analysis using data from boys and men aged 15 to 54 years showed the number of CCR2-64I alleles to be a significant risk factor for HIV seropositivity (odds ratio per allele adjusted for age and matched on ethnic group = 6.3, 95% confidence interval: 1.3-30.3); this association was not found in women. The findings are consistent with the hypothesis that CCR2-64I alleles may delay HIV disease progression without affecting susceptibility to infection among men. We did not observe this relation among women, and other factors, such as multiple pregnancies or maternal stressors (eg, breastfeeding), may have masked any protective effect of CCR2-64I alleles. Further study of this issue among women is warranted. SDF1-3'A did not differ between HIV-seropositive and HIV-seronegative individuals but was associated with increasing age among HIV-seronegative women, suggesting a protective effect against HIV-1 infection.     

Prevalence of CCR2-64I, SDF1-3'A and CCR5-Delta32 alleles in healthy Thais.

A genetic survey was performed of 200 healthy Thai blood donors for the frequency of three alleles that influence susceptibility to HIV infection and the rate of progression to HIV disease. The CCR5-Delta32 allele was not detected in this population. The CCR2-64I allele was detected at a frequency similar to that found in other Asian populations (15.7%). SDF1-3'A was detected at 33.2%, supporting a cline of increasing frequency of this allele from African and Caucasian to Asian (particularly Australasian) populations. These results have implications for the role of host genetic background in the biology and pathology of HIV in Thailand, and indicate that a systematic survey of non-Caucasian populations may reveal novel alleles important in HIV disease.     

Frequency of CCR5-Delta32 deletion in human immunodeficiency virus type 1 (HIV-1) in healthy blood donors, HIV-1-exposed seronegative and HIV-1-seropositive individuals of southern Brazilian population

The frequency of CCR5-Delta32 allele in human immunodeficiency virus type 1 (HIV-1) infection in the southern Brazilian population was determined in a cross-sectional study carried out from October 2001 to June 2004. Genomic DNA was extracted from peripheral blood cells of 134 healthy blood donors, 145 HIV-1-exposed seronegative individuals, 152 HIV-1-seropositive asymptomatic individuals, and 478 HIV-1-seropositive individuals with AIDS. A fragment with 225 base-pairs of the CCR5 gene was amplified by polymerase chain reaction. The CCR5-Delta32 homozygous deletion was observed in 2 (1.5%) blood donors and in 1 (0.7%) individual HIV-1-exposed seronegative, and was absent among all the HIV-1-seropositive individuals (Fisher's exact test, p=0.0242). The frequency of the homozygous CCR5-Delta32 deletion in the HIV-1-exposed did not differ when compared with that observed in the HIV-1 seronegative blood donors (Fisher's exact test, p=0.6093; OR: 2.18, 95% CI: 0.11-129.6). The wild-type genotype CCR5/CCR5 frequency was higher among the HIV-1-seropositive with AIDS compared to HIV-1 seropositive asymptomatic individuals (Chi-square test, p=0.0263; OR: 2.02, 95% CI: 1.03-3.97). The absence of the homozygous deletion of CCR5-Delta32 among HIV-1-seropositive individuals underscored that this genotype is an important genetic factor associated with the decreased susceptibility to HIV-1 infection. The higher frequency of heterozygosity for the CCR5-Delta32 and the CCR5-Delta32 allele in HIV-1 seropositive asymptomatic compared to HIV-seropositive with AIDS individuals also underscored that this deletion could be associated with the delay of the HIV-1 disease progression in this population. However, the low frequency of CCR5-Delta32 homozygosity observed among HIV-1-exposed seronegative individuals shows that the allele could not explain, by itself, the natural resistance to HIV-1 infection and different mechanisms of protection against HIV-1 infection that must be involved in this population.     

Distribution of HIV/AIDS protective SDF1, CCR5 and CCR2 gene variants within Cretan population.

An interesting finding in the epidemiology of human immunodeficiency virus (HIV) infection is that certain mutations in genes coding for chemokine receptors and their ligands may confer resistance to HIV-1 infection and/or AIDS progression. The mutations most frequently studied are the CCR5-delta32, CCR2-64I and SDF1-3'A. We examined the frequency of the above polymorphisms within the Cretan population, evaluating their contribution to a protective genetic background against HIV infection and progression. Two hundred blood samples were recruited at random among prospective blood donors from Crete. Genotyping was initially performed by polymerase chain reaction (PCR) analysis. CCR2 and SDF-1 PCR-amplified genomic regions were further subjected to restriction fragment length polymorphism (RFLP) analysis for genotype determination. The CCR5-delta32 allele frequency among our study group was 3.25%, although no respective homozygous samples were detected. The screening for the CCR2-64I polymorphism yielded 39 heterozygous (19.5%) and 4 homozygous (2%) subjects, revealing a CCR2-64I allele frequency of 11.75%. Among our 200 PCR-RFLP analysed samples, 73 (36.5%) were found heterozygous and 23 (11.5%) homozygous for the SDF1-3'A mutant variant. The allele frequency of the above polymorphism reached 29.75%. The frequency of the CCR5-delta32 allele among our study population seems to be remarkably lower compared to previously reported frequencies in other Caucasian groups. However, the SDF1-3'A allele frequency shows significantly higher distribution profiles within our study group compared to those observed in other Caucasian-European populations. The indicated difference could be attributed to the increased homogeneity of our population, which is well balanced and dispersed over a small geographical area. Since this polymorphism is related with delayed progression from HIV infection to AIDS, it could be used for prognostic genotyping in HIV infected Cretan individuals.     

Frequency of the CCR5-Delta32 mutant allele is not increased in Belgian hepatitis C virus-infected patients

A 32-base pair deletion in the CC-chemokine receptor 5 gene (CCR5), associated with resistance to human immunodeficiency virus type 1 (HIV-1) infection, has recently been suggested to act as an adverse host factor in hepatitis C virus (HCV) infection. To examine this hypothesis, we determined the CCR5-Delta32 allele frequency by polymerase chain reaction in a Belgian cohort of 163 HCV-infected patients and 310 healthy control subjects. The resulting CCR5-Delta32 allele frequencies were 0.080 and 0.119 for the patient group and control group, respectively. In contrast with a previous study, we could not show a statistically significant difference between the CCR5-Delta32 allele frequencies in HCV patients and controls. Moreover, genotype distributions in both populations were in agreement with Hardy-Weinberg equilibrium. Our results do not support the hypothesis that the CCR5-Delta32 mutant allele is a risk factor for hepatitis C virus infection.     

中国HIV-1感染疾病长期不进展者CCR2-64I、SDF1-3’A和CCR5Δ32的基因变异研究

目的 探讨CCR2-641、SDF1-3’A、CCR5Δ32基因变异对中国HIV—1感染疾病长期不进展者（long-term nonprogressors，LTNPs）疾病进程的影响。方法 收集17例中国HIV-1感染LTNPs和39例中国HIV-1感染疾病典型进展者（typical progressors，TPs）的抗凝全血标本，用全自动核酸提取仪提取基因组DNA，采用PCR／RFLP技术对CCR2、SDF1、CCR5基因进行检测分析。结果 LTNP组的CCR2-64I、SDF1-3’A基因突变率分别为50％和62．5％，TP组的CCR2-64I和SDF1-3’A基因突变率分别为23．08％、33．33％，LTNP组CCR2—64I、SDF1-3’A基因突变率明显高于TP组（P〈0．05）；LTNP组有1例CCR5Δ32杂合突变，未发现纯合变异，而TP组未发现CCR5Δ32突变。结论 CCR2-64I、SDF1-3’A和CCR5Δ32基因突变可能是中国HIV-1感染者疾病长期不进展的保护性因素之一。     

Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5 and CXCR4

Polymorphisms in the CCR2 gene (CCR2-64I) and the CCR5 promoter (pCCR5-59029G) have been correlated with slower HIV-1 disease progression. How these polymorphisms influence the rate of AIDS progression has remained unclear. We have therefore investigated whether these nucleotide polymorphisms will reduce the expression levels of surface CCR5 and CXCR4, and thus lead to slower AIDS progression. For this, a cohort of Chinese volunteers in Taiwan was subjected to the determination of CCR2 and pCCR5 genotypes followed by analysis of the surface CCR5 and CXCR4 expression on five cell types derived from peripheral blood mononuclear cells by flow cytometry. Several significant associations were detected between genotypes and expression levels of the proteins. The most important finding was that an increased number of CD4(+) cells expressing CCR5 correlated with pCCR5-59029A homozygosity without the interference of both the CCR2-64 and the CCR5 delta 32 (deleted 32 bp) mutations (P: = 0.0453), which is consistent with the previous data on the association of the genotype to AIDS progression. Since different genetic polymorphisms co-exist in human beings, the rate of AIDS progression as well as the risk of rheumatoid arthritis may be governed by the interplay of the array of nucleotide changes and their affected proteins.     

Distribution of two HIV-1-resistant polymorphisms (SDF1-3′A and CCR2-64I alleles) in the Polish population

Chemokine receptors (CCR2 and CXCR4) are used as coreceptors for entry of human immunodeficiency virus (HIV) into the target cells. Mutations in CCR2 (CCR2-64I) and stromal-derived factor SDF1 (SDF1-3′A), the primary ligand for CXCR4, exhibited a protective effect against the onset of acquired immune deficiency syndrome (AIDS). The frequency of the SDF1-3′A and CCR2-64I alleles were determined in blood donors from 16 provinces, covering the entire territory of Poland. Of 1063 individuals, 274 (25.8%) were carriers of the SDF1-3′A allele; 36 of them (3.4%) were homozygotes (SDF-3′A/A) while 238 (22.4%) were heterozygotes (SDF-3′G/A), resulting in a 14.6% frequency of the SDF1-3′A allele. Moreover, in the same group of individuals, 234 (22.0%) carried the CCR2-64I allele; 6 of them (0.6%) were homozygotes (CCR2-64I/I), and 228 (21.4%) were heterozygotes (CCR2-64V/I), resulting in an 11.3% frequency of the CCR2-64I allele. The highest frequencies of the SDF1-3′A allele were found in the northeastern provinces and in one of the western provinces of Poland. In contrast, allelic frequencies of CCR2-64I varied slightly among different provinces. The different pattern of prevalence of the SDF1-3′A and CCR2-64I alleles in Poland might suggest that the CCR2-64I allele was spread much earlier than the SDF1-3′A allele in the population of Poland. Received: March 25, 2002 / Accepted: July 29, 2002 Acknowledgments We thank the directors of the Transfusion Centers from the 16 administrative provinces of Poland for providing venous blood samples. This research was supported by grant no. 6PO5B09221 from the State Committee for Scientific Research (KBN) and grant no. 501-1-08-05 from K. Marcinkowski University of Medical Sciences, Poznań. Correspondence to:P.P. Jagodzinski