Chemokine Receptor Gene Polymorphisms Research Articles

Protective Effect of the Combination of Wild-Type Genotypes (G/G and G/G) of CCR2-64V and SDF1-3A' Genes in Serodiscordant Couples in Yaounde-Cameroon.

There is growing evidence that polymorphisms in chemokine and chemokine receptor genes influence susceptibility to HIV infection and disease progression. However, not much is documented about the influence of these polymorphisms in HIV serodiscordant couples in Cameroon. The objective of this study therefore was to determine the prevalence and the effect of the polymorphisms of CCR5-Δ32, CCR5 promoter 59029 A/G, CCR2-64I and SDF1-3'A gene in HIV serodiscordant couples in comparison to HIV negative seroconcordant and HIV positive seroconcordant couples in Yaoundé-Cameroon. A total of 96 couples were recruited from five hospitals, of which 60 couples were HIV serodiscordant (test group), 18 HIV negative seroconcordant and 18 HIV positive seroconcordant couples were used as controls. Their genotypes for CCR5-Δ32, CCR5 promoter, CCR2 and SDF1 were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism. The allelic frequencies of these genes in the studied population were: 0%, 26.30%, 15.30% and 1.62% respectively for CCR5-Δ32, CCR5 promoter, CCR2 and SDF1. The frequency of the combination of CCR5 promoter and SDF1- (A/A+ G/G) wild-type genotype was higher in HIV-infected partners (82.92%) compared to uninfected partners (56.1%) in HIV serodiscordant couples (p= 0.0001). The combination of wild-type CCR2 and SDF1 genotypes (G/G + G/G) was higher among uninfected partners (80.48%) in HIV serodiscordant couples compared to the infected partners (60.97) (p= 0.005). HIV negative partner protection against HIV/AIDS infection may be attributed to the combination of wild-type genotypes (G/G and G/G) of CCR2 and SDF1 genes in HIV serodiscordant couples.

Chemokine receptor gene polymorphisms and COVID-19: Could knowledge gained from HIV/AIDS be important?

Emerging results indicate that an uncontrolled host immune response, leading to a life-threatening condition called cytokine release syndrome (also termed “cytokine storm”), is the major driver of pathology in severe COVID-19. In this pandemic, considerable effort is being focused on identifying host genomic factors that increase susceptibility or resistance to the complications of COVID-19 and translating these findings to improved patient care. In this regard, the chemokine receptor-ligand nexus has been reported as potentially important in severe COVID-19 disease pathogenesis and its treatment. Valuable genomic insights into the chemokine receptor-ligand nexus have been gained from HIV infection and disease progression studies. Applying that knowledge, together with newly discovered potential host genomic factors associated with COVID-19, may lead to a more comprehensive understanding of the pathogenesis and treatment outcomes in COVID-19 patients.

Genetic variation in CCR2 and CXCL12 genes impacts on CD4 restoration in patients initiating cART with advanced immunesupression.

ObjectiveWe investigated the association of genetic polymorphisms in chemokine and chemokine receptor genes with poor immunological recovery in HIV patients starting combined antiretroviral therapy (cART) with low CD4 T-cell counts.MethodsA case-control study was conducted in 412 HIV-infected patients starting cART with CD4 T-cell count <200 cells/μL and successful viral control for two years. CD4 count increase below 200 cells/μL after two years on cART was used to define INR (immunological non-responder) patients. Polymorphisms in CXCL12, CCL5 and CCR2 genes were genotyped using sequenom’s MassARRAY platform.ResultsThirty two percent (134/412) of patients were classified as INR. After adjusting by age, route of HIV infection, length of infection before cART and viral hepatitis coinfection, CCR2 rs1799864-AG genotype was significantly associated with INR status (OR [95% CI]: 1.80 [1.04–3.11]; p = 0.04), and CXCL12 rs1801157-TT genotype showed a trend (OR [95% CI]: 2.47 [0.96–6.35]; p = 0.06).ConclusionsCCR2 rs1799864-AG or CXCL12 rs1801157-TT genotypes influence on the probability of poor CD4 recovery in the population of HIV patients starting cART with low CD4 counts. Genotyping of these polymorphisms could be used to estimate the risk of poor CD4 restoration, mainly in patients who are diagnosed late in the course of infection.

Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection.

To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion. Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter. The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.

CCR2, CCR5, and CXCL12 variation and HIV/AIDS in Papua New Guinea

Polymorphisms in chemokine receptors, serving as HIV co-receptors, and their ligands are among the well-known host genetic factors associated with susceptibility to HIV infection and/or disease progression. Papua New Guinea (PNG) has one of the highest adult HIV prevalences in the Asia-Pacific region. However, information regarding the distribution of polymorphisms in chemokine receptor (CCR5, CCR2) and chemokine (CXCL12) genes in PNG is very limited. In this study, we genotyped a total of nine CCR2-CCR5 polymorphisms, including CCR2 190G >A, CCR5 −2459G >A and Δ32, and CXCL12 801G >A in PNG (n=258), North America (n=184), and five countries in West Africa (n=178). Using this data, we determined previously characterized CCR5 haplotypes. In addition, based on the previously reported associations of CCR2 190, CCR5 −2459, CCR5 open reading frame, and CXCL12 801 genotypes with HIV acquisition and/or disease progression, we calculated composite full risk scores, considering both protective as well as susceptibility effects of the CXCL12 801 AA genotype. We observed a very high frequency of the CCR5 −2459A allele (0.98) in the PNG population, which together with the absence of Δ32 resulted in a very high frequency of the HHE haplotype (0.92). These frequencies were significantly higher than in any other population (all P-values<0.001). Regardless of whether we considered the CXCL12 801 AA genotype protective or susceptible, the risk scores were significantly higher in the PNG population compared with any other population (all P-values<0.001). The results of this study provide new insights regarding CCR5 variation in the PNG population, and suggest that the collective variation in CCR2, CCR5, and CXCL12 may increase the risk of HIV/AIDS in a large majority of Papua New Guineans.

CCR2, CX3CR1, RANTES and SDF1 genetic polymorphisms influence HIV infection in a Zimbabwean pediatric population.

There is growing evidence that polymorphisms in chemokine and chemokine receptor genes influence susceptibility to HIV infection and disease progression. However, not much is documented about the prevalence and effects of chemokine and chemokine receptor gene variations in the Zimbabwean population despite the high burden of HIV/AIDS in the country. This study therefore describes polymorphisms in CCR2, CX3CR1, SDF1 and RANTES genes in a Zimbabwean pediatric population and their effects on HIV infection in children born to HIV-infected mothers. A total of 106 children between seven and nine years of age comprising 70 perinatally exposed to HIV (34 born infected [EI] and 36 born uninfected [EU]) and 36 unexposed and uninfected (UEUI) controls were recruited. Six allelic variants in four genes were genotyped using PCR-RFLP and sequencing. Frequencies for minor alleles in the HIV uninfected groups (EU and UEUI) were CCR2 190A (16%), SDF1 801A (2%), CX3CR1 745A (9%), CX3CR1 839T (0%), RANTES In 1.1C (20%), and RANTES -403A (44%). There were significant differences between the EI and EU groups in the distribution of CCR2 190G/A genotype (15% versus 39%, respectively, p = 0.02) and CCR2 190G/A-CX3CR1 745G/G genotype combination (0% versus 33%, respectively, p = 0.002). Our findings suggest that chemokine and chemokine receptor gene variants seem to play an important role in the dynamics of HIV infection and could be used as drug or vaccine targets.

Association of chemokine receptor gene variants with HIV-1 genotype predicted tropism.

As a switch from chemokine (C-C motif) receptor 5 [CCR5 (R5)] to chemokine (C-X-C motif) receptor 4 [CXCR4 (X4)] HIV-1 tropism is associated with symptomatic and AIDS stages of infection, while chemokine receptor gene variants modify the tempo of HIV disease progression, we aimed to analyse the association between pretreatment HIV-1 tropism and chemokine polymorphisms known to restrict disease progression. V3 genotype tropism prediction was performed in a group of 221 treatment-naïve patients, with subsequent CCR5 Δ32 (rs333), CCR2 V64I (rs1799864), CCR5 promoter (-627 C/T; rs1799988) and CX3CR1 V249I (rs3732378) genotyping performed in 206 patients. Alleles with a protective effect were assigned positive values while risk alleles were assigned negative values to calculate genetic scores. χ(2) tests, Mann-Whitney U-tests and logistic and linear regression models were used for statistical analyses. R5 tropism was found in 85.5% of patients (n = 189) using a false positive rate (FPR) of 5.75% and in 72.8% of patients (n = 161) using an FPR of 10%. A higher frequency of the 5.75% FPR predicted R5 tropism was associated with the CX3CR1 A allele (P = 0.027). Lower additive genetic scores were associated with an increased frequency of 5.75% FPR predicted R5 tropism (P = 0.0059), with the trend confirmed by logistic regression [odds ratio (OR) 0.5819; 95% confidence interval (CI) 0.3457-0.9795; P = 0.0416]. Viral load tended to increase with decreasing genetic score in the logistic regression analysis (slope = -0.127 ± 0.076; P = 0.095; r(2) = 0.161). The CX3CR1 A allele and lower genetic scores may restrict the switch of HIV-1 tropism from R5 to X4. This effect may be associated with the amount of co-receptor on the cell surface. Chemokine receptor gene polymorphisms influence both disease progression and tropism variability.

Gene polymorphisms in CCR5, CCR2, SDF1 and RANTES among Chinese Han population with HIV-1 infection

Chemokines and chemokine receptors are crucial for immune response in HIV-1 infection. Although many studies have been done to investigate the relationship between chemokines and chemokine receptor gene polymorphisms and host’s susceptibility to HIV-1 infection, the conclusions are under debate. In the present study, a cohort of 287 HIV-1 seropositive patients, 388 ethnically age-matched healthy controls and 49 intravenous drug users (IDUs) HIV-1 exposed seronegative individuals (HESN) from Chinese Han population were enrolled in order to determine the influence of host genetic factors on HIV-1 infection. Seven polymorphisms on four known chemokines/chemokine receptor genes (CCR5Δ32, CCR5 m303, CCR5 59029A/G, CCR2 64I, RANTES −403A/G, RANTES −28C/G and SDF1 3′-A) were screened. CCR5Δ32 and CCR5 m303 were absent or infrequent in Chinese Han population, which may not be hosts’ genetic protective factors for HIV-1 infection. Our results showed the CCR5 59029A/G, CCR2 64I and SDF1 3′-A were not associated with host’s resistance to HIV-1 infection. The frequency of RANTES −403A allele was significantly lower in HIV-1 patients than in healthy blood donors (p=0.0005) and HESN group (p=0.035), which implied the association between A allele and reduced HIV-1 infection risk. Different genetic models were assessed to investigate this association (AA vs. GG+AG, OR=0.38 95% CI, 0.22–0.65 p=0.0004; A vs. G, OR=0.66 95% CI, 0.52–0.84 p=0.0006), which supported this association, either. The genotype and allele distribution of RANTES −28 between HIV-1 patients and healthy controls (genotype profile: p=0.072; allele profile: p=0.027) or HIV-1 seronegative group (genotype profile: p=0.036; allele profile: p=0.383) were both at the marginal level of significance, which were not observed after Bonferroni correction. All these results suggest the RANTES −403A may be associated with reduced susceptibility to HIV-1 infection, while the RANTES −28 locus not. By lack of the patients’ clinical information, whether these polymorphisms affect AIDS disease progression and their role in different HIV-1 infection routes could not performed in present study and needs to be assessed in ongoing studies.

CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer

Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are two chronic conditions, very common in aged men, that have been associated to inflammatory process. Chemokines and their receptors are recognized as critical mediators of inflammatory responses, they regulate immune cell migration and are implicated in tumor pathogenesis. The impact of two chemokine receptor gene polymorphisms, CCR2-64I (rs1799864) and CCR5-Δ32 (rs333), was evaluated in BPH and PCa. 385 DNA samples (130 BPH, 136 PCa, 119 healthy control) were genotyped. The allele frequencies were similar among control, BPH and PCa groups. Median of serum PSA levels was different between groups: 0.79, 1.45 and 6.91 ng/mL in control, BPH and PCa groups, respectively (all p<0.001). The prostate volume median was 20.00 cm(3) in the control group, thus, lower than BPH (35.35 cm(3)) and PCa (35.80 cm(3)) (both p<0.001), nevertheless no statistical significant difference was observed between BPH and PCa patients (p=0.172). Remarkably, CCR2-64I was a protective factor to PCa when compared with BPH (OR=0.550; 95%CI=0.311-0.975), although the statistically significant difference was lost after correction for multiple comparisons. No significant associations of CCR5-Δ32 variant were observed with BPH, PCa or PCa clinicopathologic status. Our data suggest the influence of CCR2-64I variant in the development of prostate cancer.

Role of Exonic Variation in Chemokine Receptor Genes on AIDS: CCRL2 F167Y Association with Pneumocystis Pneumonia

Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.

Chemokine (C-C motif) receptor 5 -2459 genotype in patients receiving highly active antiretroviral therapy: race-specific influence on virologic success.

In patients receiving highly active antiretroviral therapy (HAART), antiretroviral drug-metabolizing enzyme and transporter gene polymorphisms, as well as chemokine receptor gene polymorphisms, may influence response to treatment. In a North American, treated, adherent human immunodeficiency virus (HIV)-positive cohort (self-identified whites, n = 175; blacks, n = 218), we investigated whether CYP2B6 (516G>T, 983T>C), UGT2B7 (IVS1+985A>G, 802C>T), MDR1 3435C>T, chemokine (C-C motif) receptor 2 (CCR2) 190G>A, and CCR5 (-2459G>A, Δ32) polymorphisms influenced the time to achieve virologic success (TVLS). No difference in TVLS was observed between races. In Kaplan-Meier analyses, only 516G>T (log-rank P = .045 for comparison of GG, GT, and TT and P = .02 GG + GT vs TT) and -2459G>A (log-rank P = .04 for GG, GA, and AA and P = .02 for GG + GA vs AA) genotypes were significantly associated with TVLS in black patients but not in white patients. However, in the Cox proportional hazards model that included age, sex, baseline CD4(+) T cell count, and baseline viral load, no significant association was observed between 516G>T and TVLS, whereas the association between -2459G>A and TVLS remained significant even after including CCR2 190G>A as well as all the drug-metabolizing enzyme and transporter genotypes. These findings suggest that CCR5 -2459G>A genotype had a strong, race-specific influence on TVLS in this cohort. Understanding the possible mechanisms underlying this influence requires further studies.

CCR5 Chemokine Receptor Polymorphism in Patients With HIV-1 From Western India

To the Editors: AIDS is a set of symptoms and infections resulting from the damage to the human immune system caused by HIV. The rate of disease progression depends on viral characteristics and host factors. Entry of HIV-1 into target cells requires both CD4 and chemokine receptors. A 32-nucleotide deletion (Δ32) within the β-chemokine CCR5 gene has been described in HIV-1 subjects who remain uninfected. We investigated the frequency of Δ32 deletion in CCR5 among HIV-1-infected patients and normal uninfected healthy individuals belonging to the same ethnic background. A total of 251 samples comprised 161 patients with HIV-1 and 90 normal healthy individuals from the same ethnic group. Genomic DNA from patients and control subjects was extracted and amplified for CCR5 gene segment using polymerase chain reaction. Amplified products were analyzed on 12% acrylamide gel, which yielded an 189-bp fragment for the wild-type allele and 157-bp fragment for the deleted (mutant) allele. Our results revealed patients with HIV-1 were homozygotous for ccr5Δ32 deletion (6.21%) and heterozygous for ccr5Δ32 deletion (0.67%) compared with 6.66% and 0%, respectively, in control subjects (Table 1). Genetic susceptibility to HIV infection has proven to be influenced by chemokine receptor gene polymorphisms culturing on chomosome 3p21. The chemokine receptors CCR2V64I, CCR5-Delta 32, CCR5 m303, CXCR4,(-2459)A CCR5, G190A CCR2,744A, CX3CR1, C838T, and SDF1-3A have been implicated in HIV. Homozygocity for the CCR5 (delta32/delta32) gene is associated with strong resistance against HIV infection. Hetrozygocity for CCR5 (delta32/wt) is associated with protection of HIV disease progression. Global survey for this genotype has revealed that 13% of whites have this mutant allele, whereas in Africans, Eurasians, and Indians, the allele ranges from 5% to 10%.1 The CCR5 delta is a heterozygous deletion in Slovakian patients with HIV-1 (15.4%)2 and heterozygous deletion in white patients with HIV ( 17.5%) and in Polish patients with HIV-1 (16.1%).1 The CCR5 delta32 homozygous deletion is reported in a single German seroconverter,3 not identified in North Indians,4 but identified (6.21%) in our present investigation from Western Indians. Studies revealed that a second mutation in CCR5 that is a single base pair mutation, m303, introduces a stop codon that prevents cell surface expression of a functional CCR5 receptor. A recent study reported the CCR5Delta32 (2.8%) and CCR5m303 (0%) allele polymorphisms among Bahraini population.5 Considering the ethnicity of the Indian subcontinent, CCR5 gene studies in patients with HIV-1 from other parts of India will give us more information. Our study shows that the CCR5 allele frequency varies in different ethnic groups and 7.84% of the patients with HIV-1 have not been protected although they have the presence of the homo- or heterozygous ccr532bp deletion.TABLE 1: CCR5 Polymorphism in Patients With HIV-1 and Control SubjectsAruna Shankarkumar, PhD Umapathy Shankarkumar, PhD Kanjaksha Ghosh, MD National Institute of Immunohaematology, KEM Hospital, Parel, Mumbai, India

CCR2-64I is a risk factor for development of bladder cancer

Chemokines are potent proinflammatory cytokines that are implicated in numerous inflammatory diseases. Proinflammatory gene polymorphisms lead to variations in the production and concentration of inflammatory proteins. We investigated a possible association between polymorphisms in chemokine and chemokine receptor genes (MCP-1 A-2518G and CCR2-V64I) and bladder cancer risk. Genotypes were determined by PCR-RFLP assays in 72 bladder cancer patients and 76 unrelated age-matched healthy controls. There were significant differences in the frequencies of the MCP-1 A-2518G (P = 0.012) and CCR2-V64I genotypes (P = 0.004) between the controls and patients. The MCP-1 A-2518G GG genotype frequencies for controls and cases were 0.039 and 0.11, respectively; individuals who had the GG genotype had a 3-fold increased risk of bladder cancer (P = 0.08). The CCR2-64I/64I genotype frequencies for controls and cases were 0.02 and 0.13, respectively; subjects carrying the 64I/64I genotype had a 5.9-fold increased risk of bladder cancer compared to the other genotypes. Individuals carrying the CCR2-V64I heterozygote or homozygous variant genotype (64I/64I + wt/64I) had a 2.9-fold increased risk of bladder cancer compared with the wild-type genotype (wt/wt). CCR2-V64I heterozygote or homozygous wild-type genotype (wt/wt + wt/64I) frequencies were significantly decreased in the patient group compared with controls. We conclude that CCR2-64I is a new risk factor for bladder cancer.

Role of chemokine receptor and ATP-binding cassette transporter gene polymorphisms for biliary lesions following liver transplantation

Aims: Ischemic type biliary lesions (ITBL) and anastomotic strictures (AS) are major complications following LT, leading to reduced graft and patient survival. Genetic polymorphisms in chemokine (CC) receptors which mediate leucocyte trafficking were reported to be associated with ITBL. For late AS, others than surgical factors should be incriminated. Genetic polymorphisms of ATP-binding cassette (ABC) transporters determine serum cholesterol level and cholesterol efflux into bile and contribute to production of lithogenic bile. Aim: To investigate the role of CC-receptors and ABC transporters for development of biliary lesions after LT. Methods: We genotyped two CC-receptors (CCR5, CX3CR1) and ABCG8 in 165 LT recipients (45 with ITBL, 38 with AS, 82 controls) by PCR or PCR-RFLP. Serum concentration of chemokines CCL3 and CCL5, as ligands of CCR5, were measured by ELISA. Results: A 32-bp deletion in CCR5 gene (CCR5Δ32) was present in 29.5% of patients with ITBL compared to 13.2% without ITBL (p=0.01). CCL3 and CCL5 serum levels tended to be higher in patients with CCR5Δ32 genotype. The following genotypes of CX3CR1 were found: G745A (wild type 44.8%, heterozygous 40.6%, homozygous mutant 11.5%) and C839T (72.1%, 24.8%, 3%). The risk of AS in the carriers of 745A allele was significantly increased compared to controls (p=0.04). Analysis of ABCG8 exons 8 and 13 for single nucleotide polymorphisms (SNPs) revealed the following results: C1199A (wild type 69.1%, heterozygous 29.7%, homozygous mutant 1.2%) and C1895T (45.5%, 44.8%, 9.7%). 25% of patients with ITBL were hetero/homozygous for both SNPs of ABCG8 compared to 12.4% (p=0.04) in controls. Conclusions: CCR5Δ32 hetero/homozygosity and ABCG8 with concomitant C1895T and C1199A mutations have shown to be risk factors for ITBL occurrence. CX3CR1 745A allele carriers had increased risk of AS. These findings may have translational relevance for predicting the risk of occurrence of biliary lesions after LT.

Chemokine Receptor Gene Polymorphisms and Severity of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Sibling Donors.

Background: Single nucleotide polymorphisms (SNPs) and other genetic variations in various genes involved in the immune response have been variably associated with acute graft-versus-host-disease (GVHD). The interaction of chemokines with their receptors is crucial for organ-specific recruitment of immune cells. Trafficking of recipient antigen presenting cells as well as donor lymphocytes between lymph nodes and target tissues are especially important events in acute GVHD pathogenesis. In this pilot, retrospective study, we sought to examine the role of recipient and donor chemokine receptor gene polymorphisms in determining the incidence of severe acute GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from matched sibling donors.Methods: Patient and donor samples were genotyped for the following chemokine receptor polymorphisms: CCR5 -59029 A/G, CCR2 190 A/G (V64I), CX3CR1 745 A/G (V249I) and CX3CR1 839 C/T (T280M) and CCR5Δ32. Due to the extreme rarity of homozygosity for the Δ32 deletion in CCR5, the CCR5Δ32 homozygotes and heterozygotes were grouped together for analysis. The relationship between polymorphism genotypes and acute GVHD outcomes (Grade 0 vs Grades III/IV) were evaluated.Results: A total of 103 donor-recipient pairs were analyzed which included 58 recipients who experienced severe acute GVHD (Grades III/IV) and 45 recipients who did not develop acute GVHD (Grade 0). Compared to the wild type CCR5 allele, the presence of the CCR5Δ32 allele in the donor conferred an increased risk for severe acute GVHD (P=0.04). The odds ratio is estimated to be 6.16 (95% CI [0.73, 52.05]). Presence of CCR5Δ32 in the recipient was not associated with increased acute GVHD risk (P=0.14). For the CCR5 -59029 A/G polymorphism, there was the suggestion of a decreased trend for developing severe acute GVHD if the donor had the A/A genotype (P=0.09). A trend for an association with the incidence of severe acute GVHD was observed for the CCR2 V64I polymorphism in the recipient. (P= 0.08). Donor genotype for this polymorphism was not associated with severe GVHD (P=0.17). A trend towards increased incidence of severe GVHD was observed for the 745 A/G (V249I) polymorphism (P=0.1). No significant effect was observed for the CX3CR1 839 C/T (T280M) polymorphism in this study.Conclusions: CCR5Δ32 polymorphism in the donor was associated with severe acute GVHD in this study. This and other functional chemokine receptor polymorphisms are potential candidates for evaluation in large prospective studies in future to precisely determine their association with acute GVHD.

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case-control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3-CCR2-CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Delta32 was observed with an allele frequency of 10.7% in the control population compared to 6.5% in the KD patients (P = 0.04). Two haplotypes of the CCR3-CCR2-CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 was observed.

Genetic Polymorphisms in the Chemokine and Chemokine Receptors: Impact on Clinical Course and Therapy of the Human Immunodeficiency Virus Type 1 Infection (HIV-1)

The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-Delta32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX(3)CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.

Characterization of CCR5 chemokine receptor gene polymorphisms in Japanese and Thai populations (45.11)

Abstract Variations in the human CCR5 gene may alter the expression and/or function of the protein product, thereby altering chemokine binding/signaling or HIV infection of the cells that normally express CCR5 protein. We performed a systematic survey of genetic variations in the entire CCR5 gene as well as CCR2V64I in 50 Japanese subjects and evaluated the effects of those variations on CCR5 promoter activity. We also analyzed CCR5 promoter and CCR2V64I genotypes in 80 more Japanese and 186 Thais. Two types of non-synonymous substitutions in Japanese CCR5 gene were found. Our results showed several novel characteristics of the CCR2-CCR5 haplotype structure that were not reported from studies on Caucasians and African-Americans. Specifically, we were able to show that the G allele at position -2852 from the CCR5 translational start codon in Japanese and Thais is the representative of the CCR5 promoter haplotype that was reported to be associated with rapid progression to AIDS in HIV-infected individuals. Furthermore, nearly all non-synonymous polymorphisms in Japanese CCR5 gene occurred in haplotypes with elevated promoter activity. We thus hypothesized that there was certain selective pressure favoring low levels of CCR5 expression during human evolution.

Impact of Inversion of the CD4/CD8 Ratio on the Natural History of HIV-1 Infection

HIV-1 infection is characterized by an inverted CD4/CD8 T-cell ratio, but the distribution of inversions over time after seroconversion and whether delay of inversion is associated with a favorable prognosis are not known. T-cell counts and clinical outcomes among men in the Multicenter AIDS Cohort Study who had incident HIV-1 infection before December 31, 1995 were analyzed by Kaplan-Meier and Cox proportional hazards methods. Results were also analyzed by time-dependent multivariate methods to adjust for CD4 lymphocyte counts, viral loads, age, race, and polymorphisms in host chemokine receptor genes (CCR5-Delta32 and CCR2-64I). Among 424 cases whose date of seroconversion was known to within +/-4.5 months, 317, 52, and 55 inverted their CD4/CD8 ratio within less than 1, 1 to 2, and more than 2 years of seroconversion, respectively. Longer time to inversion was significantly associated with longer time to AIDS, even after adjusting for CD4 lymphocyte count and viral load at the first seropositive visit and over the first 3 seropositive visits. Of the 6 seroconverters who had more than 500 CD4 lymphocytes 10 years after seroconversion without receiving highly active antiretroviral therapy, 5 took more than 2 years to invert their CD4/CD8 ratio. Time from HIV-1 seroconversion to inversion of the CD4/CD8 ratio independently predicted time to AIDS. Early measurements of the CD4/CD8 ratio until inversion occurs may identify people likely to become long-term nonprogressors or slow progressors, thus facilitating detailed studies of the mechanism of HIV-1 disease progression.

Gene Polymorphisms in CCR5, CCR2, CX3CR1, SDF-1 and RANTES in Exposed but Uninfected Partners of HIV-1 Infected Individuals in North India

Repeated exposure to human immunodeficiency virus (HIV) does not always result in infection. Understanding the mechanisms that give protection against progressive infection with HIV may help in the development of a vaccine. In order to determine the influence of host genetic factors on HIV resistance, we studied 35 exposed but uninfected (EU) partners of HIV-1 infected individuals for polymorphisms in multiple chemokine and chemokine receptor genes and compared the results with those for 75 HIV-1 seronegative normal healthy controls (HC) and 50 HIV infected controls. There was no association between CCR5-Delta32, CCR2-64I, CX3CR1-280 M, CX3CR1-249I, SDF-3'A, RANTES-28G and RANTES-403A polymorphisms and susceptibility against HIV in our cohort of EU individuals. An increased frequency of SDF-1 3'A and RANTES-403A genotypes was present in EU individuals but the difference was not statistically significant when compared to healthy and HIV infected controls. These observations suggest that mechanisms other than genetic mutations of these genes might be responsible for resistance to HIV infection in these individuals.