Analysis of CCR5, CCR2, CX3CR1, and SDF1 polymorphisms in HIV-positive treated patients: impact on response to HAART and on peripheral T lymphocyte counts

Although polymorphisms of chemokine genes (SDF1, stromal cell-derived factor-1 and RANTES, regulated on activation, normal T cell expressed and secreted) and chemokine-receptor genes (CCR5, CCR2, CX(3)CR1) were shown to be associated with sensitivity to HIV infection and untreated HIV disease progression, their association with the response to highly active antiretroviral therapy (HAART) remains unclear. To explore the possible influence of such polymorphisms on the evolution of AIDS in treated patients, we have studied SDF1-3'A, CCR5Delta32, CCR2-64I, CX(3)CR1-249I, and CX(3)CR1-280M polymorphisms in HIV-infected patients under HAART (n = 169). We studied the evolution of plasma virus load and peripheral T lymphocyte counts in these patients up to 3 years after the initiation of HAART. We observed that some of the genetic polymorphisms studied had an impact on the evolution of these two parameters. After 1 year of HAART, patients with a virological response (undetectable plasma HIV-1 RNA) have a higher frequency of the homozygous SDF1-3'A genotype than other patients (p = 0.005). Similarly, patients with a CD4 increase of over 200/mm(3) from baseline after 1 year of HAART display higher frequencies of homozygous SDF1-3'A (p = 0.035) and homozygous CX(3)CR1-280M genotypes (p = 0.04) than other patients. Moreover, we showed that the CX(3)CR1- 280M allele was associated with higher peripheral CD4+ T cell counts not only in HIV+ patients but also in healthy controls (p = 0.003).     

Short communication: SDF1-3'A gene mutation is correlated with increased susceptibility to HIV type 1 infection by sexual transmission in Han Chinese

Limited information is available on host genetic polymorphisms that confer resistance to HIV-1 infection in Han Chinese who persistently remain seronegative (HEPS) despite high exposure to HIV-1 through unprotected sexual activity with known HIV-1-seropositive spouses or long-term sexual partners. The aim of this study was to investigate the correlation of CCR5-Delta32, CCR2b-64I, and SDF1-3'A polymorphisms with susceptibility to HIV-1 infection through sexual transmission in Han Chinese. A cross-sectional study was used to analyze the differences in allelic frequencies of CCR5-Delta32, CCR2b-64I, and SDF1-3'A among HEPS, healthy HIV-unexposed individuals, and HIV-1-seropositive individuals. Restriction fragment length polymorphism (RFLP) analysis was used for genotype determination. The CCR5-Delta32 mutation was not detected in the three groups (n = 260). The allelic frequencies of CCR2b-64I were 21.57%, 21.63%, and 22.12% in the three groups, respectively. There was no significant difference among the three groups in CCR2b-64I distribution. The allelic frequencies of SDF1-3'A were 20.19%, 28.37%, and 29.33% in the three groups, respectively. There was a significant difference in the allelic distribution of SDF1-3'A between HEPS and healthy HIV-unexposed individuals (p = 0.023), as well as between HEPS and HIV-1-seropositive individuals (p = 0.049). Statistical analysis showed that the allelic distributions on CCR2b-64I and SDF1-3'A were in equilibrium according to the Hardy-Weinberg equation. The mutant genotypes of CCR5-Delta32 and CCR2b-64I were not correlated with HIV-1 infection through sexual transmission in Han Chinese. SDF1- 3'A was associated with a high risk of HIV-1 infection through sexual transmission in Han Chinese.     

Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals

Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1-infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin's lymphoma (NHL). The SDF1-3'A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3'A/3'A homozygotes and 22 (10%) of 202 SDF1-+/3'A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-triangle up32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3'A frequency may contribute to the lower risk of HIV-1-associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1-infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL.     

Allelic frequencies of host genetic variants influencing susceptibility to HIV-1 infection and disease in South African populations

OBJECTIVES: Limited information is available on the prevalence in African populations of host genetic polymorphisms conferring resistance to HIV-1 infection and disease. The objective of this study was to determine the allelic frequencies in South African populations of the chemokine receptor gene variants CCR5delta32, CCR5m303 and CCR2b-641 and the CXCR4 ligand gene variant SDF1-3'A. METHOD: Cross-sectional study to determine the prevalence of these gene variants in South African subjects of African and European descent. RESULTS: The CCR5delta32 genetic variant is rare in individuals of African origin, having an allelic frequency of 0.1% (n = 1247) compared with 9.8% (n = 144) in Caucasians. The CCR5m303 mutation was not detected in Africans (n = 687), whereas an allelic frequency of 0.9% (n = 145) was identified in Caucasians. The frequency of CCR2b-641 allele was 13.1% (n = 180) in Africans, which was significantly higher that the 7.2% (n = 146) detected in Caucasians. Finally the allelic frequency of the SDF1-3'A gene variant was only 1.0% (n = 198) in Africans compared with 19.8% (n = 145) in Caucasians. CONCLUSIONS: These results indicate that genetic polymorphisms conferring resistance to HIV-1 infection are rare in the South African Black population. Except for the CCR2b-641 gene variant, individuals of African origin also had a much lower prevalence of genetic variants associated with prolonged disease progression.     

Lack of association of some chemokine system polymorphisms with the risks of death and hepatocellular carcinoma occurrence in patients with alcoholic cirrhosis: a prospective study

BACKGROUND: Polymorphisms in genes encoding for the chemokines stromal cell-derived factor-1 (SDF-1)/CXCL12, monocyte chemotactic protein-1 (MCP-1)/CCL2, or for the chemokine receptors, CC chemokine receptor 5 (CCR5) or CC chemokine receptor 2 (CCR2) have been associated with the progression of hepatitis C virus-related liver injury and with various cancer development. Their influence on the prognosis of alcoholic liver disease is unknown. PATIENTS AND METHODS: SDF-1 3'A, MCP-1(-2518), CCR5-Delta32 and CCR2-64I polymorphisms, SDF-1alpha, regulated upon activation normal T cells expressed and secreted (RANTES)/CCL5 and MCP-1 sera levels were determined in 222 alcoholic patients, included at the time of cirrhosis diagnosis and prospectively followed up. RESULTS: Carriers and noncarriers of each genetic marker had similar baseline characteristics estimating the severity of liver disease. Mean time of follow-up of the cohort was 62.9+/-43.2 months. One hundred and forty-seven out of 222 (66.3%) patients were alive at the end of the study. The occurrence of death (75/222; 33.7%) or hepatocellular carcinoma (67/222; 30.1%) during follow-up was similar among carriers and noncarriers of each polymorphism. No association between the carriage of mutated alleles and chemokine sera levels was found: CCR5-Delta32/RANTES, SDF-1 3'A/SDF-1alpha and CCR2-64I or MCP-1(-2518)/MCP-1. Baseline RANTES, SDF-1alpha and MCP-1 sera levels were associated neither with the risk of death nor with the risk of hepatocellular carcinoma. CONCLUSIONS: The present study suggests the lack of association of SDF-1 3'A, MCP-1(-2518), CCR5-Delta32 and CCR2-64I polymorphisms with death and hepatocellular carcinoma occurrence in cirrhotic alcoholic patients.     

CCR2b-64I allelic polymorphisms in advanced HIV-infected Koreans accelerate disease progression

Genetic polymorphisms of chemokine genes and chemokine-receptor genes in HIV-infected patients have been associated with delayed progression of this disease. The allelic frequencies of these genetic variants also differ between ethnic groups. To investigate the effects of the SDF1 and CCR2b genotypes on disease progression, survival of 200 HIV-infected persons for whom at least four subsequent immunologic data items had been collected was analyzed. A genotyping assay of SDF1 and CCR2b genes was carried out using polymerase chain reaction-restriction fragment length polymorphism analyses. HIV-infected persons heterozygous for the SDF1-3'A or CCR2b-64I alleles were included in the survival analysis, but homozygotes were excluded because of a very small sample number. Neither the CCR2b-+/64I allele nor the SDF1-+/3'A allele, separately or in combination, had a significant impact on survival during the asymptomatic period of HIV infection. However, CCR2b-+/64I alleles were associated with accelerated disease progression during the advanced period of HIV infection. The survival time of HIV-infected people with CCR2b-+/64I and SDF1-+/+ genotypes was significantly shorter than those of the other groups (p < 0.01), but this effect was not apparent in persons with CCR2b-+/64I alleles and SDF1-+/3'A genotypes. These results suggest that the effect of CCR2b-64I polymorphisms on disease progression may differ according to the stage of HIV infection and interactions with other gene variants.     

Genetic variations in CC chemokine receptors and hypertension

BACKGROUND: CC-chemokine receptor 5 (CCR5) is a co-receptor for human immunodeficiency virus type 1 (HIV-1) infection. Homozygosity for a 32-base pair (bp) deletion (Delta32) in the CCR5 gene confers resistance to HIV-1. Previous studies found an increased prevalence of hypertension among CCR5-Delta32 homozygotes and among carriers of a polymorphism (CCR2-64I) found on the gene that codes a closely related chemokine receptor. The present study was carried out to verify these associations. METHODS: Subjects in this cross-sectional study were selected from the Global Repository at Genomics Collaborative, which includes patients and healthy control subjects enrolled at multiple clinical sites in the United States and other nations. The current study includes 2842 subjects with hypertension and 2893 nonhypertensive control subjects from white populations in the United States and Poland. Case and control subjects were frequency matched by age, gender, and birthplace. All subjects were genotyped for CCR5-Delta32 and CCR2-64I polymorphisms by established Taqman assays. RESULTS: The CCR5-Delta32 genotype was not found to be associated with hypertension (CCR5-Delta32 heterozygosity: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.87 to 1.14; CCR5-Delta32 homozygosity: OR 1.07, 95% CI 0.68 to 1.67) among these subjects. There was also no association between CCR2-64I genotype and hypertension (CCR2-64I heterozygosity: OR 0.96, 95% CI 0.83 to 1.10; CCR2-64I homozygosity: OR 1.18, 95% CI 0.73 to 1.92). These results changed little after adjustment for potential confounding variables. CONCLUSION: The results of the present study, which is much larger than previously published studies, provide no evidence that either CCR5-Delta32 or CCR2-64I is associated with hypertension.     

Effects of the CCR5-Delta32 mutation on antiviral treatment in chronic hepatitis C

BACKGROUND/AIMS: The CC-chemokine receptor (CCR) 5-Delta32 mutation may predispose to chronic liver disease and high level viremia in hepatitis C. However, it is unclear whether CCR5-Delta32 also affects the response to antiviral treatment. METHODS: We determined CCR5 genotypes in patients with hepatitis C treated with either interferon-alpha (N=78) or interferon and ribavirin (N=78). In each group, rates of end of treatment responses (ETRs) and sustained virological responses (SVRs) were compared between CCR5-Delta32 carriers and homozygous CCR5 wildtype patients. RESULTS: ETR and SVR were achieved in 25 and 12 patients with interferon-alpha and in 52 and 45 patients with interferon/ribavirin treatment, respectively. CCR5-Delta32 carriers had significantly lower ETR rates than homozygous CCR5 wildtype patients (10.5 vs. 39.0%; P=0.02), whereas SVR rates only showed a non-significant trend (5.3 vs. 18.6%). Multivariate analysis confirmed CCR5-Delta32 carriage as an independent negative predictor for ETR in interferon-alpha monotherapy (odds ratio: 0.16; 95% confidence limits: 0.032-0.82; P=0.03). In interferon/ribavirin treated patients CCR-Delta32 carriers and CCR5 wildtype patients had similar ETR rates [19.2% vs. 23.1%] and SVR rates [20.0% vs. 21.2%]. CONCLUSIONS: Response rates to interferon-alpha monotherapy are reduced in hepatitis C virus (HCV)-infected patients carrying the CCR5-Delta32 mutation. However, interferon/ribavirin combination treatment may overcome this negative effect of CCR5-Delta32.     

Analysis of genetic polymorphisms in CCR5, CCR2, stromal cell-derived factor-1, RANTES, and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1

To determine the influence of host genetics on human immunodeficiency virus (HIV) type 1 infection, we examined 94 repeatedly exposed seronegative (ES) individuals for polymorphisms in multiple genes and compared the results with those for 316 HIV-1-seropositive and 425 HIV-1-seronegative individuals. The frequency of homozygous C-C chemokine receptor (CCR) 5- Delta 32 was higher in ES (3.2%) than in HIV-1-seropositive individuals (0.0%; P=.012). However, the CCR5-59029A, CCR2-64I, stromal cell-derived factor (SDF)-1-3'A, RANTES (regulated on activation, normally T cell-expressed and -secreted)-403A, and RANTES-28G polymorphisms were not associated with resistance to HIV-1 infection. Furthermore, we identified novel variants in the DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) repeat region and observed that heterozygous DC-SIGN reduced the risk of HIV-1 infection (3.2% in ES individuals vs. 0.0% in HIV-1-seropositive individuals; P=.011).     

CC-type chemokine receptor 5-Delta32 mutation protects against primary sclerosing cholangitis

BACKGROUND: Primary sclerosing cholangitis (PSC) is commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of biliary ducts. The pathogenesis of PSC remains unknown, but immunological, bacterial, viral, and toxic factors play a role in a genetically susceptible host. We hypothesized that CC-type chemokine receptor 5 (CCR5) would be an interesting candidate gene for susceptibility to PSC from its chromosomal location within the IBD susceptibility locus on 3p21, as well as from a functional perspective. We therefore investigated the role of the functional 32-bp deletion in this gene (CCR5-Delta32) with regard to susceptibility to PSC. METHODS: A total of 110 patients with PSC, 56 with concomitant IBD (23 with Crohn's disease, 28 with ulcerative colitis, 5 with indeterminate colitis), were collected. All of the subjects were genotyped for CCR5-Delta32 with polymerase chain reaction amplification, followed by detection on ethidium bromide-stained agarose gel. Genotypes and allele frequencies were compared with a cohort of IBD patients without PSC (n = 400) and healthy control subjects (n = 362). RESULTS: The frequency of the CCR5-Delta32 mutation in PSC (6.8%) was significantly lower compared with IBD (12.6%; P = 0.016) and healthy control subjects (12.2%, P = 0.026), suggesting a protective effect of this mutation on PSC. None of the PSC patients with severe disease necessitating liver transplantation (n = 17) carried CCR5-Delta32. CONCLUSIONS: Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC.     

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.     

Lack of higher frequency of the chemokine receptor 5-delta32/delta32 genotype in hepatitis C

PURPOSE: An elevated frequency of the CCR5-Delta32 mutation in German patients with hepatitis C with viremia has been reported. The aim of the present study was to verify whether this mutation occurs in an Italian population with hepatitis C and whether it is an adverse host factor indicative of severity of liver disease and response to antiviral therapy. STUDY: The authors amplified 189-bp (wild-type) and 157-bp (Delta32 deletion) fragments of the CCR5 gene by polymerase chain reaction in 130 patients with chronic hepatitis C. Comparisons were drawn with 110 blood donors and 135 patients with primary biliary cirrhosis. RESULTS: Four (3.1%) patients with chronic hepatitis C and 1 blood donor (0.9%) were CCR5-Delta32 homozygous, whereas there was no CCR5-Delta32 homozygosity among primary biliary cirrhosis patients; the wild-type gene was present in a similar percentage in the 3 groups of patients without any significant difference (83.1% vs 90.4% vs 83.6%, respectively). Among the patients with chronic hepatitis C, no significant correlation was found between CCR5-Delta32 homozygosity and the following parameters: histologic grade/stage, hepatitis C virus genotype, viral load, serum aspartate aminotransferase, serum alanine aminotransferase, and serum gamma-glutamyltransferase. Ninety-five patients received a standard antiviral protocol with pegylated interferon (PEG Intron)+ribavirin; a sustained response was achieved in 59 patients (62.1%), and the remainder did not respond or experienced a relapse. Response to treatment was not influenced by CCR5-Delta32 deletion. CONCLUSION: No greater frequency of CCR5-Delta32 homozygosity was seen in an Italian population of patients with chronic hepatitis C. This mutation does not seem to influence either the overall severity of liver disease or the response to viral therapy.     

Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.     

The stromal derived factor-1 mutated allele (SDF1-3'A) is associated with a lower incidence of atherosclerosis in HIV-infected patients

BACKGROUND: HIV-infected patients have higher rates of subclinical atherosclerosis. The chemokine stromal derived factor 1 (SDF-1) is the natural ligand for the CXCR4 HIV co-receptor, is highly expressed in atherosclerotic plaques, and the plasma concentration is lower in individuals homozygous for the mutant allele (SDF1-3'A). We tested the influence of SDF1-3'A on atherosclerosis in HIV-infected patients. METHODS: We performed carotid ultrasonography and determined the SDF1-3'A DNA polymorphism in 183 HIV-infected patients. Classical cardiovascular risk factors and antiretroviral therapy were also recorded. From these patients, we selected a group of 134 patients taking protease inhibitor-based antiretroviral therapy and in whom the lipid profile over an 18-month follow-up was collated. RESULTS: We found atherosclerosis in 113 (61.7%) and a lower number of patients with the SDF-1 mutated allele in the group with carotid atherosclerosis compared to those without (41.6% versus 57.1%; P = 0.04). Using a logistic regression analysis, age and dyslipidaemia were significantly associated with atherosclerosis but the SDF1-3'A allele exerted a protective effect on the development of atherosclerosis (odds ratio, 0.45; 95% confidence interval, 0.14-1.02; P = 0.05). Further, we observed that, in the selected group of patients there were lower plasma low-density lipoprotein cholesterol concentrations [mean +/- SEM, 2.06 +/- 0.34 mmol/l] throughout follow up in those patients without carotid lesions and who also carried the mutated SDF1-3'A allele (P = 0.04). CONCLUSION: The SDF1-3'A allele is associated with a lower presence of subclinical carotid atherosclerosis in an HIV-infected population.     

Chemokine receptor gene polymorphisms and risk of human T lymphotropic virus type I infection in Jamaica

Polymorphisms of some chemokine receptor genes and their ligands are associated with susceptibility and progression of human immunodeficiency virus infection. This study assessed whether these variants are also responsible for susceptibility to infection with human T lymphotropic virus (HTLV) type I. Frequencies of CCR5-Delta 32, CCR2-64I, and SDF-1-3'A genotype among 116 HTLV-I-positive and 126 HTLV-I-negative persons of African descent in Jamaica were 1.0%, 14.9%, and 5.4%, respectively. The association of HTLV-I infection with the most common variant, CCR2-64I, was examined in 532 subjects. Thirteen (5.4%) of 241 HTLV-I-negative subjects were homozygous for CCR2-64I, versus 3 (1.0%) of 291 HTLV-I-positive subjects (P=.005). Among HTLV-I carriers, provirus load and antibody titer were not significantly different in persons with CCR2-+/64I or CCR2-+/+. These findings suggest that CCR2-64I, or alleles in linkage disequilibrium with it, may affect the risk of HTLV-I infection in a recessive manner.     

The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia

The chemokine receptor CCR5 is an important co-receptor for cell fusion. A 32-bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes. The objectives of this study were to assess the effects of this 32-bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV-negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32-bp deletion, two patients being homozygous. The presence of the CCR5 32-bp gene deletion has also been analysed in 71 HIV-positive patients. In this group of patients, there was a lower than expected incidence of the 32-bp deletion. Those who possess the 32-bp deletion progress to AIDS more slowly than those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion. We confirm that heterozygosity for the 32-bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.     

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

OBJECTIVE: To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. DESIGN: Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

CCR5 expression and duration of high risk sexual activity among HIV-seronegative men who have sex with men

OBJECTIVES: To test the hypothesis that in comparison with those with shorter risk duration, individuals with longer HIV risk duration would have reduced susceptibility to HIV-1 infection as measured by CCR5 expression, and to evaluate whether variation in CCR5 expression could be explained by known genetic polymorphisms. DESIGN AND METHODS: A cross-sectional study of HIV-1 exposed but uninfected men who have sex with men. The risk duration was estimated from self-reported years since first receptive anal intercourse. CCR5 expression on peripheral blood CD4+ monocytes and T cells was determined by flow cytometry. The CCR5-Delta32 mutation and polymorphisms in the CCR5 promoter and CCR2 as well as the copy number of CCL3L1 were analyzed by polymerase chain reaction. Plasma levels of MIP-1alpha (CCL3), MIP-1beta (CCL4) and RANTES (CCL5) were also measured. As risk duration varied with age, analyses were restricted to 67 individuals aged 30-49 years. RESULTS: Multiple linear regression analyses, adjusted for age and race, showed a significant negative association between HIV risk duration and CCR5 expression on monocytes (P = 0.01), and in a separate model, a similar negative association with CCR5 expression on T cells (P = 0.03). Low CCR5 expression was attributable mainly to CCR5-Delta32 heterozygosity and the CCR5-59029G allele. CONCLUSIONS: We confirmed a role for reduced CCR5 expression in HIV-1 resistance. CCR5-Delta32 heterozygosity and the CCR5-59029G allele were significant predictors of low CCR5 expression. Individuals with high CCR5 expression who resisted infection despite long HIV risk duration form an interesting group within which to search for additional mechanisms of resistance to HIV infection.     

几种趋化性细胞因子及受体基因多态性与系统性红斑狼疮的关联研究

目的探讨基质衍生因子1-3'A(stromalcell-derivedfactor1-3'A,SDF1-3'A)、趋化性细胞因子受体2-64I(chemoattractantcellreceptor2-64I,CCR2-64I)190位点、单核趋化蛋白1(monocytechemoattractantprotein-1promoter-2518polymorphism,-2518MCP-1)基因多态性及其交互作用与系统性红斑狼疮(SLE)的相关性。方法以143例SLE病人和157名健康对照为对象进行病例对照研究。应用聚合酶链反应—限制性内切酶片段长度多态性(polymerasechainreaction/restrictionfragmentlengthpolymor-phism,PCR-RFLP)方法确定SDF1-3'A和-2518MCP-1基因多态性,应用突变特异性扩增系统(amplifica-tionrefractorymutationsystem,ARMS)确定CCR2-64I基因多态性。结果-2518MCP-1、CCR2-64I、SDF1-3'A等位基因及基因型频率在SLE和健康对照组之间差异无显著性。但-2518MCP-1A/G基因型对照组高于病例组(χ2=4.11,P=0.04)。基因间交互作用分析发现,当SDF1-3'A、-2518MCP-1、CCR2-64I基因型分别为G/G、A/G和G/G时,对SLE发病可能具有保护作用(P<0.05)。其他基因型间均未见交互作用(P>0.05)。结论单个-2518MCP-1、CCR2-64I、SDF1-3'A基因多态性与SLE易感性无关联,但他们之间可能存在交互作用。