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Department of Pediatrics, Division of Infectious Diseases, Center for Molecular Genetics
Center for AIDS Research, University of California, San Diego, La Jolla
Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
Background.
The impact of CX3CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1infected adults.
Methods.
A cohort of 1055 HIV-1infected children were genotyped for 2 CX3CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1related disease progression, including central nervous system (CNS) impairment, was evaluated.
Results.
Children with the CX3CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.303.68], P = .003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.003.14], P = .05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.004.78], P = .049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.854.83], P = .11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.240.73]; P = .002) and CNS impairment (RH, 0.39 [95% CI, 0.390.22]; P = .001). Of note, these effects remained significant after CD4+ lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis.
Conclusions.
CX3CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4+ lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX3CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.
Human chemokines and chemokine receptors are involved in HIV infection and disease progression [1]. CX3CR1 belongs to a family of G-proteincoupled receptors and is a leukocyte chemotactic and adhesion receptor for fractalkine [2]. CX3CR1 is a recently identified HIV-1 coreceptor [3] that is expressed in monocytes, T lymphocytes, NK cells, astrocytes, neurons, brain microglia, and many tissues, with particularly high levels present in the brain [3, 4].
Two nonsynonymous polymorphisms in the coding region of the CX3CR1 gene were initially identified as possibly being associated with more-rapid disease progression in HIV-1infected adults [5]: a GA polymorphism at nt 745, which changes valine to isoleucine at aa 249 (V/I249) in the sixth transmembrane domain of the CX3CR1 protein, and a CT polymorphism at nt 849, which changes threonine to methionine at aa 280 (T/M280) in the seventh transmembrane domain of the CX3CR1 protein. It has been proposed that reduced CX3CR1 expression and fractalkine binding in individuals with the CX3CR1 M/M280 genotype could compromise normal immune responses, leading to accelerated progression of HIV-1 disease [5]. However, subsequent studies failed to observe such associations between these polymorphisms and HIV-1 disease in adults [68]. Recently, Faure et al. [9] reported that HIV-1infected persons homozygous for CX3CR1 M280 progressed to AIDS more rapidly than did those with other genotypes. Moreover, they suggested that this deleterious effect predicted that a cohort of seroprevalent adults would be depleted of M280 carriers, because these patients would have been at a higher risk for death before recruitment to a study. Faure et al. [5] also studied the impact of the V/I249 polymorphism on disease progression but found no association. Brumme et al. [10] found a trend toward an association of the I249-T280 and I249-M280 haplotypes with early immunological failure in HIV-1infected adults.
The expression of CX3CR1 and its ligand, fractalkine, is increased during HIV-1 infection and is reduced on treatment with highly active antiretroviral therapy (HAART) [11], suggesting that they play an important role in directing the immune response against HIV-1. Fractalkine expression has been reported to be up-regulated in the brains of patients with AIDS, and fractalkine produced during interactions between monocytes and HIV-1infected macrophages is thought to play a role in HIV-1associated dementia by regulating the trafficking of monocytes in brain parenchyma [1215].
On the basis of the available information on fractalkine and CX3CR1, we hypothesized that decreased expression of CX3CR1, due to the presence of specific CX3CR1 genetic variations, would lead to inefficient fractalkine-CX3CR1 binding that could interfere with the immunologic response to HIV-1 and, thus, impact overall disease progression and central nervous system (CNS) impairment. We have previously shown in a cohort of HIV-1infected children that the CCR5 wild type (wt)/32 and CCR5 59029G/A genotypes were significant predictors of HIV-1related disease progression [16]. We believed that the impact of genetic variants of CX3CR1 might be more easily observed in this cohort of children because of the more-rapid disease progression and higher frequency of CNS impairment associated with HIV-1 infection in children, compared with that in adults.
PATIENTS AND METHODS
Patient populations.
The patients studied formed a cohort of seroprevalent children with symptomatic HIV-1 infection who participated in randomized, double-blind, multicenter Pediatric AIDS Clinical Trials Group (PACTG) cohorts 152 (n = 462) [17] or 300 (n = 593) [18], which were designed (1) to compare the effects of monotherapy with either zidovudine (ZDV) or didanosine (ddI) versus the effects of combination therapy with ZDV plus ddI and (2) to compare the effects of combination therapy with ZDV plus lamivudine (3TC) versus the effects of ddI monotherapy and of combination therapy with ZDV plus ddI, respectively. Of the 1055 children studied, 576 (55%) were female. The median age was 2.4 years (10th and 90th percentiles, 0.5 and 9.4 years, respectively). Of the 1055 children, 320 (30%) were followed for <12 months, 451 (43%) were followed for 1223 months, 198 (19%) were followed for 2435 months, and 86 (8%) were followed for 36 months. A total of 229 (22%) were identified as having HIV-1related disease progression during the course of the 2 studies. Details of the characteristics of children, eligibility criteria, study end points, disease progression, and neuropsychological tests used have been described elsewhere [1618]. Informed consent was obtained from guardians of the study participants. This study followed the human experimentation guidelines of the US Department of Health and Human Services and the University of California, San Diego review board.
Genotyping.
CX3CR1 V/I249 and T/M280 genotyping was performed by real-time polymerase chain reaction (PCR) using melting curve analysis (LightCycler). One set of primers and 2 sets of fluorescence-labeled hybridization probes were used in this assay; primer sequences were as follows: forward primer, 5-TTGGCTTCCTACTCCC; reverse primer, 5-TCCCATACAGGTGGTAA. For detection of the CX3CR1 745G/A polymorphism (V/I249), the sensor and anchor probe sequences were as follows: 5-TAACGTTGTAGGGTGTCCAGAfluorescein isiothiocyanate (FITC) and LCR640-AGGAAAAACACGATGACCACC-Phos; the melting curve was analyzed in channel F2, with the G/G and A/A genotypes having melting-temperature values of 63°C and 59°C, respectively. For detection of the CX3CR1 849C/T polymorphism (T/M280), the sensor and anchor probe sequences were LCR705-TGAGACGGTTGCATTTAGCC-Phos and 5-GGCTGGCCCTCAGTGTG-FITC; the melting curve was analyzed in channel F3, with C/C and T/T genotypes having melting-temperature values of 64°C and 55°C, respectively. Probes were hybridized to the complementary strand of target DNA, and underlined C nucleotides in the above sequences show the sites of polymorphisms; the amplicon length was 336 nt. The specificity of genotyping assays was confirmed by conventional PCRrestriction fragment length polymorphism analysis [19].
Statistical methods.
Analysis of variance and analysis of covariance were used to compare markers of disease status at trial entry. The Mantel-Haenszel test, stratified by age, age squared, and race/ethnicity, was used to evaluate differences in genotype and allele frequencies. Analyses of progression to a study end point were performed using Kaplan-Meier estimates and proportional-hazards models stratified by study and randomized treatment. Analyses that stratified further by race/ethnicity gave very similar results; therefore, data are presented without specific reference to race/ethnicity.
RESULTS
Distribution of CX3CR1 genotypes and haplotypes.
Because the impact of specific polymorphisms in CX3CR1 on HIV-1associated disease could vary with the diverse genetic backgrounds present in different racial/ethnic groups, we examined the distribution of genotypes within our pediatric cohort. Table 1 summarizes the distribution of CX3CR1 genotypes and haplotypes by race/ethnicity. Of note, only 6 genotypes (V/V249-T/T280, V/I249-T/T280, V/I249-T/M280, I/I249-T/T280, I/I249-T/M280, and I/I249-M/M280) were detected. Because the V249 allele is in complete linkage disequilibrium with the T280 allele, as confirmed elsewhere by Faure et al. by use of a likelihood-ratio test [5], we used the same nomenclature and inference for genotypes and haplotypes (table 1).
Associations between disease status at study entry and CX3CR1 polymorphisms.
At study entry, none of the CX3CR1 genotypes or haplotypes was significantly associated with CD4+ lymphocyte count, CD4+ lymphocyte percentage, plasma HIV-1 RNA load, weight for age and sex z score, or cognitive score (data not shown).
CX3CR1 polymorphisms and HIV-1related disease progression.
The children with the CX3CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.303.68], P = .003; and I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.003.14], P = .050) in the whole cohort (P = .009) (figure 1A) and in the subset with the CCR5 wt/wt genotype (P < .001) (figure 1B). In both the whole cohort and the CCR5 wt/wt subset, there was little difference in the rate of disease progression between children carrying the V/I249 genotype and those carrying the V/V249 genotype. The effect of the I/I249 genotype persisted in a multivariate analysis that adjusted for the CCR5 wt/32, CCR5 59029G/A, and CX3CR1 T/M280 polymorphisms (table 2).
There were no significant effects of CX3CR1 280 genotype on HIV-1related disease progression in the whole cohort (P = .22) (figure 1C) or in the subset with the CCR5 wt/wt genotype (P = .09) (figure 1D). There was also no significant association found for CX3CR1 280 genotype in multivariate analysis (table 2).
CX3CR1 polymorphisms and HIV-1related CNS impairment.
There was a trend toward more-rapid progression to CNS impairment in children with the I/I249 genotype than in children with either the V/I249 or the V/V249 genotype (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.004.78], P = .049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.854.83], P = .11) in the whole cohort (P = .14) (figure 2A); this association was marginally significant in the subset with the CCR5 wt/wt genotype (P = .051) (figure 2B). The trend in the overall study population persisted in multivariate analyses adjusted for the CCR5 wt/32, CCR5 59029G/A, and CX3 CR1 T/M280 polymorphisms but was not statistically significant (data not shown).
The CX3CR1 M/M280 genotype was associated with greater CNS impairment in the whole cohort (P = .014) (figure 2C) and in children with the CCR5 wt/wt genotype (P = .009) (figure 2D). However, these analyses should be viewed cautiously, because the number of children with the CX3CR1 M/M280 genotype was small (i.e., only 5 children, including 2 whose disease progressed, had the M/M280 genotype).
CX3CR1 haplotypes and HIV-1related disease progression and CNS impairment.
We next examined the impact of presence of specific CX3CR1 haplotypes on disease progression. Children with the V249-T280 haplotype were less likely to develop disease and had a slower rate of disease progression than did children without this haplotype (P = .005) (figure 3A). The improved outcome for the cohort of children with the V249-T280 haplotype was further supported in a multivariate analysis adjusted for CCR5 and CCR5 59029 genotype (RH, 0.43 [95% CI, 0.250.73]; P = .002) (table 2). In contrast, children with the I249-T280 haplotype had shorter progression-free survival, in both the whole cohort (P = .018) (figure 3B) and the subset with the CCR5 wt/wt genotype (P = .008); this association with disease progression was also maintained in a multivariate analysis adjusted for the CCR5 wt/32 and CCR5 59029G/A polymorphisms (table 2). There was no significant association between I249-M280 haplotype and progression-free survival in the whole cohort (P = .22) (figure 3C) or in the subset with the CCR5 wt/wt genotype (P = .09), in both univariate and multivariate analyses (table 2).
Children with the V249-T280 haplotype had a lower risk of a CNS end point (P = .052) (figure 3D), which persisted in children with the CCR5 wt/wt genotype (P = .015). The association was marginal in multivariate analyses adjusted for CCR5 and CCR5 59029 genotype (RH, 0.47 [95% CI, 0.201.08]; P = .075). There were no significant differences in CNS impairment in children with versus without the I249-T280 haplotype (P = .11) or in those with versus without the I249-M280 haplotype (P = .96), in the whole cohort or in the subset with the CCR5-wt/wt genotype, in both univariate and multivariate analyses (data not shown).
Influence of the CX3CR1 I/I249 genotype and V249-T280 haplotype on HIV-1 disease progression after adjusting for CD4+ lymphocyte count and HIV-1 RNA load at baseline.
Because CD4+ lymphocyte count and percentage and plasma HIV-1 RNA load are the strongest predictors of risk of disease progression in children as well as adults [2023], we examined the impact of the CX3CR1 polymorphisms in multivariate analyses adjusting for baseline CD4+ lymphocyte count or HIV-1 RNA load. When adjusted for baseline CD4+ lymphocyte count and for the CCR5 wt/32, CCR5 59029G/A, and CX3CR1 T/M280 polymorphisms, the RH for CX3CR1 I/I249 versus V/V249 in a multivariate analysis was 2.40 (95% CI, 1.324.38; P = .004) for HIV-1related disease progression. Similarly, CX3CR1 haplotypes (present vs. absent) V249-T280 and I249-T280 remained significantly associated with disease progression in multivariate analyses (RH, 0.45 [95% CI, 0.260.76], P = .003 and RH, 1.51 [95% CI, 1.092.08], P = .012, respectively). When baseline plasma HIV-1 RNA load and the CCR5 wt/32, CCR5 59029G/A, and CX3CR1 T/M280 polymorphisms were controlled for, the RH for CX3CR1 I/I249 versus V/V249 in a multivariate analysis was 2.40 (95% CI, 1.234.69; P = .01) for disease progression. For the CX3CR1 haplotypes (present vs. absent) V249-T280 and I249-T280, the multivariate analyses identified an RH of 0.38 (95% CI, 0.210.68; P = .001) and a RH of 1.30 (95% CI, 0.891.90; P = .17), respectively.
We next evaluated, in univariate and multivariate analyses, the RHs for disease progression by CX3CR1 genotype and haplotype, adjusted for baseline CD4+ lymphocyte count, baseline plasma HIV-1 RNA load, and the CCR5 wt/32 and CCR5 59029G/A polymorphisms. In the multivariate analyses, only CX3CR1 I/I249 versus V/V249 and CX3CR1 haplotype V249-T280 (present vs. absent) remained significantly associated with disease progression (RH, 2.41 [95% CI, 1.244.69], P = .01 and RH, 0.40 [95% CI, 0.220.71], P = .002, respectively). When similar multivariate analyses were used, the RHs for development of CNS impairment for CX3CR1 I/I249 versus V/V249 and CX3CR1 haplotype V249-T280 (present vs. absent) were 2.47 (95% CI, 0.906.75; P = .08) and 0.37 (95% CI, 0.160.86; P = .022), respectively. In this multivariate model, none of the other genotypes remained significantly associated with both disease progression and CNS impairment.
Influence of the CX3CR1 I/I249 genotype and V249-T280 haplotype on HIV-1 disease progression after adjusting for CD4+ lymphocyte count and viral RNA load over time.
To further explore the importance of CX3CR1 polymorphisms, we adjusted for changes in CD4+ lymphocyte count and plasma HIV-1 RNA load during follow-up by including these as time-dependent variables in proportional-hazards models. Of note, the impact of the CX3CR1 I/I249 genotype and V249-T280 haplotype remained significantly associated with disease progression and development of neurocognitive impairment, whereas the CCR5 wt/32 and CCR5 59029A/A genotypes lost significance in the models (table 3).
DISCUSSION
An increasing body of literature supports the concept that host and microbial genetics are important determinants of infection and disease outcome. Viruses use chemokines and their receptors as their own receptors, apparently in an attempt to evade the immune system. With the identification of chemokine receptors as coreceptors for HIV-1 infection, mutations in genes encoding these receptors and their natural ligands have been shown to modify the risk of HIV-1 infection and disease progression. To date, most genetic variants identified as having an impact on HIV-1related disease progression have their effect through modification of the ability of the virus to bind to and efficiently infect susceptible cells. Although CX3CR1 has been identified as a potential coreceptor for HIV-1, it appears to play a role in viral attachment and entry that is minor compared with that of the dominant coreceptors, CCR5 and CXCR4. Thus, we believe that the impact of polymorphisms in CX3CR1 on HIV-1 disease progression is more likely to be through its fundamental role in directing inflammatory cells to specific sites of infection to initiate innate and adaptive immunity [24].
The impact of polymorphisms in CX3CR1 on disease progression in HIV-1infected adults remains controversial. In at least 2 HIV-1infected cohorts, no association was observed between the CX3CR1 M280 allele and disease progression [6, 7]. In a third study, similar frequencies of CX3CR1 249 and 280 genotypes were observed in patients with rapid progression and those without progression [8]. In contrast to the findings in these recent studies of adultsbut in agreement with those in studies by Faure et al. [5, 9]our findings strongly indicate that genetic variants that alter the expression of functional CX3CR1 can profoundly influence the risk and rate of HIV-1related disease in children. Moreover, in multivariate analyses, our data indicate that a specific CX3CR1 genotype and haplotype strongly predict both disease progression and CNS impairment independently of markers such as CD4+ lymphocyte count and plasma HIV-1 RNA load, as well as other genetic variants, including the CCR5 wt/32, CCR5 59029G/A, and CX3CR1 T/M280 polymorphisms.
In the present study, children with the wild-type CX3CR1 V/V249 genotypewhich has been associated with greater binding to fractalkine, compared with that in individuals with the I/I249 genotype [5]experienced slower HIV-1 disease progression than did children with the I/I249 genotype; however, the disease progression in V/I249 heterozygotes was similar to that in children with the V/V249 genotype. A similar trend was observed by Brumme et al. [10]; however, in their study that included V/I249 heterozygotes, this effect was only marginally significant (P = .07). Similarly, the T280 allelic variant, also associated with enhanced binding of fractalkine, was associated with slower disease progression, compared with the M280 allele. Furthermore, Faure et al. [5] found that CX3CR1 expression was not significantly different among haplotypes; however, fractalkine binding affinity was highest in the V249-T280 haplotype, compared with the I249-T280 and I249-M280 haplotypes.
The strength of the impact of the CX3CR1 I/I249 genotype on disease progression in HIV-1infected children is further supported by the multivariate analyses including the CCR5 wt/32, CCR5 59029G/A, and CX3CR1 T/M280 polymorphisms, demonstrating that the CX3CR1 249-I/I genotype and the V249-T280 haplotype have a significant impact on the rate of disease progression. These findings contrast with those of earlier studies of adults, conducted by Faure et al. [5], which failed to find an impact of the V/I249 polymorphism on disease progression. It is unclear why Faure et al. did not observe a significant impact of CX3CR1 polymorphisms in their cohort; one possible reason is that their study sample consisted of seroprevalent adults, which suggests that the impact of these polymorphisms may be greater in children than in adults. This explanation is unlikely, however, because Brumme et al. [10] observed trends for associations of the I249-T280 and I249-M280 haplotypes with immunological failure in HIV-1infected adults. Their study, however, did not evaluate the impact of the V/I249 polymorphismindependent of the T/M280 polymorphismon HIV-1related disease progression.
In addition to having an important influence on overall HIV-1related disease, the polymorphisms in CX3CR1 are also, on the basis of our observations, associated with CNS impairment in children. In children with the CCR5 wt/wt genotype, we observed a significant association between the presence of the CX3CR1 I/I249 genotype and an increased risk for neurocognitive disease in univariate analysis, with a similar trend present in multivariate analysis. The same trend of increased risk was observed in children with the M/M280 genotype, albeit with a small number of children. Thus, because CX3CR1 is normally expressed in higher quantities in the brain than in other organs [4] and because CX3CR1/fractalkine expression is affected by HIV-1 infection [1115], it would appear that genetic variants producing less CX3CR1 may place HIV-1infected children at increased risk for CNS impairment. Haplotype data provide additional support for the role of CX3CR1 variants in the development of CNS impairment, with children with the V249-T280 haplotype experiencing less than one-half the risk for development of CNS disease seen in children without the V249-T280 haplotype.
At baseline, no effects of CX3CR1 polymorphisms were observed in our cohort, suggesting that these polymorphisms exert their effects during later stages of HIV-1 infection. These findings are consistent with those of the study by Faure et al. [5], in which the divergence of disease progression among CX3CR1 genotypic groups was observed only after 30 months of infection. These observations further support the hypothesis that the effects of polymorphisms in CX3CR1 are on the recruitment of immunomodulatory cells to sites of HIV-1 infection and have the broadest impact on the ability of the immune system to sustain suppression of the virus. The hypothesis that reduced CX3CR1 expression and fractalkine binding in individuals with the I/I249 and M/M280 genotypes can compromise normal immune responses is also supported by recent data demonstrating that increased expression of CX3CR1 on CD8+ and CD4+ lymphocytes is associated with disease progression in HIV-infected adults [24]. Interestingly, CX3CR1 appears to be the main homing receptor of CD4+ and CD8+ lymphocytes, since the expression of most other chemokine receptors is reduced with advancing HIV-1related disease. The importance of CX3CR1 in cell trafficking is further supported by the expanding list of other diseases associated with inflammation that are influenced by CX3CR1 expression, such as coronary artery [19, 25, 26] and renal [27] inflammatory diseases.
Of particular note, the disease-progression impact of the CX3CR1 I/I249 genotype and the protective impact of the V249-T280 haplotype on HIV-1related disease progression were independent of CD4+ lymphocyte count and plasma HIV-1 RNA load, both at baseline and follow-up. These findings suggest that CX3CR1 polymorphisms provide additional information regarding the control of HIV-1, independent of CD4+ lymphocyte count. The mechanism for the effect may be through its chemotactic function in recruitment of lymphocytes, monocytes, and NK cells to the site of HIV-1 infection. In this regard, Combadiere et al. [24] have demonstrated that CX3CR1 plays an important role in homing and antiviral potency of CD8+ effector-memory T lymphocytes in HIV-1infected patients.
Our results also demonstrate that the prevalence of the CX3CR1 V/I249 and T/M280 polymorphisms differ significantly by race/ethnicity. The I249 and M280 alleles and haplotypes were most prevalent in non-Hispanic white children and least common in non-Hispanic black children. Thus, the impact of these polymorphisms on HIV-1 disease may be greatest in non-Hispanic white children. Most other studies have included non-Hispanic white adults. It is important to note, therefore, that we found no significant differences by race/ethnicity in the associations between CX3CR1 polymorphisms and disease progression or development of CNS impairment. Also, in contrast to observations by Faure et al. [5], who found no CX3CR1 polymorphisms among 45 West African individuals, African American children in our study had the same genotypic variants as did non-Hispanic white and Hispanic children, albeit at lower frequencies.
To our knowledge, ours is the first study to examine the impact of genetic variants of CX3CR1 on HIV-1 infection in children. Compared with adults, children have more-rapid HIV-1 disease progression, higher absolute counts of CD4+ lymphocytes, higher HIV-1 RNA loads, and more neurocognitive impairment. Thus, the impact of CX3CR1 polymorphisms on HIV-1 infection in children could be fundamentally different from that in adults. Additionally, although our cohort was a seroprevalent population, the timing of infection for this perinatally infected cohort is known and is not affected by the widely disparate timing and routes of infection that may be present in adult cohorts. Also, whereas antiretroviral therapy was uncontrolled in previous cohorts, treatment was well documented in the cohort in the present study. Moreover, although the children in our cohort received 1 or 2 nucleoside reverse-transcriptase inhibitors, these regimens were standardized for each participant, and we did not find any dependence of the reported associations on the type of antiretroviral therapy received. Thus, our findings indicate that the CX3CR1 I/I249 genotype is associated with more-rapid disease progression and CNS impairment in HIV-1infected children and that the presence of the V249-T280 haplotype is associated with improved clinical outcome.
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