Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection

The role that host genetics plays in the modification of the rate of human immunodeficiency virus 1 (HIV-1)-related disease progression was evaluated in a seroprevalent cohort of 1049 children with symptomatic HIV-1 infection who participated in 2 clinical trials in the United States. Variants including CCR2-V64I, CCR5-wt/Delta32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5-59356-C/T, and SDF1-3'-G/A were identified by polymerase chain-reaction genotyping. Children with the CCR5-wt/Delta32 genotype experienced significantly delayed disease progression, including less neurocognitive impairment. In the CCR5-wt/wt group, the most rapid disease progression was in those with the CCR5-59029-A/A genotype, which was present in 23% of the children. Although the SDF1-3'-A/A variant was associated with more-rapid disease progression, it occurred in <2% of the children studied. Modest or little impact was associated with the CCR5-59353, CCR5-59356, or CCR2 genotypes. Thus, in children with the CCR5-wt/wt genotype, variants at CCR5-59029 have the broadest impact on disease progression. These data suggest that, in children, host genetics plays an important role in HIV-1-related disease progression and neurological impairment.     

CCR5 promoter polymorphisms, CCR5 59029A and CCR5 59353C, are under represented in HIV-1-infected long-term non-progressors. The Australian Long-Term Non-Progressor Study Group

OBJECTIVE: To determine the influence of CCR5 promoter polymorphisms on HIV-1 progression to AIDS and to evaluate the interaction between CCR5 structural polymorphisms and those occurring in the regulatory region of the same gene. PARTICIPANTS: Seventy-one HIV-1-infected long-term non-progressors with a CD4+ T cell count of > 500 x 10(6)/I more than 8 years after infection were compared with 75 HIV-1-infected individuals who had progressed to AIDS and/or death within 8 years and with a further 119 HIV-1-positive patients who had CD4+ T cell counts of 200-500 x 10(6)/l. An additional 92 HIV-negative individuals were also studied. METHODS: CCR5 delta32 genotype was determined by PCR with primers spanning the 32 base pair deletion. CCR2-64I, CCR5 59029A/G and CCR5 59353C/T genotypes were determined by PCR followed by restriction fragment length polymorphism analysis. RESULTS: Strong linkage disequilibrium between the CCR5 59029A and CCR5 59353C polymorphic variants was identified. CCR5 59029A and CCR5 59353C homozygotes were found to be significantly under-represented in the long-term non-progressor group as compared with the other HIV-1-positive groups, with the effect being more marked in the absence of the CCR5 delta32 and CCR2 64I mutations. CONCLUSIONS: This study provides the first evidence for an association between CCR5 promoter polymorphisms and long-term asymptomatic HIV-1 infection, with individuals lacking the CCR5 59029A/CCR5 59353C homozygous genotype likely to progress more slowly towards AIDS and/or death.     

CCR5 promoter polymorphisms in a Kenyan perinatal human immunodeficiency virus type 1 cohort: association with increased 2-year maternal mortality

The CCR5 chemokine receptor acts as a coreceptor with CD4 to permit infection by primary macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains. The CCR5Delta32 mutation, which is associated with resistance to infection in homozygous individuals and delayed disease progression in heterozygous individuals, is rare in Africa, where the HIV-1 epidemic is growing rapidly. Several polymorphisms in the promoter region of CCR5 have been identified, the clinical and functional relevance of which remain poorly defined. We evaluated the effect of 4 CCR5 promoter mutations on systemic and mucosal HIV-1 replication, disease progression, and perinatal transmission in a cohort of 276 HIV-1-seropositive women in Nairobi, Kenya. Mutations at positions 59353, 59402, and 59029 were not associated with effects on mortality, virus load, genital shedding, or transmission in this cohort. However, women with the 59356 C/T genotype had a 3.1-fold increased risk of death during the 2-year follow-up period (95% confidence interval [CI], 1.0-9.5) and a significant increase in vaginal shedding of HIV-1-infected cells (odds ratio, 2.1; 95% CI, 1.0-4.3), compared with women with the 59356 C/C genotype.     

Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C

BACKGROUND & AIMS: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection. METHODS: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant. RESULTS: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048). CONCLUSIONS: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.     

Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy

BACKGROUND: Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous. Polymorphisms in chemokine receptor genes modulate the natural history of HIV-1 infection. In comparison with subjects with other genotypes, the prognosis for HIV-1-infected CCR5-delta32 heterozygotes is more favorable and that for CCR5 promoter allele 59029A homozygotes is less favorable. METHODS: HIV-1-infected adults with a CD4+ lymphocyte count > or = 200 cells x 10(6)/l and a plasma HIV RNA level > or = 1000 copies/ml were treated with indinavir, zidovudine and lamivudine for 6 months. HIV RNA levels were measured at 4-week intervals. Genotyping for chemokine receptor gene polymorphisms (CCR5-delta32, CCR5 59029A/G, CCR2-641) was performed. We examined whether the time to first HIV RNA < 200 copies/ml, frequency of viral suppression failure (HIV RNA > or = 200 copies/ml between weeks 16 and 28 of therapy), or reduction from the pre-treatment HIV RNA level differed by genotype. RESULTS: Time to first HIV RNA < 200 copies/ml was not predicted by genotype. Among 272 Caucasian patients, viral suppression failure was more common among patients with the CCR5 +/+ ? CCR2+/+ ? CCR5-59029 A/A genotype (28%) than among all other subjects combined (relative risk, 2.0; P = 0.06). After 24 weeks of therapy, genotype groups differed in the reduction of the HIV RNA level from baseline (P = 0.02); patients with the CCR5 +/+ ? CCR2+/+ ? CCR5-59029 A/A genotype had a mean reduction of 2.12 log10 copies/ml compared to 2.64 log10 copies/ml among all other groups combined. CONCLUSION: Polymorphisms in chemokine receptor genes may explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy.     

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).     

Stromal cell-derived factor-1 genotype, coreceptor tropism, and HIV type 1 disease progression

This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P=.009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5 Delta 32 and CCR2-64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4-tropic viruses (P=.012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease.     

Reduced prevalence of the CCR5 delta32 heterozygous genotype in human immunodeficiency virus-infected individuals with AIDS dementia complex.

Heterozygosity for a 32-bp deletion in the CCR5 gene (CCR5 Delta32), which encodes the coreceptor for macrophage-tropic non-syncytium-inducing (NSI) human immunodeficiency virus type 1 (HIV-1) variants, results in a lower CCR5 expression and reduced NSI HIV-1 replication. Because infection of macrophages and microglial cells by NSI HIV-1 is considered to be instrumental for the development of AIDS dementia complex (ADC), we studied whether the CCR5 Delta32 heterozygous genotype correlated with a reduced frequency of ADC. Two (4.1%) of 49 patients with ADC versus 27 (14. 5%) of 186 AIDS patients without ADC were heterozygous for CCR5 Delta32 (P=.05). In contrast, a point mutation in the first transmembrane domain of CCR2 (CCR2 64I) did not show this protective effect (P=.57). The reduced prevalence of the CCR5 Delta32 allele among patients with ADC may indicate a reduced or absent reservoir of macrophage-tropic NSI HIV-1 in the brain of CCR5 Delta32 heterozygotes.     

Better CD4+ T cell recovery in Brazilian HIV-infected individuals under HAART due to cumulative carriage of SDF-1-3'A, CCR2-V64I, CCR5-D32 and CCR5-promoter 59029A/G polymorphisms

Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3'A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3'A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/microl/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure.     

Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis

OBJECTIVE: Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis. METHODS: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. RESULTS: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed. CONCLUSION: The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.     

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.     

Influence of CCR5 promoter haplotypes on AIDS progression in African-Americans

OBJECTIVES: To test the hypothesis that the CCR5 promoter variants in HIV-1-infected African-Americans affect the rate of progression to AIDS and to determine the extent of linkage disequilibrium between the CCR5P1 allele and the CCR5 59029A variant (referred to here as CCR5-2459A), both of which have been shown independently to accelerate AIDS progression in Caucasians. DESIGN: We used survival analysis to assess the effects of CCR5 promoter variants in HIV-1 seroincident Caucasians and African-Americans. SUBJECTS AND METHODS: Genotypes were determined for 806 Caucasians and 1067 African-Americans, which included 700 seroconverters, enrolled in four HIV/AIDS natural history cohort studies. These genotypes were used to determine linkage and haplotypes for CCR2 and CCR5 alleles. Survival analysis was used to assess the effect of CCR2, CCR5, and CCR5 promoter haplotypes on progression to AIDS in seroincident African-Americans. RESULTS: A survey of Caucasians and African-Americans demonstrated complete linkage disequilibrium between CCR5P1 and CCR5-2459A sites. The composite CCR5P1 haplotype (including the CCR5-2459A allele) is shown to be associated with rapid progression to AIDS endpoints in both African-American and Caucasian cohorts, but the effect is recessive in Caucasians and dominant in African-Americans. This is probably due to the presence of modulating genes or as yet unidentified polymorphisms that may differ between racial groups.     

Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load

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-1-infected adults. METHODS: A cohort of 1055 HIV-1-infected children were genotyped for 2 CX3CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related 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}, 1.30-3.68], P=.003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14], P=.05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.00-4.78], P=.049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P=.11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P=.002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; 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.     

Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus

The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.     

Chemotactic cytokine receptor 5 (CCR5) gene promoter polymorphism (59029A/G) is associated with diabetic nephropathy in Japanese patients with type 2 diabetes: a 10-year longitudinal study

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (-28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES -28C/G polymorphisms was assessed. The frequency of the RANTES -28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p=0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy (p=0.03, odds ratio=2.41, 95% CI=1.09-5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.     

CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression

OBJECTIVE AND DESIGN: We have recently shown that the number of CCR5 molecules at the surface of peripheral blood CD4 T cells (CCR5 density) correlates with the viral RNA plasma level in HIV-1-infected individuals. As viral load is a strong predictor of outcome in HIV infection, the present study examines the correlation between CCR5 density and HIV-1 disease progression. METHODS: Using a quantitative flow cytometry assay, we measured CCR5 density in HIV-1-infected adults and control healthy volunteers. The CCR5 genotype (presence of a Delta 32 allele) was also determined. RESULTS: CCR5 density was stable over time on non-activated, HLA-DR(-)CD4 T cells of infected individuals. In a study cohort of 25 patients, asymptomatic and non-treated, we observed a correlation between CCR5 density on HLA-DR(-)CD4 T cells and the CD4 T cell slope (P = 0.026), which was independent of the presence or absence of the Delta 32CCR5 deletion. In particular, slow progressors expressed lower CCR5 densities than non-slow progressors (P = 0.004) and non-infected control subjects (P = 0.002). CONCLUSION: These results are compatible with the hypothesis that CCR5 density, which is a key factor of HIV-1 infectability, determines in-vivo HIV production, and thereby the rate of CD4 cell decline. Consequently, CCR5 density quantitation could be a new valuable prognostic tool in HIV-1 infection. Moreover, these data emphasize the therapeutic potential of treatments that reduce functional CCR5 density.     

CCR2 and CCR5 genotypes in HIV type 1-infected adolescents: limited contributions to variability in plasma HIV type 1 RNA concentration in the absence of antiretroviral therapy

In HIV-1-infected individuals, plasma viral RNA concentration as well as preservation of CD8+ naive T cells can vary by age. Host genetic factors previously shown to mediate HIV-1 pathogenesis in adults and children may operate differently in HIV-1-infected adolescents. Our PCR-based haplotyping of genetic variants at the loci encoding CC (beta) chemokine receptor 2 (CCR2) and CCR5 revealed nine haplotypes (designated A through G*2) in 179 seronegative and 228 seropositive adolescent participants from the Reaching for Excellence in Adolescent Care and Health (REACH) Study of the Adolescent Medicine and HIV/AIDS Research Network. The influence of CCR2-CCR5 haplotypes and genotypes on plasma HIV-1 RNA level was assessed in 207 AIDS-free seropositive individuals (mostly African-American females) who either did not receive therapy or had discontinued therapy for 6-12 months during initial follow-up between 1996 and 1999. The CCR2-64I-coding haplotype F*2 and the infrequent CCR5 Delta32-bearing haplotype G*2 had negligible impact on HIV-1 RNA level (p > 0.83) and CD4+ T cell counts (p > 0.30). In contrast, nine carriers of the E/E genotype had significantly higher (p = 0.007) plasma HIV-1 RNA level and slightly reduced CD4+ cell counts (p = 0.15) compared with those not carrying E/E or F*2 or G*2. The effect of E/E on HIV-1 RNA was stronger (p < 0.001) in a multivariable model adjusted for F*2 or G*2 (p = 0.45), race (p = 0.23), gender (p = 0.002), age (p = 0.26), and history of antiretroviral therapy (p < 0.001). Thus, among the major CCR2-CCR5 haplotypes/genotypes in chronically infected and predominantly African-American adolescents, only the E/E genotype appeared to influence early host-virus equilibration.     

The CCR5Delta32 allele slows disease progression of human immunodeficiency virus-1-infected children receiving antiretroviral treatment

The role of the CCR5Delta32 allele in human immunodeficiency virus (HIV)-1-related disease progression was analyzed for 457 antiretroviral-na?ve children who had participated in the Pediatric AIDS Clinical Trials Group 152 study, which demonstrated that didanosine (ddI) or zidovudine + ddI treatments were superior to zidovudine alone. The CCR5Delta32 allele was detected at an overall frequency of 6.1% (28/457). At study entry, heterozygote children (wild type [wt]/Delta32) had higher baseline median CD4(+) counts/mm(3) than wt/wt children had (1035 vs. 835 cells/mm(3); P=. 043), higher mean weight-for-age Z scores (-0.15 vs. -0.84; P=.01), and a trend toward less cortical atrophy (P=.059). During antiretroviral treatment and study follow-up, there was a trend toward less disease progression and death among heterozygote children than among wt/wt children (P=.056; relative hazard, 0.28; 95% confidence interval, 0.07-1.13) independent of the antiretroviral treatment to which they were randomized.     

RANTES -28G delays and DC-SIGN - 139C enhances AIDS progression in HIV type 1-infected Japanese hemophiliacs

The relationships between host immune factors and HIV-1 disease progression are still in dispute. Unlike CCR5Delta32, which has been found to delay disease progression of HIV-1, there still remain several factors whose effect on the clinical course is unconfirmed. To clarify the relationships, we selected seven single-nucleotide polymorphisms (SNPs) out of the previously reported factors, namely, RANTES promoter -28G/-403A, RANTES In1.1C, SDF-1 3'A, IL-4 promoter -589T, and DC-SIGN promoter -139C/-336C, and examined these in Japanese HIV-1-infected hemophiliacs (n = 102). The genotypes were examined by the direct sequencing method, and the distributions of genotype and allelic frequencies were compared between two groups, slow progressors (n = 54) who did not develop AIDS more than 10 years after intravenous infection and others (progressors) (n = 48). The allelic frequency of RANTES -28G was significantly higher in slow progressors (0.185) than in the progressor group (0.074) [p = 0.023, OR = 0.35, 95% CI (0.142, 0.880)]. DC-SIGN promoter -139C, and appeared in progressors with significantly higher allelic frequency (0.333) than slow progressors [0.204, p = 0.040, OR = 1.95, 95% CI (1.039, 3.677)]. With RANTES -403A, RANTES In1.1C, SDF-1 3' A, IL-4 -589T, and DC-SIGN -336C, no significant difference was observed in allelic frequencies between the two groups. These results suggest that RANTES -28G was associated with delayed AIDS progression, while DC-SIGN -139C was associated with accelerated AIDS progression in HIV-1-infected Japanese hemophiliacs.