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The CCR5Δ32 Allele Slows Disease Progression of Human Immunodeficiency Virus—1—Infected Children Receiving Antiretroviral Treatment

  1. Charlene F. Barroga1,
  2. Claire Raskino4,
  3. Moena C. Fangon1,
  4. Paul E. Palumbo5,
  5. Carol J. Baker6,7,
  6. Janet A. Englund8 and
  7. Stephen A. Spector1,2,3
  1. 1Department of Pediatrics, Division of Infectious Diseases, School of Medicine
  2. 2Center for Molecular Genetics, University of California San Diego, La Jolla
  3. 3Center for AIDS Research, University of California San Diego, La Jolla
  4. 4Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
  5. 5Univeristy of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark
  6. 6Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  7. 7Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas
  8. 8Department of Pediatrics, University of Chicago Children's Hospital, Chicago, Illinois
  1. Reprints or correspondence: Dr. Stephen A. Spector, Pediatrics, Infectious Diseases, University of California, San Diego, Stein Research Bldg., Rm. 427, 9500 Gilman Dr., La Jolla, CA 92093-0672 (saspector{at}ucsd.edu).

  1. Presented in part: Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, 31 January–4 February 1999 (slide presentation no. 269).

 
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Abstract

The role of the CCR5Δ32 allele in human immunodeficiency virus (HIV)-1-related disease progression was analyzed for 457 antiretroviral-naïve 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 CCR5Δ32 allele was detected at an overall frequency of 6.1% (28/457). At study entry, heterozygote children (wild type [wt]/Δ32) had higher baseline median CD4+ counts/mm3 than wt/wt children had (1035 vs. 835 cells/mm3 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.

The chemokine receptor CCR5 is the primary co-receptor for macrophage-tropic, non-syncytium inducing (NSI) strains of human immunodeficiency virus (HIV)—1, in conjunction with CD4 [1–4]. In adults, a homozygous 32-bp deletion in the coding region of the CCR5 gene, which results in a truncated, nonfunctional receptor, is protective toward HIV-1 infection [5, 6], whereas one deleted allele is associated with slower progression to AIDS after HIV-1 infection [5–8]. Several polymorphisms in the regulatory region of CCR5 that influence the rate of disease progression have been identified in adults [9–11]. More recently, CCR5 promoter polymorphisms that enhance the rate of perinatal transmission have been identified in children [12]. Because of the pivotal role of CCR5 in the acquisition of HIV-1 and the rate of disease progression in adults [4], and the high frequency of primary perinatal infection with NSI macrophage-tropic strains [13], identification of the role of CCR5 in perinatal transmission and subsequent disease progression is of particular importance. As in adult HIV-1 transmission, we and others found that newborns with a single CCR5Δ32 allele are not protected from HIV-1 infection [12, 14–19]. However, there is controversy as to the impact of the CCR5Δ32 allele on pediatric HIV-1—related disease progression [16–21]. Additionally, to our knowledge, no study has examined the impact of CCR5 genotypes in HIV-1—infected children who had participated in a randomized trial of antiretroviral therapy with long-term follow-up.

Pediatric AIDS Clinical Trials Group (PACTG) 152 was designed to compare the efficacy of zidovudine, didanosine (ddI), and zidovudine + ddI [22]. This study is one of two large clinical studies performed within the PACTG of antiretroviral-naïve children, for whom disease progression was assessed on the basis of clinical end points. Thus, the cohort provides a unique opportunity to evaluate the impact of the CCR5Δ32 allele on the clinical status of the children at study entry and its role in disease progression during study follow-up and antiretroviral treatment. Our findings indicate that children with 1 CCR5Δ32 allele had less severe HIV-1—related disease at study entry and exhibited slower disease progression during the study.

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Subjects and Methods

Subjects

Children enrolled in PACTG 152 were from 78 sites in 20 states of the United States and Puerto Rico. Of the 831 children enrolled in PACTG 152, 457 had peripheral blood mononuclear cells (PBMC) available for CCR5 genotyping (PBMC DNA from 7 subjects yielded no CCR5 signal). No significant differences were present when the 457 children analyzed for this study were compared with the entire cohort as to median age, racial/ethnic distribution, mean weight-for-age Z (WAZ) scores, HIV-1 plasma RNA load, CD4+ lymphocyte counts, or randomization to the different antiretroviral treatments. Of the 457 children, 402 (88%) were infected perinatally, whereas 55 children acquired HIV-1 via another route of transmission. PACTG 152 was a randomized, double-blind, placebo-controlled trial of zidovudine or ddI monotherapy or zidovudine + ddI combination therapy in HIV-1 infected infants and children between the ages of 3 months and 18 years who were antiretroviral naïve or had experienced ⩽6 weeks of previous therapy. Only 43 (10%) of the 457 children had received prior antiretroviral therapy, 38 of whom had received zidovudine, and 14 (3%) of the mothers had received zidovudine during pregnancy or labor. The children were stratified according to age at entry: 3 months to <30 months or ⩾30 months to 18 years. A full description of the study cohort has been published elsewhere [22]. The zidovudine treatment group was unblinded earlier than the other 2 treatment arms were because of increased numbers of study end points [23].

CCR5 genotyping assay

Genomic DNA was extracted from PBMC by using the Qiamp Blood Extraction kit (Qiagen, Valencia, CA), which was modified to utilize vacuum instead of centrifugation. Genomic DNA (500 ng-1mg) was amplified by the polymerase chain reaction (PCR) with primers 5′-TTCATTACACCTGCAGCTCTCATTTTC-3′ and 5′-TCACAGCCCTGTGCCTCTTCTTCTCAT-3′ to generate 182- and 150-bp fragments of the wild-type (wt) and deleted allele, respectively [5]. The PCR reaction contained 1 × low salt buffer (Stratagene, San Diego), 125 µM of each dNTP, 0.4 µM of each primer, and 2.5 U of TaqPlus polymerase (Stratagene). PCR conditions were an initial denaturation step of 95°C for 5 min, followed by 30 cycles of 94°C for 1 min, 55°C for 1 min, and 72°C for 2 min and a final extension of 72°C for 10 min. One fifth of the PCR product was run in 4% methaphor agarose (FMC Bioproducts, Rockland, ME) and visualized by ethidium bromide staining [24]. Samples with the wt/Δ32 genotype were retyped by extracting DNA from duplicate samples or performing another PCR analysis. Deleted and wt fragments were gel purified by using the Qiagen gel extraction kit and were sequenced with the ABI 373 automated DNA sequencer (Applied Biosystems, Inc., Foster City, CA).

Virologic and immunologic measurements

Plasma HIV-1 RNA quantification was performed on batched specimens after study closure, using the nucleic acid sequence-based HIV-1 RNA amplification system (Organon Teknika Corp, Durham, NC) as described elsewhere [25]. T lymphocyte subsets were determined in real time, using standard flow cytometric methods.

Clinical evaluations

The patients were weighed at study entry and every 4 weeks, and age- and sex-standardized Z scores were calculated [22]. Central nervous system (CNS) evaluations included neurocognitive testing, motor function evaluations, and brain growth assessments [22, 26]. Neurocognitive tests were performed within 14 days before enrollment and on an age-appropriate schedule thereafter. Tests administered were the Bayley Scales of Infant Develoment (for ages 3–30.5 months), the McCarthy Scales of Children's Abilities (ages 31 months-6 years), and the Wechsler Intelligence Scale for Children-Revised (WISC-R; ages 6 years-15 years and 11 months) or the Wechsler Adult Intelligence Scale-Revised (WAIS-R; ages >16 years). The mean standard score for each test was 100, with SDs of 16 for the Bayley and McCarthy tests and 15 for the WISC-R and WAIS-R tests. A score <70 or ∼2 SD below the normal population mean was considered to indicate severe cognitive impairment. Neurologic examinations evaluating the patients' motor function and muscle tone and bulk were conducted within 14 days before enrollment and then every 4 weeks for children <30 months old and every 12 weeks for older children. Neuroimaging of the head by computed tomography or magnetic resonance imaging was obtained within 30 days of enrollment and every 96 weeks thereafter [26].

Statistical methods

Baseline variables were compared between CCR5 genotype groups, using the χ2 or Fisher exact test [27] for categorical variables; the Wilcoxon rank sum test [27] for median ages, CD4+ lymphocyte counts, and plasma HIV-1 RNA levels; and analysis of variance (ANOVA) or analysis of covariance (ANCOVA [adjusted comparisons]) [27] for mean WAZ scores, log10-transformed CD4+ counts, and log10-transformed HIV-1 RNA levels. A quadratic term was included for age as a covariate in ANCOVA models. ANOVA or ANCOVA was also used to compare study follow-up measurements of WAZ scores, log10-transformed CD4+ counts, and cognitive score changes between CCR5 genotype groups. For these analyses, the average follow-up measurement was calculated for each subject, pooling observations through week 48. These average measurements were then compared between the 2 CCR5 genotype groups, weighting subjects in the analysis according to the number of follow-up observations that they contributed. The Wilcoxon rank sum test was used to compare the presence and severity of cortical atrophy between CCR5 genotype groups during follow-up. Distributions of time to clinical end points were estimated by the Kaplan-Meier method, and statistical comparisons were made by the log-rank test with stratification by randomized study treatment [28].

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Results

Distribution of the CCR5Δ32 allele

Of the 457 children genotyped for CCR5, 239 (52.3%) were African American, 143 (31.3%) Hispanic, 62 (13.6%) white, 1 (0.2%) Asian/Pacific Islander, and 12 (2.6%) other or not known (table 1). The heterozygote genotype was detected at a frequency of 6.1% (28 of 457 children), and the frequencies of the heterozygote genotype among white, African American, and Hispanic children were 14.5%, 3.8%, and 5.6%, respectively (P = .006), consistent with the heterozygote frequencies found among white and African American adults [7]. None of the 457 HIV-1—infected children was homozygous for the CCR5Δ32 allele. Children 3 months to <30 months old (n = 254) comprised 55.6% of the study population, while 203 (44.4%) children were ⩾30 months to 18 years old. The heterozygote genotype frequency was equally distributed among the children <30 months old and ⩾30 months old (5.5% vs. 6.9%; P = .54). The median age of the children with the heterozygote genotype was 2.53 years, versus 2.10 years for the wt/wt children (P = .69).

Figure 1
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Figure 1

Influence of the CCR5Δ32 allele at study entry and during the study on (A) mean log10 CD4+ lymphocyte counts and (B) mean weight-for-age Z (WAZ) scores. P = .014 and .011 at study entry and P = .010 and .023 during the study for the mean log10 CD4+ lymphocyte counts and WAZ scores, respectively. wt, wild type. Bars are 95% confidence limits.

Figure 2
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Figure 2

Effect of the CCR5 genotype on human immunodeficiency virus type 1 (HIV-1) disease progression. Shown are Kaplan-Meier plots for time to clinical disease progression or death among HIV-1—infected children in the Pediatric AIDS Clinical Trials Group 152 study, considering 2 central nervous system (CNS) criteria as end point (A), 1 CNS criterion as end point (B), or Kaplan-Meier survival plots for time to death (C). P values are based on stratified log rank test. RH, relative hazard; endpt, end point; wt, wild type.

Table 1
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Table 1

Distribution of the CCR5Δ32 allele by race/ethnicity, age, and treatment in 457 human immunodeficiency virus type 1—infected children enrolled in Pediatric AIDS Clinical Trials Group 152.

Impact of the CCR5Δ32 heterozygote genotype at study entry

At study entry, children with the heterozygote genotype had significantly higher mean WAZ scores: −0.15 versus −0.84, or 0.69 point higher than the mean score of children with the wt/wt genotype (P = .01; table 2). When scores were adjusted for race/ethnicity, the mean for the heterozygote children was also 0.69 point higher than the mean for the wt/wt children (P = .011). Children with the heterozygote genotype entered the study with a higher median CD4+ lymphocyte count than that of children with the wt/wt genotype (1035 vs. 835 cells/mm3, respectively; P = .043) (table 2). When adjusted for age and race/ethnicity, the mean baseline log10 CD4+ count among the heterozygote children was 0.22 log10, or 1.65-fold higher than that of the wt/wt children (P = .014). Among children who had HIV RNA data available, baseline plasma HIV-1 RNA tended to be lower in the wt/Δ32 group (n = 15) than in the wt/wt group (n = 303; 100,000 vs. 170,000 copies/mL, respectively), although the difference was not statistically significant (P = .24; table 2). When adjusted for age and race/ethnicity, the mean baseline log10 RNA level was 0.23 log10 lower (41% reduction) among the wt/Δ32 than among the wt/wt children (P = .30). Thus, at study entry, heterozygote children showed evidence of significantly greater CD4+ lymphocyte counts and WAZ scores than did wt/wt children.

Table 2
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Table 2

Baseline characteristics of the 457 human immunodeficiency virus type 1 (HIV-1)—infected children in Pediatric AIDS Clinical Trials Group 152, by CCR5 genotype.

Because HIV-1 infection in children is often accompanied by CNS dysfunction [29, 30], the effect of the CCR5Δ32 allele on CNS abnormalities was evaluated. Among the children who had baseline neuroimaging studies, none of the 27 heterozygote children had evidence of cortical atrophy, compared with 55 (13.1%) of the 419 wt/wt children (P = .062). However, although a lower proportion of heterozygote than of wt/wt children had cognitive scores <70 at study entry (7.7% [n = 26] vs. 18.2% [n = 379]), the difference was not statistically significant (P = .28), and no difference in motor function was observed between the 2 groups.

Impact of the CCR5Δ32 heterozygote genotype on HIV-1—related disease progression

The impact of the CCR5Δ32 allele on disease progression during the study was examined across all treatment regimens used in the PACTG 152. The primary clinical end point was time to death or disease progression, manifested by weight growth failure, development of ⩾2 serious opportunistic infections, malignancy, or CNS dysfunction (that is, any two of the criteria cognitive decline, impaired brain growth, or neurologic deterioration) [23]. The proportion of children with specimens available for analysis for the CCR5 genotype from the entire PACTG 152 cohort (457 of 831) was equally distributed among the 3 treatment groups: 150 (32.8%) received zidovudine, 159 (34.8%) received ddI, and 148 (32.4%) received zidovudine + ddI. The heterozygote genotype frequency was not significantly different among the 3 treatment arms: 7.3% (11 of 150 children) in the zidovudine monotherapy, 5.7% (9 of 159 children) in the ddI monotherapy, and 5.4% (8 of 148 children) in the zidovudine + ddI combination therapy (P = .75; table 1). Because the findings of the original study indicated that children randomized to receive zidovudine monotherapy experienced more clinical end points than did children randomized to either ddI or zidovudine + ddI [23], analyses were performed with and without adjustment for treatment randomization. Because the zidovudine monotherapy was unblinded early, only clinical data collected prior to unblinding (median follow-up, 22 months) were analyzed for that treatment arm, whereas follow-up data through study closure were used for the ddI and combination treatment arms (median follow-up, 30 and 31 months, respectively).

Heterozygote children entered the study with higher CD4+ lymphocyte counts, and these remained higher during the study: ∼0.19 log10, or 1.56-fold higher than the wt/wt group (P = .04), or 0.22 log10 (1.65-fold higher; P = .01) when adjusted for treatment, race/ethnicity, and age at entry (figure 1A). Similarly, the heterozygote children entered the study with a mean WAZ score higher than that of the wt/wt group, and their WAZ score remained higher during the course of the study. The mean WAZ score during the first 48 weeks of follow-up was 0.53 point higher in the heterozygote group than in the wt/wt group (P = .032), or 0.57 point higher when adjusted for treatment and race/ethnicity (P = .023; figure 1B).

Neurocognitive scores were followed up with the Bayley, McCarthy, and WISC-R/WAIS-R tests every 12, 24, or 48 weeks, respectively, and were compared for a total of 330 wt/wt subjects and 22 wt/Δ32 subjects from whom a baseline and ⩾1 follow-up neurocognitive score were obtained. The mean change from the baseline neurocognitive score was 4.3 points higher for the wt/Δ32 children than for the wt/wt children (P = .22), or 5.5 points higher (P = .10) when adjusted for treatment, race/ethnicity, primary language (English vs. others), baseline cognitive score, and type of test performed. No significant difference in abnormal motor function was observed between the 2 CCR5 genotype groups during follow-up study. The development of cortical atrophy was compared between the 2 groups of children who did not have cortical atrophy at study entry, using the patients' worst neuroimaging follow-up result. In the wt/Δ32 group, 2 (10.5%) of 19 children developed cortical atrophy during follow-up (both mild), compared with 21 (8.2%) of 257 wt/wt children (10 mild; 11 moderate/marked atrophy; P = .77).

Kaplan-Meier progression-free survival analysis demonstrated that children with the heterozygote genotype showed a trend toward less disease progression than wt/wt children did (figure 2A). Only 2 (7.1%) of the 28 wt/Δ32 children met a primary clinical end point (disease progression or death), compared with 102 (23.8%) of the 429 wt/wt children (stratified by treatment), with a relative hazard (RH) of 0.28 and a 95% confidence interval (CI) of 0.07–1.13 (P = .056). The 2 primary end points in the heterozygote patients were CNS deterioration and CNS deterioration with weight growth failure on the same date. In the wt/wt group, the primary end points were weight growth failure (55 children), CNS deterioration (22 children), other multiple disease progression end points (11 children), and death (14 children). For the above analyses, ⩾2 CNS criteria (cognitive decline, neurologic deterioration, or impaired brain growth) were used, consistent with the CDC class C definition of HIV-related encephalopathy in children [31]. When a less stringent single criterion of CNS deterioration was used as an end point, as has been done in subsequent PACTG studies, 4 (14.3%) of 28 wt/Δ32 children versus 141 (32.9%) of 429 wt/wt children met disease progression or death (RH = 0.38, stratified log rank P = .047; figure 2B). In the Kaplan-Meier survival analysis, with death only as the end point, only one (3.6%) of 28 heterozygote children died during follow-up, compared with 54 (12.6%) of 429 wt/wt children (P = .16; RH = 0.27; 95% CI, 0.04–1.93; figure 2C). The 402 perinatally infected children, when analyzed separately, showed similar trends in the Kaplan-Meier progression-free survival and survival analyses (data not shown).

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Discussion

The CCR5Δ32 genotype has been associated with protection from HIV-1 infection in the homozygous state and a 2–3-year delay in disease progression among white adults [4–8]. Limited studies in children report conflicting results; a delay in disease progression has been observed by some [18–21] and no effect of CCR5Δ32 by others [14, 17]. A small number of children were analyzed in most of these studies, with ∼42–108 HIV-1—infected children from the United States, Spain, and Italy and a larger group from France (n = 276) [19]. We sought to analyze the impact of CCR5 on the disease progression of a large cohort of HIV-1—infected children who were enrolled in a controlled clinical trial of antiretroviral therapy with long-term follow-up. Because these children were, for the most part, antiretroviral naïve (only 43 children had had <6 weeks of antiretroviral therapy, of whom 38 had received zidovudine, and only 3% [14 of 457] of their mothers had had zidovudine during pregnancy), we were able to assess the influence of the CCR5 genotype on the children's extensive baseline immunologic, virologic, and clinical status prior to treatment. Our study also reflects the demographics of HIV-1—infected children and women in the United States [22].

None of the 457 HIV-1—infected children, 402 of whom were perinatally infected, was homozygous for the CCR5Δ32 allele, a finding similar to those reported in studies of 3147 HIV-1—infected adults [5–8] and 859 HIV-1—infected children [14–21]. In all studies of children, the homozygous Δ32/Δ32 genotype has been found only among perinatally exposed but uninfected white children [16, 19], but not in uninfected African Americans [12]. Our findings are similar to those of other reports in that a single Δ32 allele (the CCR5 wt/Δ32 genotype) does not appear to protect against HIV-1 vertical transmission [12, 14–19]. Our results and others' may imply that infants homozygous for the CCR5Δ32 allele are protected against perinatal transmission of HIV-1. Conversely, Kostrikis et al. [12] have recently shown that a polymorphism in the regulatory region of the CCR5 gene (CCR5-59356-T/T) is associated with an increased rate of perinatal transmission, especially among African Americans, and that this locus is linked with other promoter polymorphisms and the CCR5 wt genotype.

The CCR5Δ32 allele was found at a lower frequency among the perinatally HIV-1—infected children enrolled in PACTG 152 than in the general US population or infected white adults, mostly due to the greater proportion of African Americans and Hispanics in the study population. When analyzed by race/ethnicity, the distribution parallels that of adults. The presence of 1 CCR5Δ32 allele conferred significant protection against disease progression in HIV-1—infected children. Several measures of disease status indicate that children with the heterozygote genotype progressed more slowly than those with the homozygous wt genotype. At study entry, they had significantly higher mean WAZ scores and higher CD4+ lymphocyte counts. Although a lower count of HIV-1 RNA copies/mL was observed among the heterozygote group at study entry, this was not statistically significant, probably because of the fewer observations available. The higher WAZ scores and CD4+ lymphocyte counts were maintained over 48 weeks of study follow-up.

Several measures of disease progression were evaluated in the PACTG 152, including CD4+ lymphocyte counts, HIV-1 RNA copies/mL, weight growth failure, opportunistic infections, and ⩾1 CNS abnormalities (cortical atrophy, neurocognitive decline, and motor dysfunction) or death, and were correlated with the CCR5 genotype. Progression-free survival analyses showed that heterozygote children had a trend toward reduced risk of disease progression or death in comparison with wt/wt children, with only 2 (7.1%) of 28 wt/Δ32 children meeting a primary end point, compared with 102 (23.8%) of 429 wt/wt children (RH = 0.28; 95% CI, 0.07–1.13; P = .056). When only 1 CNS criterion was analyzed with the other measures of disease progression, Kaplan-Meier progression-free survival analyses showed that 4 (14.3%) of 28 wt/Δ32 children versus 141 (32.9%) of 429 wt/wt children met disease progression or death (RH = 0.38, stratified log rank P = .047). A study by Misrahi et al. [19] involving French children reported a highly significant impact of the CCR5 wt/Δ32 genotype on disease progression. Although our findings are consistent with those based on the French cohort, several important differences are noted. First, the French study analyzed the impact of CCR5 wt/Δ32 on disease progression in a more homogeneous population consisting entirely of white children, in whom 26 (9.6%) of the 126 subjects had the wt/Δ32 genotype. In contrast, our study had a lower proportion of heterozygote children, only 28 (6%) of 457, with 239 (52%) of the 457 being African Americans. Second, the children participating in PACTG 152 were randomized to receive specific antiretroviral therapy, whereas there was not as close control of treatment in the French cohort. Additionally, different definitions of disease progression were used for evaluating the 2 cohorts, which might also impact the findings of the 2 studies. Despite these differences, both studies observed a benefit of the CCR5 wt/Δ32 genotype on disease progression.

Kaplan-Meier survival analyses that considered only death as an end point revealed that only one (3.6%) of 28 heterozygote children died during follow-up, compared with 54 (12.6%) of 429 wt/wt children (P = .16; RH = 0.27; 95% CI, 0.04–1.93). The small number of deaths in this cohort may have prevented this analysis from attaining statistical significance, as opposed to a lack of protective effect of the CCR5Δ32 allele.

Extensive baseline neurologic measurements, such as motor dysfunction, cognitive impairment, and cortical atrophy, were analyzed according to the CCR5 genotype. There were no significant differences in motor dysfunction and cognitive impairment at study entry between the heterozygote and wt/wt children. However, there was a trend toward less cortical atrophy among the heterozygote children at baseline (P = .062). Although the P value was not significant, this could be due to power limitations and not a lack of effect. In the analysis between CCR5 genotype and cortical atrophy, only 28 of the 457 children were heterozygotes. In another analysis, Raskino et al. [26] reported a highly significant association between baseline cortical atrophy and shorter survival times when 797 (96%) of the 831 children enrolled in PACTG 152 were analyzed. Hence, our findings provide a suggestion of a protective effect of 1 CCR5Δ32 allele against cortical atrophy with a larger group of children. The protection of the CCR5Δ32 allele against CNS progression appears unique for children and has not been observed in adults [24]. The influence of CCR5 could be due to the predominance of NSI strains in young children and the preferential utilization of CCR5 early during infection [13]. CCR5 has been localized in the brains of HIV-1—infected children [32], and several studies revealed the presence of CCR5 in brain microglia, neurons, and astrocytes [33, 34] in addition to CCR3 and CXCR4, implicating the chemokine receptors in CNS infection [35].

Other chemokine and chemokine receptor variants, such as CCR2V64I, SDF1-3′A [36–38], and the CCR5 promoter polymorphisms [9–12], which delay or accelerate HIV-1—related disease progression in adults, are currently being analyzed in HIV-1—infected children. Results from these studies should help us understand the role of host genetic factors in the response of children to HIV-1 disease and antiretroviral treatment. To our knowledge, these are the first data demonstrating an impact of chemokine receptor genotype on disease progression in a randomized clinical trial of antiretroviral treatment of HIV-1—infected children. Future comparative studies of the clinical benefits of different antiretroviral therapies in children may need to control for chemokine receptor genotypes.

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Footnotes

  • Informed consent was obtained from the patients or their parents or guardians in accordance with the guidelines of the local institutions where the study was conducted and the US Department of Health and Human Services. The study design was approved for implementation by the Pediatric AIDS Clinical Trials Group and all local institutional review boards at the study sites prior to the initiation of the study.

  • Financial support: University of California, San Diego, Center for AIDS Research (grants AI27563, AI39004, and AI35214).

  • Received January 4, 2000.
  • Revision received May 1, 2000.
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  1. J Infect Dis. (2000) 182 (2): 413-419. doi: 10.1086/315704
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