CCR2andCCR5Genotypes in HIV Type 1-Infected Adolescents: Limited Contributions to Variability in Plasma HIV Type 1 RNA Concentration in the Absence of Antiretroviral Therapy

Abstract

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.

CCL3L1 and CCL4L1: variable gene copy number in adolescents with and without human immunodeficiency virus type 1 (HIV-1) infection

“…Subjects selected for this study included 184 HIV-1 seronegatives (population controls) and 227 HIV-1 seropositives (161 African Americans and 66 others) with known history of exposure to antiretroviral therapy (ART) and up to four measurements of HIV-1 viral load (RNA copies per ml) in plasma and corresponding CD4 þ T-cell counts during ART-free þ T-cell counts at multiple ART-free intervals allowed the classification of three distinct disease groups (37 controllers, 134 intermediates and 56 noncontrollers) among HIV-1 seropositives. 24 Several immunogenetic effects established in other studies of HIV-1 infection have been corroborated in this cohort. 21,24 Quantification of CCL3L1 and CCL4L1 gene copy number Several 5 0 nuclease (TaqMan) assays were designed to quantify the copy numbers of CCL3L1, CCL3, CCL4L1 and CCL4, when the single-copy gene hemoglobin, beta (HBB), served as the internal control.…”

“…24 Several immunogenetic effects established in other studies of HIV-1 infection have been corroborated in this cohort. 21,24 Quantification of CCL3L1 and CCL4L1 gene copy number Several 5 0 nuclease (TaqMan) assays were designed to quantify the copy numbers of CCL3L1, CCL3, CCL4L1 and CCL4, when the single-copy gene hemoglobin, beta (HBB), served as the internal control. TaqMan assay for CCL3L1 was similar to that used earlier, 17 with minor modifications.…”

“…However, HHD was not associated with HIV-1-related outcomes in this study population, 24 and the relationship did not confound the joint analyses of CCR2-CCR5 genotypes in combination with CCL3L1 and CCL4L1 copy numbers.…”

“…21,24 This new classification scheme also captured other variants (e.g., the 59029G SNP and the P1 haplotype) that have been prominently associated with HIV-1 disease progression. 51,52 Because the favorable and unfavorable haplotypes and their combinations as defined elsewhere 20,23,24,53 probably act in concert with CCL3L1 and CCL4L1 copy numbers, 17 combinations of CCR2-CCR5 haplotypes and CCL3L1/CCL4L1 gene copy numbers were further evaluated for association with HIV-1-related outcome measures.…”

HLA‐DRB1and‐DQB1Alleles and Haplotypes in Zambian Couples and Their Associations with Heterosexual Transmission of HIV Type 1

“…First, HLA relationships may simply reflect the genetic background of the study population, the viruses circulating in it at the time of study, or other cohort characteristics. Indeed, several established genetic associations have been recognized more readily in selected, rather than all, ethnic groups studied, because of different marker frequencies or strength of relationships [33][34][35]. Nonetheless, multivariable analysis has reinforced our confidence that neither other known genetic NOTE.…”