The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
Jianming Tang
Publications and source records attributed to Jianming Tang.
Host genetic profiles predict virological and immunological control of HIV-1 infection in adolescents.
OBJECTIVE: To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-1-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. METHODS: HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1-seropositive adolescents (ages 13-18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of -1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6-12-month interval when no antiretroviral therapy was taken. RESULTS: HLA-B*57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 x 10(6) cells/l) consistently had more positive (+1 to +2) than negative (-1 to -4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16,000 copies/ml and CD4 cells < 450 x 10(6) cells/l) or the remainder (n = 134) of the cohort (overall P < 0.0001). CONCLUSION: A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents.
Adolescent↗
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.
Acquired Immunodeficiency Syndrome↗
Favorable and unfavorable HLA class I alleles and haplotypes in Zambians predominantly infected with clade C human immunodeficiency virus type 1.
The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8(+) cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log(10) VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log(10) VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.
Adult↗
Distribution of chemokine receptor CCR2 and CCR5 genotypes and their relative contribution to human immunodeficiency virus type 1 (HIV-1) seroconversion, early HIV-1 RNA concentration in plasma, and later disease progression.
At the CC (beta) chemokine receptor 2 (CCR2) and CCR5 loci, combinations of common single-nucleotide polymorphisms (SNPs) and a 32-bp deletion (Delta32) form nine stable haplotypes (designated A through G*2). The distribution of these CCR2-CCR5 haplotypes was examined among 703 participants in the Multicenter AIDS Cohort Study (MACS), the District of Columbia Gay (DCG) Study, and the San Francisco Men's Health Study (SFMHS). Highly exposed and persistently seronegative (HEPS; n = 90) Caucasian men from MACS more frequently carried heterozygous G*2 (Delta32) genotypes (especially A/G*2) and less frequently carried the homozygous E/E genotype compared with 469 Caucasian seroconverters (SCs) from the same cohort (P = 0.004 to 0.042). Among 341 MACS Caucasian SCs with 6- to 12-month human immunodeficiency virus type 1 (HIV-1) seroconversion intervals and no potent antiretroviral therapy, mean plasma HIV-1 RNA level during the initial 42 months after seroconversion was higher in carriers of the E/E genotype and lower in those with the 64I-bearing haplotype F*2 or the Delta32-bearing haplotype G*2 (and especially genotypes A/G*2 and F*2/G*2). A multivariable model containing these CCR markers showed significant composite effects on HIV-1 RNA at each of four postconversion intervals (P = 0.0004 to 0.050). In other models using time to AIDS as the endpoint, the same markers showed more modest contributions (P = 0.08 to 0.24) to differential outcome during 11.5 years of follow-up. Broadly consistent findings in the larger MACS Caucasian SCs and the smaller groups of MACS African-American SCs and the DCG and SFMHS Caucasian SCs indicate that specific CCR2-CCR5 haplotypes or genotypes mediate initial acquisition of HIV-1 infection, early host-virus equilibration, and subsequent pathogenesis.
Acquired Immunodeficiency Syndrome↗
C-C chemokine receptor 2 and C-C chemokine receptor 5 genotypes in patients treated for chronic hepatitis C virus infection.
We explored the influence of the major CCR5 promoter or coding region variants as haplotypes and genotypes in a cohort of 250 chronically infected HCV patients receiving combined interferon/ ribavirin therapy. No haplotype, including the D32-bearing haplotype (G*2) reportedly associated in homozygotes with high HCV viral load (VL), showed a similar effect. Patients with genotype C/G*2 showed slightly lower median VL (p = 0.05). Neither the G*2 haplotype nor the C/G*2 genotype influenced viral dynamics during the initial 12 wk of treatment (p = 0.53). The genotype E/E was more frequent among sustained responders (15.5%) than non-responders (7.8%), and VL declined further among E/E homozygotes during the initial 12 wk of treatment, particularly those with HCV genotype 1 (p = 0.016). Differential receptor expression due to E/E homozygosity in HCV infection remains to be confirmed.
Adult↗