Vyakarnam Annapurna, Sidebottom David, Murad Shahed, Underhill James A, Easterbrook Philippa J, Dalgleish Angus G, Peakman Mark
Department of Infectious Diseases, Guy's, King's and St Thomas' School of Medicine, London, UK.
Immunology. 2004 May;112(1):136-42. doi: 10.1111/j.1365-2567.2004.01848.x.
Polymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)-1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV-1 infected long-term non-progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan-Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/ micro l, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB115-DQB106 haplotype (hazard ratio (HR) 0.69, 95% CI 0.46-1.01, P = 0.06). A similar effect was not observed with the DRB113-DQB106 haplotype (HR 1.18, 95% CI 0.75-1.88, P = 0.46), but was observed when DQB106 alleles were considered irrespective of their DR association (HR 0.74, 95% CI 0.52-1.05, P = 0.06). Major HLA-DQ6 alleles encode aspartate (Asp) at position 57 on the DQbeta chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQbeta57 Asp+ alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over-represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow-up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB115-DQB106 haplotype compared to IPs at 14+ years (38.46 versus 18.18%), though this difference did not reach statistical significance. When DQB106 alleles irrespective of their DR association were considered, the protective effect was greater (76.9% LTNPs versus 18.18% IPs, P = 0.04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.
人类白细胞抗原（HLA）II类基因的多态性可能通过调节病毒特异性CD4免疫反应来影响抗原呈递以及控制人类免疫缺陷病毒（HIV）-1的能力。为了研究这种多态性对疾病进展的影响，我们对46名HIV-1感染的长期非进展者（LTNP）、87名中度进展者（IP）和26名快速进展者组成的队列进行了研究。对该队列中所有患者的CD4细胞计数低于350个/微升的时间进行Kaplan-Meier生存分析，结果显示，与没有DRB115-DQB106单倍型的患者相比，携带该单倍型的患者CD4下降速率有减缓趋势（风险比（HR）为0.69，95%置信区间为0.46-1.01，P = 0.06）。对于DRB113-DQB106单倍型未观察到类似效果（HR为1.18，95%置信区间为0.75-1.88，P = 0.46），但当不考虑DR关联而仅考虑DQB06等位基因时则观察到了类似效果（HR为0.74，95%置信区间为0.52-1.05，P = 0.06）。主要的HLA-DQ6等位基因在DQβ链的第57位编码天冬氨酸（Asp），该表型与预防其他免疫紊乱相关。因此，我们检测了所有DQβ57 Asp+等位基因的频率，但未发现其对CD4下降速率有显著影响。为了研究与较慢CD4下降相关的基因型在疾病进展缓慢的患者中是否比例过高，我们对随访时间延长至14年以上的部分患者进行了分类分析。我们发现，与14年以上的中度进展者相比，14年以上的长期非进展者中拥有DRB115-DQB106单倍型的比例更高（分别为38.46%和18.18%），尽管这种差异未达到统计学显著性。当不考虑DR关联而仅考虑DQB106等位基因时，保护作用更强（长期非进展者为76.9%，中度进展者为18.18%，P = 0.04）。我们的结果突出了HLA DQB1*06等位基因对HIV疾病进程的潜在保护作用。
