Protective and Enhancing HLA Alleles, HLA-DRB1*0901 and HLA-A*24, for Severe Forms of Dengue Virus Infection, Dengue Hemorrhagic Fever and Dengue Shock Syndrome

BackgroundDengue virus (DV) infection is one of the most important mosquito-borne diseases in the tropics. Recently, the severe forms, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), have become the leading cause of death among children in Southern Vietnam. Protective and/or pathogenic T cell immunity is supposed to be important in the pathogenesis of DHF and DSS.Methodology/Principal FindingsTo identify HLA alleles controlling T cell immunity against dengue virus (DV), we performed a hospital-based case control study at Children's Hospital No.2, Ho Chi Minh City (HCMC), and Vinh Long Province Hospital (VL) in Southern Vietnam from 2002 to 2005. A total of 211 and 418 patients with DHF and DSS, respectively, diagnosed according to the World Health Organization (WHO) criteria, were analyzed for their characteristic HLA-A, -B and -DRB1 alleles. Four hundred fifty healthy children (250 from HCMC and 200 from VL) of the same Kinh ethnicity were also analyzed as population background. In HLA class I, frequency of the HLA-A*24 showed increased tendency in both DHF and DSS patients, which reproduced a previous study. The frequency of A*24 with histidine at codon 70 (A*2402/03/10), based on main anchor binding site specificity analysis in DSS and DHF patients, was significantly higher than that in the population background groups (HCMC 02-03 DSS: OR = 1.89, P = 0.008, DHF: OR = 1.75, P = 0.033; VL 02-03 DSS: OR = 1.70, P = 0.03, DHF: OR = 1.46, P = 0.38; VL 04-05 DSS: OR = 2.09, P = 0.0075, DHF: OR = 2.02, P = 0.038). In HLA class II, the HLA-DRB1*0901 frequency was significantly decreased in secondary infection of DSS in VL 04-05 (OR = 0.35, P = 0.0025, Pc = 0.03). Moreover, the frequency of HLA-DRB1*0901 in particular was significantly decreased in DSS when compared with DHF in DEN-2 infection (P = 0.02).ConclusionThis study improves our understanding of the risk of HLA-class I for severe outcome of DV infection in the light of peptide anchor binding site and provides novel evidence that HLA-class II may control disease severity (DHF to DSS) in DV infection.

【背景】登革病毒（Dengue virus, DV）感染是热带地区最主要的虫媒传染病之一。近年来，登革出血热（Dengue hemorrhagic fever, DHF）与登革休克综合征（Dengue shock syndrome, DSS）这两类重症登革热已成为越南南部儿童死亡的首要致死原因。目前认为，保护性及/或致病性T细胞免疫在登革出血热和登革休克综合征的发病机制中发挥重要作用。
【方法与主要结果】为明确调控登革病毒特异性T细胞免疫的人类白细胞抗原（Human Leukocyte Antigen, HLA）等位基因，本研究于2002年至2005年在越南南部的胡志明市第二儿童医院（Ho Chi Minh City Children's Hospital No.2, HCMC）及永隆省医院（Vinh Long Province Hospital, VL）开展了一项基于医院的病例对照研究。共纳入符合世界卫生组织（World Health Organization, WHO）诊断标准的登革出血热患者211例、登革休克综合征患者418例，对其HLA-A、HLA-B及HLA-DRB1等位基因特征进行分型分析。同期纳入450名同属京族的健康儿童作为人群对照，其中250名来自胡志明市，200名来自永隆省。
在HLA I类分子层面，登革出血热与登革休克综合征患者的HLA-A*24等位基因频率均呈现升高趋势，这一结果与既往研究结论相符。通过对登革休克综合征及登革出血热患者的主要肽锚定结合位点特异性进行分析发现，第70位密码子为组氨酸的A*24等位基因（A*2402/03/10）的频率显著高于人群对照组：2002-2003年胡志明市队列中，登革休克综合征组比值比（OR）=1.89，P=0.008，登革出血热组OR=1.75，P=0.033；2002-2003年永隆省队列中，登革休克综合征组OR=1.70，P=0.03，登革出血热组OR=1.46，P=0.38；2004-2005年永隆省队列中，登革休克综合征组OR=2.09，P=0.0075，登革出血热组OR=2.02，P=0.038。
在HLA II类分子层面，2004-2005年永隆省队列中，继发感染所致登革休克综合征患者的HLA-DRB1*0901等位基因频率显著降低（OR=0.35，P=0.0025，校正P值Pc=0.03）。此外，在登革病毒2型（DEN-2）感染患者中，登革休克综合征组的HLA-DRB1*0901等位基因频率显著低于登革出血热组（P=0.02）。
【结论】本研究从肽锚定结合位点的视角，深化了我们对HLA I类分子与登革病毒感染重症结局相关性的认知，并为HLA II类分子可调控登革病毒感染的疾病严重程度（从登革出血热进展为登革休克综合征）提供了全新的实验证据。