Research Article: 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

Date Published: October 1, 2008

Publisher: Public Library of Science

Author(s): Nguyen Thi Phuong Lan, Mihoko Kikuchi, Vu Thi Que Huong, Do Quang Ha, Tran Thi Thuy, Vo Dinh Tham, Ha Manh Tuan, Vo Van Tuong, Cao Thi Phi Nga, Tran Van Dat, Toshifumi Oyama, Kouichi Morita, Michio Yasunami, Kenji Hirayama, Eva Harris

Abstract: 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.

Partial Text: Dengue virus (DV) infection has become one of the most important mosquito-borne diseases in the tropics [1]. An estimated 50 million people worldwide are infected with DV each year [2]. There are two principal severe forms of DV infection, namely dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Other severe forms such as encephalitis and spastic tetraparesis occur less frequently [3]. Children younger than 15 years of age account for 90% of the severe cases in Southeast Asian countries [4] where the DHF/DSS incidence has increased about 5 fold more rapidly since 1980 than in the previous 30 years [5]. These severe forms of DV infection have become the leading cause of death among children in Southern Vietnam [6].



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