Research Article

Genetic Polymorphisms of HLA and HLA-related Proteins: Implications on Dengue Virus Infection  

Harapan Harapan1,2 , Jonny K. Fajar2 , Said A. Khalilullah2 , Wira Winardi2,3 , Kurnia F. Jamil1
1 Tropical and Infection Diseases Division, Internal Medicine Department, School of Medicine Syiah Kuala University, Banda Aceh, Indonesia
2 Medical Research Unit, School of Medicine Syiah Kuala University, Banda Aceh, Indonesia
3 Postgraduate School, Biomedical Department, Taipei Medical University, Taiwan
Author    Correspondence author
Journal of Mosquito Research, 2013, Vol. 3, No. 1   doi: 10.5376/jmr.2013.03.0001
Received: 16 Jan., 2013    Accepted: 23 Jan., 2013    Published: 15 Feb., 2013
© 2013 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Harapan et al., 2013, Genetic Polymorphisms of HLA and HLA-Related Proteins: Implications on Dengue Virus Infection, Journal of Mosquito Research, Vol 3, No.1 1-10 (doi: 10.5376/jmr.2013.03.0001)


Dengue diseases pathogenesis is not yet completely understood. Several human immunities are controlled by the expression of human leukocyte antigen (HLA) and expressions of HLA molecules are increased in dengue viral (DENV) infection. The role of cytotoxic T lymphocyte recognizing DENV epitopes presented by the HLA is the basis for immunity of DENV infection. The genes encoding classical HLA class I (HLA-A, -B, -C) and class II (HLA-DR, DQ and DP) are the most polymorphic in the human genome, and specific polymorphisms in human HLA gene regions influence peptide epitope binding. Here we have reviewed the implication of HLA and HLA-related gene polymorphisms on DENV infection susceptibility, protection and severity. We found several studies have identified HLA alleles associated with DENV infection susceptibility and severity such as A*0207, A*1, A*2, A*24, A*31, B blank, B*13, B*40, B*46, B*51, B*52, B*53, B*57, DR1, DRB1*08, DRB1*12, DRB1*15 and TNF-α �308A allele. Whereas some HLA alleles such as A*0203, A*03, A*29, A*33, B*13, B*14, B*15, B*18, B*44, B*49, B*52, B*62, B*76, B*77, DRB1*0901, DRB1*02, DRB1*03, DRB1*04, and DRB1*07 are associated with DENV infection protection. In addition, HLA class III and HLA-related proteins - mayor histocompatibility complex class I chain-related protein A and B (MICA and MICB) and lymphotoxin-alpha (LTA) - also associated with DENV infection. In summary, HLA and several HLA-related proteins clearly play important roles on DENV infection susceptibility, protection and severity.

Dengue virus infection; DHF; DSS; SNP; Dengue disease severity; Polymorphism study; HLA

1. Introduction
Dengue virus (DENV), a mosquito-borne flavivirus infection of major international public health threat, cause a spectrum of disease in humans, ranging from dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). It is estimated that 50 million DENV infections occur annually worldwide and it increased dramatically in recent years (Guzman et al., 2010; WHO, 2009). Approximately 2.5 billion people live in dengue endemic countries and two fifths of the world's population is at risk from DENV (WHO, 2006; 2009).

Vast majority of individuals infected with DENV result in no symptoms and only about 2% develop DHF, strongly suggesting the important role of host genetic factors (Coffey et al., 2009). Halstead et al (2001) found that an absence of DHF in Haiti and West Africa despite hyper endemic transmission of multiple DENV serotypes. Furthermore, a study found that blacks were less frequent develop to DHF/DSS during DENV epidemics in Cuba (Coffey et al., 2009). Although pre-existing immunity may be a confounding factor in DENV infection development but these studies reveal strong evident that genetic predisposition is an important factor as well.

Development of DHF or DSS is not completely understood. Progression of the dengue diseases is different in each individual. It probably involves several factors, such as immune response, antibody dependent enhancement, virus virulence, and host genetic (Panchal et al., 2012). Secondary viral infection and host immunological factors are often associated with the development of DENV pathogenesis (Furuta et al., 2012). Interestingly, several human immunities are controlled by the expression of human leukocyte antigen (HLA) and expression of HLA molecules are increased in DENV infection (Lan et al., 2008; Lan and Hirayama, 2011). HLA allele polymorphisms have correlation with T cell differentiation profile and it will determine the variation of viral infection response (Lan and Hirayama, 2011). Several studies have shown a correlation between HLA and DENV infection. Sierra et al (2007) found that amino acid peptides on poly DENV protein bind to HLA class I and class â…¡ allotype have a correlation with susceptibility and protection against DENV infection. Study conducted by Apanna et al (2010) also documented that HLA class I and class â…¡ had association with susceptibility and protection of DENV infection. HLA also linked to development of dengue diseases pathogenesis. Lan et al (2008) found a correlation between HLA class I and â…¡ and DENV infection development. Study conducted by Azeredo et al (2010) also found that certain types of HLA genes are found in patients with DSS. In addition, study about association of HLA and response to vaccination has been reported (Poland et al., 2008). Therefore, this paper will discuss about the association of HLA and HLA-related protein gene polymorphisms with susceptibility, severity, and protection against DENV infection in brief view setting.

2. Discussion
The role of HLA in the immune system is to help the immune system to distinguish body protein with foreign protein, such as viruses and bacteria (Panchal et al., 2012). It displays peptide antigens to T lymphocytes resulting in introduction of elements and triggers an immune response (Lan and Hirayama, 2011). HLA system consists of a variety of genes, play important roles in human immune system. HLA is encoded by the major histocompatibility complex (MHC), located on chromosome 6p21 consisting of approximately 0.5% (>150) protein coding genes (Appanna et al., 2010; Xie et al., 2010; Wagenaar et al., 2004). HLA region is divided to two classical regions, class I (HLA-A, B, C) and class â…¡ (HLA-DR, DQ, and DP) and an intervention region (classâ…¢) (Xie et al., 2010). Genes encoding HLA class I and class â…¡ are the most polymorphic genomes in humans (Lan and Hirayama, 2011).

2.1 HLA class I
HLA class I gene encodes polypeptide α chain of HLA class I molecules; whereas the β chain of HLA class I is encoded by beta2-microglobulin, a gene located on chromosome 15. α chain of HLA class I has 5 domain: 2 peptide-binding domain (α1 and α2), 1 immunoglobulin-like domain (α3), transmembrane region, and cytoplasmic tail. HLA region consists of approximately 200 HLA class I genes, but the most important HLA in the immunity is HLA-A, HLA-B, and HLA-C. HLA class I is expressed on all somatic cells and platelet although the levels of expression depend on their respective networks (Klein and Sato, 2000). α1 and α2 domain contain various amino acid sequences, and determine the HLA class I antigenic specificity molecules. α3 and β2m domains together form a immunoglobulin constant like-fold. Light chains α1 and α2 domain form a structure consisting of eight β strands and two α helix antipararel that have a role as antigen peptides binding site (Choo, 2007).

Several studies have identified HLA alleles associated with DENV infection susceptibility and severity such as A*0207, A*1, A*2, A*24, A*31, B blank, B*13, B*40, B*46, B*51, B*52, B*53, and B*57 (Chaturvedi et al., 2006; Panchal et al., 2012; Wagenaar et al., 2004). Whereas some HLA alleles such as A*0203, A*03, A*29, A*33, B*13, B*14, B*15, B*18, B*44, B*49, B*52, B*62, and B*76, B*77 are associated with protection of DENV infection (Chaturvedi et al., 2006; Panchal et al., 2012; Wagenaar et al., 2004). See Table 1.

 Table 1 Human leukocyte antigen (HLA) alleles associated with susceptibility, severity, and protection against dengue hemorrhagic fever

The associations between MHC class I and CD8+ have an important role in the process of DENV infection. MHC class I molecule will bind to the protein fragments or endogenous peptide and interact with CD8+. Furthermore CD8+ represents antigen-specific and responds to destroy infected cells. All cells in the human body that express MHC class I molecules can be the targets of CD8+. The role of CD8+ in the infection process is to monitor all cells in the body and prepare to destroy cells that express foreign antigen fragments on MHC class I molecules. Antigen presentation by MHC class I molecules to CD8+ would normally lead to protective immunity, but if there is an abnormality of immune response, it will cause disease (Panchal et al., 2012).

Several studies have reported the association of DHF with HLA antigens in ethnically and geographically distinct populations. Contribution of these genes to disease pathogenesis has been analyzed by Fernández-Mestre et al (2009) in Venezuelan patients with DF and DHF. This study analyzed the frequency of HLA class I (-A, -B and –C) and class â…¡ (-DRB1) polymorphisms in patients with dengue diseases and the relationship with the clinical manifestations. This study found that patients with DENV infection, HLA-B*15 and B*49 were significantly lower compared with controls. Contrary, HLA-B*57 increased significantly compared with controls. In addition, patients with hemorrhagic manifestations, HLA-B*40 was higher compared to healthy group. In other study, HLA- A*0207 and HLA-B*51 were susceptible to both DHF and DSS (Stephen et al., 2002). HLA-A*29 and A*33 were protective against DENV infection development in Cuba (Paradoa et al., 1987) and Vietnam (Loke et al., 2001).

Appanna et al (2010) compared the genotype variants of HLA Class 1 (-A and -B) in patients with DENV infection and healthy individuals from several ethnic groups in Malaysia. They found that HLA-B*53 and HLA-A*30 were increase significantly and A*03 was decrease significantly in total population compared to healthy individuals. In Malay DHF patients, allele B*13, A*26, and A*68 increased significantly and allele HLA-B*18 decrease significantly compared to healthy group. Among Indian DHF patients, HLA-A*31 was increased. In Chinese DHF patients, HLA-A*24 and HLA-A*32 were increased significantly.

2.2 HLA Class â…¡
HLA class â…¡ genes encode α and β polypeptide chains in HLA class â…¡ molecules. α and β HLA class â…¡ have four domains, peptide-binding domain (α1 and β1) immunoglobulin-like domains (α2 and β2), a transmembrane region and cytoplasmic tail. HLA class â…¡ is expressed by immune cells including B cells, activated T cells, macrophages, dendritic cells and thymic epithelial cell (Klein and Sato, 2000). There are six major subtypes of HLA class â…¡: DPA1, DPB1, DQA1, DQB1, DRA, and DRB1 (Panchal et al., 2012). HLA class â…¡ molecules have an important role in exogenous antigen presentation to T helper cells (Zhou et al., 2011). The process of lymphocyte activation during DENV infection is an important contribution in dengue diseases pathogenesis. Based on this fact, a study clearly confirmed HLA class â…¡ gene polymorphisms correlate with clinical manifestations of DENV infection (Chaturvedi et al., 2006). Several studies have identified HLA alleles associated with DENV infection susceptibility and severity such as DR1, DRB1*08, DRB1*12, and DRB1*15. Whereas some HLA alleles such as DRB1*0901, DRB1*02, DRB1*03, DRB1*04, and DRB1*07 are associated with protection against DENV infection (Chaturvedi et al., 2006; Panchal et al., 2012; Wagenaar et al., 2004). See Table 1.

T lymphocytes CD4+ and CD8+ cells have important role in DENV infection pathogenesis (Kurane et al., 2011). T cells reactive against DENV mediate DHF pathogenesis through endothelium cell apoptosis and induce cytokine secretion that results in increased vascular permeability. CD4+ has an important role against infection, such as antibody response maturisation, macrophage activation, increase natural killer (NK) cell activity, and antibody switching. The relationship between CD4+ and MHC class â…¡ has an important role in controlling the infection process. Activated CD4+ recognizes antigen presented by MHC class â…¡. Furthermore CD4+ releases cytokines in response to antigen stimulation and also capable of lysing infected cells (Chaturvedi et al., 2006; Rothman, 2011).

In DENV infection, CTL has an important role to recognize DENV epitopes. DENV epitopes involved in this process is nonstructural protein (NS). It is the bifungsional protein that controls serine protease and nucleic acid activity. Protease is an important part for virus life cycle (Chaturvedi et al., 2006). The epitopes recognized by DEN-specific are located in most of the structural and non-structural proteins, but NS3 is the protein that is most dominantly recognized (Kurane et al., 2011). There are several CTLs, however only JK34, JK15, JK44, JK5, JK4, JK43, JK10, JK39, JK28, and JK26 that have important role in DENV infection process (Chaturvedi et al., 2006; Okamoto et al., 1998). CD4+ and CD8+ recognize NS3 of DENV through JK34. NS3 recognizing through JK34 is mediated by the HLA-DPw2 restriction. NS3 recognizing through JK4 and JK43 is mediated by HLA-DR15 allele restriction. NS3 recognition process occurs very specific. Several CTL involved in NS recognizing, such as JK15 recognizes DV3 NS3, JK44 recognizes DV1 and DV2 NS3, and JK5 recognizes DV1 and DV3 NS3. This recognition process involves not only one epitope (NS3), but also NS1 and NS2a (Chaturvedi et al., 2006).

The correlation of HLA class â…¡ genes with both enhanced and decreased susceptibility to DHF has been reported. Several studies have reported the association of DHF with HLA class â…¡ antigens. Fernández-Mestre et al (2009) analyzed the frequency of HLA class I (-A, -B and –C) and class â…¡ (-DRB1) polymorphisms in DF and DHF patients, and its relationship with clinical manifestations of disease in Venezuelan. In patients with DENV infection, DRB1*02 and DRB1*03 decreased significantly compared with healthy individuals. It suggested that these allele groups could be associated with diminished infection susceptibility. Among DF patients there was a significant increase of DRB1*15 compared with healthy individuals. It suggested that this allele could be associated with infection susceptibility. Another study conducted in Mexican found that HLA-DRB1 played as protective allele in the patients with DENV infection compared to healthy individuals. It suggest that class â…¡ MHC antigens probably process and present immunological determinants of protein E (envelope protein of DENV) and HLA-DRB1*04 may present these viral antigens to CD4+ lymphocytes leading immune response activation and consequently protected from DHF (LaFleur et al., 2002). A study conducted in Southern found that HLA-DRB1*0901 decreased significantly in patients with DSS compared to control and HLA- DRB1*0901 decreased significantly in DSS compared with DHF (Lan et al., 2008). Other study found HLA-DRBI*04 and HLA-DRBI*07 were protective alleles to DENV infection (Sierra et al., 2007).

Several HLA class â…¡ members are associated with susceptibility to dengue infection. Recently, Malavige et al (2011) compared DRB1*08 and DRB1*12 alleles in 110 DHF patients and 119 control individuals. It showed that the frequency of DRB1*08 allele was 28.7 times higher in DSS patients than in normal population and HLA-DRB1*12 was higher in primary DENV infection compared with control. A Study conducted by Falcón-Lezama et al (2009) found HLA-DQB1*0202 was positively associated with DF only. It concluded that HLA-DQB1 alleles have association with the risk of symptomatic disease development, DF and DHF. Furthermore, a study conducted in Southern Brazilian population showed that HLA-DQ1 was found to be susceptibility alleles to patients with DENV infection (Polizel et al., 2004).
2.3 HLA classâ…¢
HLA classâ…¢ genes do not code for HLA molecules. HLA classâ…¢ consists of complement components (C2, C4, factor B), 21-hydoxylase, and tumor necrosis factors (TNFs) (Choo, 2007). Proteins produced by HLA classâ…¢ have function for the inflammatory process or other immune system activity (Panchal et al., 2012). Several SNPs found in the regulatory region influence transcription of TNF-α gene and circulating level of TNF-α and thus increases the susceptibility to human diseases including viral diseases (Qidwai and Khan, 2011; Tumangger and Jamil, 2010). A study found that TNF-α was able to increase endothelium cell (EC) permeability in vitro, which suggests its possible role in DHF pathogenesis (Dewi et al., 2004). In an animal model of DENV-induced hemorrhage study, Chen et al (2007) found that there was correlation positive between TNF-α levels in several tissues and EC apoptosis and hemorrhage. In addition, TNF-α level has been shown to be high in sera of DENV infected mice (Atrasheuskaya et al., 2003). A clinical study found that high TNF-α concentration was correlated with thrombocytopenia among dengue infection patients (Bozza et al., 2008). Another study found that plasma levels of TNF-α is significantly higher in DHF than in DF (Chakravarti and Kumaria, 2006).

Harapan et al (2013) stated that TNF-α is associated with DHF/DSS development by many pathways including: (a) TNF-α is a potent EC activator therefore it enhances permeability of capillary; (b) TNF-α induces EC to produce reactive nitrogen and oxygen species and induces apoptotic cell death; (c)TNF-α induces tissue factors gene expression on monocytes and EC; (d) TNF-α represses thrombomodulin gene expression on EC; (e) TNF-α effect IL-6 production directly, therefore TNF-α effect coagulation and fibrinolysis; and (f) TNF-α mediates in peripheral T-cell deletion.

Interestingly, Loke et al (2002) found no association between TNF-α –238G/A and –308G/A polymorphisms and DHF in Vietnamese patients. However, other study in a Venezuelan study, Fernandez-Mestre et al (2004) confirmed that the TNF-α –308 variant allele more frequent found in DHF compared with DF patients. Fernandez-Mestre et al (2004) documented an association between TNF-α –308A allele in DF patients with hemorrhagic manifestations, suggesting this variant allele as a possible risk factor for bleedings in DENV infection. In other study, the TNF-α –238A polymorphism combined with lymphotoxin-alpha (LTA)-3 haplotype were correlated significantly with DHF compared with DF (Vejbaesya et al., 2009). More recently, Perez et al (2010) confirmed that the allele distribution of TNF-α promoter polymorphism revealed the association of allele A (high production of TNF-α) to DHF significantly in Cuba. A higher frequency of carriers of genotype –308GG (low production of TNF-α) was observed in controls, whereas the DHF group showed a major distribution of AA and AG genotypes (high production of TNF-α). However, the association between genotype AA and DHF was not significant.

2.4 HLA-Related Proteins
2.4.1 Mayor Histocompatibility Complex (MHC) class I chain-related protein A and B (MICA and MICB)

MICA and MICB genes, member of the MIC family, have an open reading frame and encode cell surface expressed molecules (Bahram, 2000; Kennedy et al., 2002). MICA is stress-induced antigens that are recognized by cytotoxic T cells and natural killer cells (Lanier, 2000). MICA has critical role in the surveillance of transformed infected and damaged cells. The MICA gene has been identified as 46.4 kb located on on the short arm of human chromosome 6 (Kennedy et al., 2002). Previous studies have demonstrated polymorphic (GCT)n triplet repeats in the transmembrane region of the MICA gene, designated A4, A5, A6, A9, and A5.1, representing four, five, six, and nine copies of (GCT), and (GCT)4(GGCT), respectively (Cheng et al., 2000; Kennedy et al., 2002). MICB molecules are ligand of NKG2D receptors on NK cells, gamma/delta T cells, NKT cells, and CD8aß T cells, has significant role in mediating immune responses by stimulating innate and adaptive immune (Kopp et al., 2009). Some study found several polymorphisms in MICB gene (Raulet, 2003; Steinle et al., 2001). MICB gene contains a microsatellite polymorphism named C1_2_A in intron 1 comprising 16 alleles (Kopp et al., 2009).

The pathogenesis of DHF has been considered to the massive immune activation of T cells and NK (Harapan et al., 2013). Abnormal expression of the immune regulatory molecules, MICB, leads to disturbances of regulatory T cell and NK immune response (Jumnainsong et al., 2008) The MICB plays a significant role in the immune response. The mechanism of T cell and NK cell silencing by down regulation of NKGD cells induced by soluble ligands or chronic exposure to cell surface bound ligands may represent an important mechanism in immune responses (Jumnainsong et al., 2008; Marsh et al., 2004). Recently, one study by García et al (2011) in Cuban populations, investigated the association of non classical HLA class I MICA and MICB genes with disease outcome during DENV infection. They found that a tendency for MICA*008 and MICB*008 was associate with susceptibility to DENV when symptomatic versus asymptomatic cases were compared. Garcia and group also found a stronger association of both allelic forms was observed for the dengue fever patients compared with the asymptomatic dengue infection group rather than the severe cases. This study concluded that the polymorphisms of MICA and MICB gene contribute to susceptibility against DENV infection in human.

2.4.2. Lymphotoxin-alpha (LTA)
LTA are pleuripotent vasoactive immunomodulators produced mainly by activated monocytes and lymphocytes. LTA are encoded by adjacent gene loci in the central or classâ…¢ region of the human MHC between HLA class I and â…¡ genes on the short-arm of chromosome 6 (Horton et al., 2004). TNF and LTA share the same receptors (Vejbaesya et al., 2009). LTA promotes adhesion of molecules and cytokines from EC and vascular smooth-muscle cells and play crucial role in contributing to inflammatory cocktail (Ross, 1999). This indicated that LTA plays crucial role in DENV infection pathogenesis. A variety of SNPs have been identified in non-coding promoter-like regions, adjacent to exons encoding LTA (Fanning et al., 1997). Furthermore, linkage disequilibrium between LTA, and other HLA class I and â…¡ genes within the MHC contributes to the formation of haplotypes or stable combinations of SNP defined alleles, that vary in composition and frequency both within and between different ethnic groups (Baena et al., 2002; Fanning et al.,1997; Shaw et al., 2004).

Several studies suggested that the polymorphisms in the LTA gene may influence susceptibility to the progression of chronic chagas cardiomyopathy (Ramasawmy et al., 2007) and coronary artery disease and myocardial infarction (Knight et al., 2004; Tanaka and Ozaki, 2006), heart failure (Ozaki et al., 2002), asthma and other diseases (Knight et al., 2004).

An SNP identified within the LTA and TNF promoter has been reportedly associated with DENV infection. Vejbaesya et al (2009) analyzed several polymer- phisms in TNF and LTA genes from patient with subclinical DENV infection, primary and secondary DF, and DHF in Thailand. They found that TNF-238A marking the TNF-4, LTA-3 haplotype increased significantly in secondary DHF patients compared to secondary DF. They also found two that extended MHC haplotypes containing TNF-4 and LTA-3, together with HLA-B48, B57 and DPB1*0501, were detected only in secondary DHF. This finding indicate that polymorphism in functionally distinct MHC- encoded proteins contributes to the risk of developing severe secondary DENV infection and are worthy of further investigation.

3. Conclusion
In summary, we have shown that there are many scientific evidences that have proven the fact indicating host genetic factors as important components in dengue disease. The roles of HLA and HLA-related genes controlling DENV infection have been proven by several scientific studies. HLA alleles associated with DENV infection susceptibility, severity and protection. In term of HLA-related proteins, MICA, MICB and LTA also associated with dengue manifestations. In suggestion, further analysis of the genetic basis of DENV infection may contribute to the development of new therapeutic and preventative interventions.

Authors' Contributions
HH was the principal investigator, responsible for work design, data collection and interpretation, drafted the first and final manuscript, and revised the manuscript. JKF and SAK participated in data collection and interpretation, and drafted the first draft of manuscript. WW advised the work and revised the manuscripts. KFJ advised and supervised the work. All authors read and approved the final manuscript.

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