Susceptible and Protective HLA Class 1 Alleles against Dengue Fever and Dengue Hemorrhagic Fever Patients in a Malaysian Population

Appanna, Ramapraba; Ponnampalavanar, Sasheela; See, Lucy Lum Chai; Sekaran, Shamala Devi

doi:10.1371/journal.pone.0013029

Cited by 62 publications

(57 citation statements)

References 42 publications

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“…1B). The high level of immunodominance of B*35:01 is relevant in the context of previous studies correlating B*35:01 expression with decreased risk of severe dengue disease (28,29).…”

Section: B*35:01-restricted Responses Dominate the Cd8mentioning

confidence: 88%

Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Alwis

Bangs

Angelo

et al. 2016

J Virol

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Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8 ؉ T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35:01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8 ؉ T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-␥) responses were associated with effector memory phenotypes, which were also detected in non-B*35:01-expressing T cells. However, only the B*35:01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8 ؉ T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity. IMPORTANCEDengue is an increasingly significant public health problem as its mosquito vectors spread over greater areas; no vaccines against the virus have yet been approved. An important step toward vaccine development is defining protective immune responses; toward that end, we here characterize the phenotype of the immunodominant T cell responses. These DENV-reactive T cells express high levels of the receptor programmed death 1 protein (PD-1), while those from disease-susceptible alleles do not. Not only does this represent a possible correlate of immunodominance, but it raises the hypothesis that PD-1 might be a regulator that prevents excessive damage while preserving antiviral function. Further, as this study employs distinct populations (Nicaraguan and Sri Lankan donors), we also confirmed that this pattern holds despite geographic and ethnic differences. This finding indicates that HLA type is the major determinant in shaping T cell responses.

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“…1B). The high level of immunodominance of B*35:01 is relevant in the context of previous studies correlating B*35:01 expression with decreased risk of severe dengue disease (28,29).…”

Section: B*35:01-restricted Responses Dominate the Cd8mentioning

confidence: 88%

Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Alwis

Bangs

Angelo

et al. 2016

J Virol

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“…A role for T cells in control of DENV infection is suggested by several studies that implicate HLA associations as a genetic component to variable susceptibility to DENV disease (20)(21)(22)(23)(24)(25)(26). However, it has not been addressed whether these associations might indicate a positive or detrimental role for T-cell responses.…”

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confidence: 99%

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8 ⁺ T cells

Weiskopf

Angelo

Azeredo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

533

645

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The role of CD8 + T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8 + responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8 + T cells is associated with protection from dengue virus disease.

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“…Relatedly, a role for T cells in control of disease has been suggested by several studies that correlate the expression of certain HLA molecules with susceptibility to or protection from DENV disease (9)(10)(11)(12)(13)(14)(15). HLA molecules are one of the most polymorphic host factors in humans, with several thousand variants thus far known (16,17).…”

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confidence: 99%

Dengue virus infection elicits highly polarized CX3CR1⁺cytotoxic CD4⁺T cells associated with protective immunity

Weiskopf

Bangs

Sidney

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

266

300

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Dengue virus (DENV) is a rapidly spreading pathogen with unusual pathogenesis, and correlates of protection from severe dengue disease and vaccine efficacy have not yet been established. Although DENV-specific CD8 + T-cell responses have been extensively studied, the breadth and specificity of CD4 + T-cell responses remains to be defined. Here we define HLA-restricted CD4 + T-cell epitopes resulting from natural infection with dengue virus in a hyperepidemic setting. Ex vivo flow-cytometric analysis of DENVspecific CD4+ T cells revealed that the virus-specific cells were highly polarized, with a strong bias toward a CX3CR1 A ll four of the dengue virus serotypes (DENV 1-4) have spread rapidly within countries and across regions in the past few decades, resulting in an increased frequency of epidemics and severe dengue disease. Multiple serotypes circulate simultaneously in many tropical countries, and recent outbreaks have been reported in Europe and the continental United States (1, 2). These circumstances make dengue the most prevalent and rapidly spreading mosquito-borne viral disease in humans (3). Recent reports estimate that 390 million infections occur each year, with ∼25% of cases resulting in symptomatic disease (2).All four dengue serotypes can cause a spectrum of disease, ranging from self-limiting dengue fever to potentially lethal severe dengue disease, such as states of dengue hemorrhagic fever and Dengue shock syndrome, which are associated with the plasma leakage syndromes leading to visceral organ injury (4). It is not yet fully understood why only a subset of people infected with DENV progresses to severe disease. One risk factor for severe disease is the acquisition of DENV-reactive Abs before secondary infection with a different serotype (heterologous infection). These Abs can either be acquired from a previous infection with a different serotype or, in the case of infants, acquired from an immune mother (5, 6). It has been shown that subneutralizing levels of DENV-specific Abs exacerbate disease in a phenomenon termed Ab-dependent enhancement of infection (7,8). In brief, dengue-specific crossreactive Abs produced after an initial DENV infection combine with those produced after a second viral infection to form immune complexes that perpetuate infection by increasing the number of infected cells and, therefore, viral output per cell (6).The observation that only a minority of patients develops severe disease suggests that host genetic factors may play an important role in disease severity. Relatedly, a role for T cells in control of disease has been suggested by several studies that correlate the expression of certain HLA molecules with susceptibility to or protection from DENV disease (9-15). HLA molecules are one of the most polymorphic host factors in humans, with several thousand variants thus far known (16,17). Each HLA variant is present with variable frequency, depending on ethnic lineage and geographic locality. For HLA class I MHC restricted responses, it has been recently shown tha...

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Susceptible and Protective HLA Class 1 Alleles against Dengue Fever and Dengue Hemorrhagic Fever Patients in a Malaysian Population

Cited by 62 publications

References 42 publications

Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8 ⁺ T cells

Dengue virus infection elicits highly polarized CX3CR1⁺cytotoxic CD4⁺T cells associated with protective immunity

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Susceptible and Protective HLA Class 1 Alleles against Dengue Fever and Dengue Hemorrhagic Fever Patients in a Malaysian Population

Cited by 62 publications

References 42 publications

Immunodominant Dengue Virus-Specific CD8 + T Cell Responses Are Associated with a Memory PD-1 + Phenotype

Immunodominant Dengue Virus-Specific CD8 + T Cell Responses Are Associated with a Memory PD-1 + Phenotype

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8 + T cells

Dengue virus infection elicits highly polarized CX3CR1+cytotoxic CD4+T cells associated with protective immunity

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Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Immunodominant Dengue Virus-Specific CD8 ⁺ T Cell Responses Are Associated with a Memory PD-1 ⁺ Phenotype

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8 ⁺ T cells

Dengue virus infection elicits highly polarized CX3CR1⁺cytotoxic CD4⁺T cells associated with protective immunity