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# T-Cell Immunity to Infection with Dengue Virus in Humans

1 , * , 1

Frontiers in Immunology

Frontiers Media S.A.

DENV, T cells, protection, pathogenesis, HLA, vaccines

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### Abstract

Dengue virus (DENV) is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans. Up to 400 million DENV infections occur every year, and severity can range from asymptomatic to an acute self-limiting febrile illness. In a small proportion of patients, the disease can exacerbate and progress to dengue hemorrhagic fever and/or dengue shock syndrome, characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations. A unique challenge in vaccine development against DENV is the high degree of sequence variation, characteristically associated with RNA viruses. This is of particular relevance in the case of DENV since infection with one DENV serotype (primary infection) presumably affords life-long serotype-specific immunity but only partial and temporary immunity to other serotypes in secondary infection settings. The role of T cells in DENV 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 to severe disease. Our recent study has suggested an HLA-linked protective role for T cells. Herein, we will discuss the role of T cells in protection and pathogenesis from severe disease as well as the implications for vaccine design.

### Most cited references50

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### The genetic structure and history of Africans and African Americans.

(2009)
Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.
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### Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas.

(1997)
The recent emergence and spread of dengue hemorrhagic fever in the Americas have been a major source of concern. Efforts to control this disease are dependent on understanding the pathogenicity of dengue viruses and their transmission dynamics. Pathogenicity studies have been hampered by the lack of in vitro or in vivo models of severe dengue disease. Alternatively, molecular epidemiologic studies which associate certain dengue virus genetic types with severe dengue outbreaks may point to strains with increased pathogenicity. The comparison of nucleotide sequences (240 bp) from the E/NS1 gene region of the dengue virus genome has been shown to reflect evolutionary relationships and geographic origins of dengue virus strains. This approach was used to demonstrate an association between the introduction of two distinct genotypes of dengue type 2 virus and the appearance of dengue hemorrhagic fever in the Americas. Phylogenetic analyses suggest that these genotypes originated in Southeast Asia and that they displaced the native, American genotype in at least four countries. Vaccination and other control efforts should therefore be directed at decreasing the transmission of these "virulent" genotypes.
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### Economic Impact of Dengue Illness in the Americas

(2011)
The growing burden of dengue in endemic countries and outbreaks in previously unaffected countries stress the need to assess the economic impact of this disease. This paper synthesizes existing studies to calculate the economic burden of dengue illness in the Americas from a societal perspective. Major data sources include national case reporting data from 2000 to 2007, prospective cost of illness studies, and analyses quantifying underreporting in national routine surveillance systems. Dengue illness in the Americas was estimated to cost $2.1 billion per year on average (in 2010 US dollars), with a range of$1–4 billion in sensitivity analyses and substantial year to year variation. The results highlight the substantial economic burden from dengue in the Americas. The burden for dengue exceeds that from other viral illnesses, such as human papillomavirus (HPV) or rotavirus. Because this study does not include some components (e.g., vector control), it may still underestimate total economic consequences of dengue.
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### Author and article information

###### Journal
Front Immunol
Front Immunol
Front. Immunol.
Frontiers in Immunology
Frontiers Media S.A.
1664-3224
07 March 2014
2014
: 5
###### Affiliations
1Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA, USA
###### Author notes

Edited by: Scott B. Halstead, International Vaccine Institute, South Korea

Reviewed by: Scott B. Halstead, International Vaccine Institute, South Korea; William Messer, Oregon Health and Sciences University, USA

*Correspondence: Daniela Weiskopf, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA e-mail: daniela@ 123456liai.org

This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology.

###### Article
10.3389/fimmu.2014.00093
3945531
Copyright © 2014 Weiskopf and Sette.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

###### Page count
Figures: 0, Tables: 0, Equations: 0, References: 76, Pages: 6, Words: 5539
###### Categories
Immunology
Review Article

Immunology

protection, denv, hla, t cells, pathogenesis, vaccines