Immunodominance changes as a function of the infecting dengue virus serotype and primary versus secondary infection
Open accessAbstract
Dengue virus (DENV) is the causative agent of dengue fever (DF). This disease can be caused by any of four DENV serotypes (DENV1 to -4) which share 67 to 75% sequence homology with one another. The effect of subsequent infections with different serotypes on the T cell repertoire is not fully understood. We utilized mice transgenic for human leukocyte antigens (HLA) lacking the alpha/beta interferon (IFN-α/β) receptor to study responses to heterologous DENV infection. First, we defined the primary T cell response to DENV3 in the context of a wide range of HLA molecules. The primary DENV3 immune response recognized epitopes derived from all 10 DENV proteins, with a significant fraction of the response specific for structural proteins. This is in contrast to primary DENV2 infection, in which structural proteins are a minor component of the response, suggesting differential antigen immunodominance as a function of the infecting serotype. We next investigated the effect of secondary heterologous DENV infection on the T cell repertoire. In the case of both DENV2/3 and DENV3/2 heterologous infections, recognition of conserved/cross-reactive epitopes was either constant or expanded compared to that in homologous infection. Furthermore, in heterologous infection, previous infection with a different serotype impaired the development of responses directed to serotype-specific but not conserved epitopes. Thus, a detrimental effect of previous heterotypic responses might not be due to dysfunctional and weakly cross-reactive epitopes dominating the response. Rather, responses to the original serotype might limit the magnitude of responses directed against epitopes that are either cross-reactive to or specific for the most recently infecting serotype. IMPORTANCE DENV transmission occurs in more than 100 countries and is an increasing public health problem in tropical and subtropical regions. At present, no effective antiviral therapy or licensed vaccine exists, and treatment is largely supportive in nature. Disease can be caused by any of the four DENV serotypes (DENV1 to -4), which share a high degree of sequence homology with one another. In this study, we have addressed the question of how the T cell repertoire changes as a function of infections with different serotypes and of subsequent heterologous secondary infections. This is of particular interest in the field of dengue viruses, in which secondary infections with different DENV serotypes increase the risk of severe disease. Our results on the evolution of the immune response after primary and secondary infections provide new insights into HLA-restricted T cell responses against DENV relevant for the design of a vaccine against DENV.
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CD8+ T cells are generally less tolerant of amino substitutions than CD4+ T cells.
“This effect is counterbalanced by CD8+ T cells being generally less tolerant of amino substitutions as compared to CD4+ T cells.”
From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [64]
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Self-citation
- Authors
- Weiskopf, D., Angelo, M. A., Sidney, J., Peters, B., Shresta, S., & Sette, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2014-10
- Volume
- 88
- Issue
- 19
- Pages
- 11383-11394
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC4178794
- OpenAlex
- W2119939554
- Cited by
- 90
- References
- 50
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 13 · 2019: 9 · 2018: 6 · 2017: 16 · 2016: 10 · 2015: 9 · 2014: 2
- FWCI
- 12.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (U54AI057517, HHSN272200900042C)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- dengue virus, T cell receptor repertoire, cross-reactive epitopes, primary infection, dengue virus type 2, DENV-3, structural proteins, HLA transgenic mice, epitope recognition, dengue, vaccine development, T cell immunity
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Viral, Antigens, Viral, Cross Reactions, Dengue, Dengue Virus, HLA Antigens, Humans, Mice, Transgenic, Molecular Sequence Data, Serotyping, T-Lymphocytes, Viral Structural Proteins, Gene Expression, Conserved Sequence, Viral Nonstructural Proteins, Epitopes, T-Lymphocyte, Mice, Receptor, Interferon alpha-beta
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