Highly Differentiated, Resting Gn-Specific Memory CD8+ T Cells Persist Years after Infection by Andes Hantavirus

PLoS Pathogens

Marcela Ferrés¹  Elena Llop²  Pablo Vial³  Rebecca Graumann³  Valeska Simon³  Francisca Valdivieso³  Andrés Mori³  Tobias Manigold³  Constanza Castillo⁴  Brian Hjelle⁵ 

[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile;Facultad de Medicina, Universidad de Chile, Santiago, Chile;Institute of Science, Medical School, Clínica Alemana Universidad del Desarrollo, Santiago, Chile;Universidad de la Frontera, Temuco, Chile;University of New Mexico, Albuquerque, New Mexico, United States of America

关键词: T cells;    Memory T cells;    Enzyme-linked immunoassays;    Andes virus;    Cytotoxic T cells;    Immune response;    Cell-mediated immunity;    Hantavirus;   

DOI  :  10.1371/journal.ppat.1000779

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In man, infection with South American Andes virus (ANDV) causes hantavirus cardiopulmonary syndrome (HCPS). HCPS due to ANDV is endemic in Southern Chile and much of Argentina and increasing numbers of cases are reported all over South America. A case-fatality rate of about 36% together with the absence of successful antiviral therapies urge the development of a vaccine. Although T-cell responses were shown to be critically involved in immunity to hantaviruses in mouse models, no data are available on the magnitude, specificity and longevity of ANDV-specific memory T-cell responses in patients. Using sets of overlapping peptides in IFN-γ ELISPOT assays, we herein show in 78 Chilean convalescent patients that Gn-derived epitopes were immunodominant as compared to those from the N- and Gc-proteins. Furthermore, while the relative contribution of the N-specific response significantly declined over time, Gn-specific responses remained readily detectable ex vivo up to 13 years after the acute infection. Tetramer analysis further showed that up to 16.8% of all circulating CD3+CD8+ T cells were specific for the single HLA-B*3501-restricted epitope Gn465–473 years after the acute infection. Remarkably, Gn465–473–specific cells readily secreted IFN-γ, granzyme B and TNF-α but not IL-2 upon stimulation and showed a ‘revertant’ CD45RA+CD27−CD28−CCR7−CD127− effector memory phenotype, thereby resembling a phenotype seen in other latent virus infections. Most intriguingly, titers of neutralizing antibodies increased over time in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest intrinsic, latent antigenic stimulation of Gn-specific T-cells. However, it remains a major task for future studies to proof this hypothesis by determination of viral antigen in convalescent patients. Furthermore, it remains to be seen whether Gn-specific T cells are critical for viral control and protective immunity. If so, Gn-derived immunodominant epitopes could be of high value for future ANDV vaccines.

【 授权许可】

CC BY