Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naïve individual during the 2016 outbreak in Miami, FL

ABSTRACT Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8+ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8+ T cell response was elicited, major histocompatibility complex class I-restricted CD8+ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8+ T cells was developed, and virus-specific memory CD8+ T cells were generated in these mice. The CD8+ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8+ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection. IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8+ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8+ T cells in vivo, which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8+ T cell responses were generated and that CD8+ T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.

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ENVELOPED VIRUS-LIKE PARTICLES (eVLPs) EXPRESSING MODIFIED FORMS OF ZIKA VIRUS PROTEINS E AND NS1 PROTECT MICE FROM ZIKA VIRUS INFECTION

10.1101/666966 ◽

2019 ◽

Author(s):

Anne-Catherine Fluckiger ◽

Jasminka Bozic ◽

Abebaw Diress ◽

Barthelemy Ontsouka ◽

Tanvir Ahmed ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Zika Virus ◽

Neutralizing Antibody ◽

T Cell Response ◽

Bivalent Vaccine ◽

Virus Like Particles ◽

Enveloped Virus ◽

Zika Virus Infection ◽

Virus Proteins

AbstractWhile Zika virus (ZIKV) infection induces mild disease in the majority of cases, it has been identified as responsible for microcephaly and severe neurological disorders in recent 2015-2016 outbreaks in South America and the Caribbean. Since then, several prophylactic vaccine strategies have been studied. Here, we describe the development of a ZIKV candidate vaccine consisting of bivalent enveloped virus-like particles (eVLPs) expressing a modified form of E and truncated NS1 (EG/NS1) proteins. In EG/NS1, the E transmembrane/cytoplasmic tail has been replaced with those domains from the VSV G protein and a β-domain of NS1 was fused in-frame to Gag from Moloney murine leukemia virus (MLV). Immunization of BALB/C mice demonstrated that bivalent EG/NS1 and monovalent EG eVLPs induced comparable levels of antibody (Ab) titers but that EG/NS1 induced much higher neutralizing activity, comparable to naturally acquired anti-ZIKV immunity. In contrast, monovalent NS1 eVLPs did not induce a significant anti-NS1 Ab response but promoted strong T cell immunity that was also elicited with EG/NS1 eVLPs. ZIKV challenge studies in C57BL/6-IFNαR−/−mice demonstrated that EG/NS1 eVLPs conferred 100% protection against clinical disease after ZIKV challenge compared to 80% protection after EG eVLP vaccination, with protection against challenge correlating with neutralizing antibody titers and overt signs of infection.Author SummaryZika virus has caused rapidly spreading epidemics with potentially severe neurological symptoms including microcephaly in new born babies. Rapid progress has been made with several candidate vaccines under clinical evaluation but no vaccine or treatment is yet available. In this context, we have produced and tested recombinant virus-like particles that incorporate one or two Zika virus proteins, E and NS1 that have been modified for optimal efficacy. Our immunogenicity studies in mice showed a synergistic effect of both proteins in the bivalent vaccine. NS1 induced a strong T cell response enhancing the neutralizing antibody production induced by the E protein. In challenge experiments, the bivalent vaccine protected 100% of mice from clinical signs of Zika virus infection. These products could be further used to explore Zika virus correlates of protection and evaluated as vaccine candidates.

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An epidemic Zika virus isolate suppresses antiviral immunity by disrupting antigen presentation pathways

Nature Communications ◽

10.1038/s41467-021-24340-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ryan D. Pardy ◽

Stefanie F. Valbon ◽

Brendan Cordeiro ◽

Connie M. Krawczyk ◽

Martin J. Richer

Keyword(s):

T Cell ◽

Zika Virus ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Cross Presentation ◽

Cell Immunity ◽

Asian Lineage ◽

Insight Into ◽

Host Tissues

AbstractZika virus (ZIKV) has emerged as an important global health threat, with the recently acquired capacity to cause severe neurological symptoms and to persist within host tissues. We previously demonstrated that an early Asian lineage ZIKV isolate induces a highly activated CD8 T cell response specific for an immunodominant epitope in the ZIKV envelope protein in wild-type mice. Here we show that a contemporary ZIKV isolate from the Brazilian outbreak severely limits CD8 T cell immunity in mice and blocks generation of the immunodominant CD8 T cell response. This is associated with a more sustained infection that is cleared between 7- and 14-days post-infection. Mechanistically, we demonstrate that infection with the Brazilian ZIKV isolate reduces the cross-presentation capacity of dendritic cells and fails to fully activate the immunoproteasome. Thus, our study provides an isolate-specific mechanism of host immune evasion by one Brazilian ZIKV isolate, which differs from the early Asian lineage isolate and provides potential insight into viral persistence associated with recent ZIKV outbreaks.

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Cytotoxic T-cell Response against Steroidogenic Acute Regulatory Protein using DNA Vaccination Followed by Vaccinia Virus Infection in a Mouse Adrenal Carcinoma Model

Hormone and Metabolic Research ◽

10.1055/s-2004-814571 ◽

2004 ◽

Vol 36 (06) ◽

pp. 411-414 ◽

Cited By ~ 2

Author(s):

M. Reincke ◽

D. Ortmann ◽

J. Hausmann ◽

F. Beuschlein

Keyword(s):

T Cell ◽

Virus Infection ◽

Cell Response ◽

Regulatory Protein ◽

Dna Vaccination ◽

T Cell Response ◽

Steroidogenic Acute Regulatory Protein ◽

Cytotoxic T Cell ◽

Adrenal Carcinoma ◽

Steroidogenic Acute Regulatory

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Premature Induction of an Immunosuppressive Regulatory T Cell Response during Acute Simian Immunodeficiency Virus Infection

The Journal of Infectious Diseases ◽

10.1086/500368 ◽

2006 ◽

Vol 193 (5) ◽

pp. 703-712 ◽

Cited By ~ 191

Author(s):

Jacob D. Estes ◽

Qingsheng Li ◽

Matthew R. Reynolds ◽

Stephen Wietgrefe ◽

Lijie Duan ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Simian Immunodeficiency Virus ◽

Regulatory T Cell ◽

Cell Response ◽

T Cell Response ◽

Simian Immunodeficiency Virus Infection ◽

Immunodeficiency Virus

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Modification of the HIV-specific CD8+ T-cell response in an HIV elite controller after chikungunya virus infection

AIDS ◽

10.1097/qad.0000000000001129 ◽

2016 ◽

Vol 30 (12) ◽

pp. 1905-1911 ◽

Cited By ~ 4

Author(s):

Yanina Ghiglione ◽

María Julia Ruiz ◽

Jimena Salido ◽

César Trifone ◽

Omar Sued ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Cell Response ◽

Chikungunya Virus ◽

Cd8 T Cell ◽

T Cell Response ◽

Elite Controller

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Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

Journal of Virology ◽

10.1128/jvi.01992-17 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 16

Author(s):

Bobby Brooke Herrera ◽

Wen-Yang Tsai ◽

Charlotte A. Chang ◽

Donald J. Hamel ◽

Wei-Kung Wang ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Dengue Virus ◽

Zika Virus ◽

Cell Response ◽

Vaccine Development ◽

T Cell Responses ◽

T Cell Response ◽

Zikv Infection ◽

Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

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