CD4+T cells mediate protection against Zika associated severe disease in a mouse model of infection

Abstract

Zika virus (ZIKV) has gained worldwide attention since it emerged, and a global effort is underway to understand the correlates of protection and develop diagnostics to identify rates of infection. As new therapeutics and vaccine approaches are evaluated in clinical trials, additional effort is focused on identifying the adaptive immune correlates of protection against ZIKV disease. To aid in this endeavor we have begun to dissect the role of CD4+T cells in the protection against neuroinvasive ZIKV disease. We have identified an important role for CD4+T cells in protection, demonstrating that in the absence of CD4+T cells mice have more severe neurological sequela and significant increases in viral titers in the central nervous system (CNS). The transfer of CD4+T cells from ZIKV immune mice protect type I interferon receptor deficient animals from a lethal challenge; showing that the CD4+T cell response is necessary and sufficient for control of ZIKV disease. Using a peptide library spanning the complete ZIKV polyprotein, we identified both ZIKV-encoded CD4+T cell epitopes that initiate immune responses, and ZIKV specific CD4+T cell receptors that recognize these epitopes. Within the ZIKV antigen-specific TCRβ repertoire, we uncovered a high degree of diversity both in response to a single epitope and among different mice responding to a CD4+T cell epitope. Overall this study identifies a novel role for polyfunctional and polyclonal CD4+T cells in providing protection against ZIKV infection and highlights the need for vaccines to develop robust CD4+T cell responses to prevent ZIKV neuroinvasion and limit replication within the CNS.

Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus–Specific CD8+ T Cells

“…Future studies will address the immune profiles of human ZIKV-specific CD4 + T cells and compare the functionalities of CD4 + T cells with the ones of CD8 + T cells. Indeed, recent studies in humans and mouse models have shown the importance of ZIKV-specific CD4 + T cells in protecting from severe ZIKV severe and Ab development (25)(26)(27). Additionally, it would be of interest to test whether disease severity during the acute phase impacts the gene transcription and protein expression in ZIKVspecific T cells.…”

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

“…In addition, the cytotoxic profile of the CD4+ T cells present 12 months after DENV infection and during heterologous ZIKV challenge correlate with better performance relative to the early (3 months) or late (2.5 years) (24) periods of time after the primary DENV infection. The role of CD4+T cells in flavivirus infection has been extensively documented (56) (57). Importantly, Weiskopf et al and others have also shown that DENV CD4+T cells are readily detectable early following DENV infection, and the frequency of DENV-specific CD107a+ CD4+T correlate with enhanced protection against DENV disease (58, 59) and play a key role in controlling secondary flavivirus infections (26).…”

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

“…The ZIKV strain PRVABC59 used was a kind gift of Robert Lanciotti (CDC). The ZIKV used was grown in Vero cells from the American Type Culture Collection (ATCC CCL-81) and stored at −80 • C, as described previously [19,22,49]. The human serum samples were obtained from the University of North Carolina/ National Institute of Health (UNC/NIH) Traveler Study through BEI Resources, NIAID, NIH: human convalescent plasma.…”