CD4⁺ and CD8⁺ T‐cell immunity to Dengue – lessons for the study of Zika virus

Abstract

SummaryDengue virus (DENV) and Zika virus (ZIKV) are rapidly emerging mosquito-borne flaviviruses that represent a public health concern. Understanding host protective immunity to these viruses is critical for the design of optimal vaccines. Over a decade of research has highlighted a significant contribution of the T-cell response to both protection and/or disease enhancement during DENV infection, the latter being mainly associated with sub-optimal cross-reactive T-cell responses during secondary infections. Phase IIb/III clinical trials of the first licensed tetravalent dengue vaccine highlight increased vaccine efficacy in dengue-immune as opposed to dengue-naive vaccinees, suggesting a possible immunoprotective role of pre-existing DENV-specific T cells that are boosted upon vaccination. No vaccine is available for ZIKV and little is known about the T-cell response to this virus. ZIKV and DENV are closely related viruses with a sequence identity ranging from 44% and 56% for the structural proteins capsid and envelope to 68% for the more conserved non-structural proteins NS3/NS5, which represent the main targets of the CD4 + and CD8 + T-cell response to DENV, respectively. In this review we discuss our current knowledge of T-cell immunity to DENV and what it can teach us for the study of ZIKV. The extent of T-cell cross-reactivity towards ZIKV of pre-existing DENV-specific memory T cells and its potential impact on protective immunity and/or immunopathology will also be discussed.Keywords: T cells; memory; virus; human; cell trafficking DENV and ZIKV: similarities and differences Dengue virus (DENV) and Zika virus (ZIKV) belong to the Flavivirus genus of the Flaviviridae family of viruses along with other arthropod-borne viruses that may have significant impact on human health such as Yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and tick-borne encephalitis virus (TBEV).No specific antiviral therapeutic is available for these viruses and treatments are supportive in nature. Protective vaccines are available for JEV, TBEV and YFV and a partially protective vaccine has recently been licensed for DENV. 1 The live-attenuated YFV vaccine, which is safe and extremely effective, was shown to elicit long-lived neutralizing antibodies and a strong CD4 + and CD8 + Tcell response, 2,3 components that we believe are key to a successful vaccine. However, the co-circulation of DENV as four distinct serotypes (DENV 1-4) and the risk of immunopathology associated with sub-optimal cross-reactive B-cell and T-cell responses to heterologous serotypes represent critical factors for the development of a fully protective DENV vaccine.Dengue virus, ZIKV and the other flaviviruses are enveloped viruses with a 10Á7-kb positive-strand RNA genome encoding for a single polyprotein that is posttranslationally cleaved into three structural proteins (capsid, membrane, envelope) and seven non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). DENV 1-4 serotypes share approximately 70% amino ac...

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

“…indicated that, following heterologous DENV infection, memory CD8 + T cells expanded that recognized conserved NS proteins (33). In fact, NS3 and NS5 represent the main targets of the CD8 + T cell response to flaviviruses (34, 35). One study reported more cross-reactive T cell responses to full length NS3 helicase, because of higher sequence homology, than that to the protease region alone (36).…”

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

“…ZIKV is a flavivirus most closely related to dengue virus (DENV) (5,6) but also related with Japanese encephalitis virus (JEV), West Nile virus (WNV), and yellow fever virus (YF), all of which are transmitted primarily by mosquitoes (7). Understanding host protective immunity to this virus is critical for the design of optimal vaccines, but little is currently known about the immune responses to ZIKV in humans since infections with ZIKV have not been frequent in the past (8,9). This is in contrast to a substantial wealth of information related to T cell immunity against the closely related DENV (10)(11)(12).…”

“…The main protein targets of CD4 and CD8 T cell immunity are presently unknown for ZIKV. This dearth of information is a severe knowledge gap, as robust T cell responses may be required for optimal ZIKV vaccine efficacy (9).…”

“…Importantly, previous DENV infection can in some instances increase severity of a second DENV infection with a heterologous serotype, likely through antibody-dependent enhancement (ADE) of infection and disease (26). In the phase IIb/III clinical trials of the first licensed tetravalent dengue vaccine, increased vaccine efficacy in DENV-preexposed as opposed to DENV-naive vaccinees was observed, suggesting a protective role of preexisting crossreactive DENV-specific T cells that are boosted upon vaccination (9). Thus, it is also possible that preexposure to either ZIKV or DENV infection will influence the disease course following infection with the other virus in either a favorable or detrimental fashion.…”

Mapping innate and adaptive immune function in arbovirus infections

“…Another ongoing unknown is the consequence of sequential infections with Zika and Dengue: is the antigenic relationship one that fosters cross‐reactive protection or pathogenic enhancement of virion uptake? The relationship between T‐cell recognition of Dengue and Zika was recently evaluated by Rivino and Lim . While there is a substantial dataset of Dengue T‐cell recognition, there is much yet to be resolved about Zika adaptive immunity.…”