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Zika Virus: Immunity and Vaccine Development

2016; Cell Press; Volume: 167; Issue: 3 Linguagem: Inglês

10.1016/j.cell.2016.09.020

ISSN

1097-4172

Autores

Theodore C. Pierson, Barney S. Graham,

Tópico(s)

Malaria Research and Control

Resumo

The emergence of Zika virus in the Americas and Caribbean created an urgent need for vaccines to reduce transmission and prevent disease, particularly the devastating neurodevelopmental defects that occur in utero. Rapid advances in Zika immunity and the development of vaccine candidates provide cautious optimism that preventive measures are possible. The emergence of Zika virus in the Americas and Caribbean created an urgent need for vaccines to reduce transmission and prevent disease, particularly the devastating neurodevelopmental defects that occur in utero. Rapid advances in Zika immunity and the development of vaccine candidates provide cautious optimism that preventive measures are possible. Zika virus (ZIKV) is a mosquito-transmitted flavivirus of African origin discovered in 1947 from a febrile Rhesus macaque caged in the Zika forest in Uganda (Dick et al., 1952Dick G.W. Kitchen S.F. Haddow A.J. Zika virus. I. Isolations and serological specificity.Trans. R. Soc. Trop. Med. Hyg. 1952; 46: 509-520Abstract Full Text PDF PubMed Scopus (1854) Google Scholar). Human ZIKV infections were documented rarely, despite serological evidence suggesting widespread exposure (Wikan and Smith, 2016Wikan N. Smith D.R. Zika virus: history of a newly emerging arbovirus.Lancet Infect. Dis. 2016; 16: e119-e126Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). The potential for significant ZIKV transmission and disease was first appreciated during a 2007 outbreak on Yap Island of the Federated States of Micronesia that affected roughly three-quarters of the population. ZIKV-associated illness was described as a self-limiting mild illness characterized by rash, fever, conjunctivitis, arthralgia, and arthritis (Duffy et al., 2009Duffy M.R. Chen T.H. Hancock W.T. Powers A.M. Kool J.L. Lanciotti R.S. Pretrick M. Marfel M. Holzbauer S. Dubray C. et al.Zika virus outbreak on Yap Island, Federated States of Micronesia.N. Engl. J. 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Oswaldo Cruz. 2015; 110: 569-572Crossref PubMed Scopus (842) Google Scholar). By the summer of 2016, more than 40 countries in the Western Hemisphere had reported locally acquired infections spread by the invasive mosquito species, Aedes aegypti, following a path through the Americas similar to that of the chikungunya virus only a few years earlier (Lessler et al., 2016Lessler J. Chaisson L.H. Kucirka L.M. Bi Q. Grantz K. Salje H. Carcelen A.C. Ott C.T. Sheffield J.S. Ferguson N.M. et al.Assessing the global threat from Zika virus.Science. 2016; 353: aaf8160Crossref PubMed Scopus (254) Google Scholar). Unexpectedly, in addition to Guillain-Barré syndrome, the ZIKV epidemic in the Americas has been linked to devastating neurodevelopmental defects in infants of women infected while pregnant, including microcephaly (Johansson et al., 2016Johansson M.A. Mier-y-Teran-Romero L. Reefhuis J. Gilboa S.M. Hills S.L. Zika and the Risk of Microcephaly.N. Engl. J. 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Flaviviruses are spherical virions that package a positive-strand RNA genome within a host-derived lipid envelope (Heinz and Stiasny, 2012Heinz F.X. Stiasny K. Flaviviruses and their antigenic structure.J. Clin. Virol. 2012; 55: 289-295Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). ZIKV entry into cells is facilitated by a number of cellular factors shown previously to promote infection of other flaviviruses, including molecules of the TIM/TAM family and the C-type lectin DC-SIGN (Hamel et al., 2015Hamel R. Dejarnac O. Wichit S. Ekchariyawat P. Neyret A. Luplertlop N. Perera-Lecoin M. Surasombatpattana P. Talignani L. Thomas F. et al.Biology of zika virus infection in human skin cells.J. Virol. 2015; 89: 8880-8896Crossref PubMed Scopus (833) Google Scholar); gene expression studies reveal that many of these molecules are expressed on relevant cell and tissue types in vivo (Nowakowski et al., 2016Nowakowski T.J. Pollen A.A. Di Lullo E. Sandoval-Espinosa C. Bershteyn M. Kriegstein A.R. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells.Cell Stem Cell. 2016; 18: 591-596Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, Tabata et al., 2016Tabata T. Petitt M. Puerta-Guardo H. Michlmayr D. Wang C. Fang-Hoover J. Harris E. Pereira L. Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission.Cell Host Microbe. 2016; 20: 155-166Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). Flavivirus internalization is typically clathrin dependent and provides virions access to acidic compartments of the endosome, where low pH-dependent membrane fusion occurs. The viral genome is translated in the cytoplasm as a single open reading frame that is cleaved subsequently by viral and host proteases to yield three structural proteins (capsid [C], premembrane [prM], and envelope [E]) and seven non-structural proteins. New virions are assembled on membranes derived from the endoplasmic reticulum as non-infectious immature virus particles on which prM and E associate as heterodimers organized as trimeric spikes with icosahedral symmetry. During transit through the Golgi, prM is cleaved by a host furin-like protease to become an infectious mature particle covered by E and membrane (M) proteins (Pierson and Diamond, 2012Pierson T.C. Diamond M.S. Degrees of maturity: the complex structure and biology of flaviviruses.Curr. Opin. Virol. 2012; 2: 168-175Crossref PubMed Scopus (156) Google Scholar). The structure of mature ZIKV has been solved at high resolution, revealing 90 antiparallel E dimers arranged in a herringbone pattern (Kostyuchenko et al., 2016Kostyuchenko V.A. Lim E.X. Zhang S. Fibriansah G. Ng T.S. Ooi J.S. Shi J. Lok S.M. Structure of the thermally stable Zika virus.Nature. 2016; 533: 425-428Crossref PubMed Scopus (355) Google Scholar, Sirohi et al., 2016Sirohi D. Chen Z. Sun L. Klose T. Pierson T.C. Rossmann M.G. Kuhn R.J. The 3.8 Å resolution cryo-EM structure of Zika virus.Science. 2016; 352: 467-470Crossref PubMed Scopus (544) Google Scholar), similar to the structure of both West Nile (WNV) and dengue (DENV) viruses (Kuhn et al., 2002Kuhn R.J. Zhang W. Rossmann M.G. Pletnev S.V. Corver J. Lenches E. Jones C.T. Mukhopadhyay S. Chipman P.R. Strauss E.G. et al.Structure of dengue virus: implications for flavivirus organization, maturation, and fusion.Cell. 2002; 108: 717-725Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar, Mukhopadhyay et al., 2003Mukhopadhyay S. Kim B.S. Chipman P.R. Rossmann M.G. Kuhn R.J. Structure of West Nile virus.Science. 2003; 302: 248Crossref PubMed Scopus (313) Google Scholar, Zhang et al., 2013Zhang X. Ge P. Yu X. Brannan J.M. Bi G. Zhang Q. Schein S. Zhou Z.H. Cryo-EM structure of the mature dengue virus at 3.5-Å resolution.Nat. Struct. Mol. Biol. 2013; 20: 105-110Crossref PubMed Scopus (298) Google Scholar). The E protein is a three-domain class II viral fusion protein that has critical roles in virus entry and assembly. E protein domain III (E-DIII) is an immunoglobulin-like fold hypothesized to contribute to viral attachment because it protrudes furthest from the surface of the virion, and some mutations in this domain result in increased binding to heparin sulfate on target cells (Chen et al., 1997Chen Y. Maguire T. Hileman R.E. Fromm J.R. Esko J.D. Linhardt R.J. Marks R.M. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate.Nat. Med. 1997; 3: 866-871Crossref PubMed Scopus (829) Google Scholar, Rey et al., 1995Rey F.A. Heinz F.X. Mandl C. Kunz C. Harrison S.C. The envelope glycoprotein from tick-borne encephalitis virus at 2 A resolution.Nature. 1995; 375: 291-298Crossref PubMed Scopus (1234) Google Scholar). E-DII is an elongated oligomerization domain that contains a highly conserved fusion loop (DII-FL) at the distal end. Domain I E-DI is a β-barrel domain connected to both E-DII and E-DIII by flexible hinges. A single asparagine (N)-linked carbohydrate is attached to E-DI at residue 154; in this position, the N-linked carbohydrate may function to shield the DII-FL. The E protein is anchored into the viral membrane by a helical stem and two antiparallel transmembrane domains. The structure of ZIKV prM and its orientation on the immature virion are unknown but is likely to be relatively similar to other flaviviruses, such as DENV, for which structural information is available (Li et al., 2008Li L. Lok S.M. Yu I.M. Zhang Y. Kuhn R.J. Chen J. Rossmann M.G. The flavivirus precursor membrane-envelope protein complex: structure and maturation.Science. 2008; 319: 1830-1834Crossref PubMed Scopus (392) Google Scholar). The innate immune response to flavivirus infection has a key role in orchestrating protection, as evidenced by the enhanced susceptibility of mice lacking innate immune sensors, signaling pathways, and effector molecules, as well as the numerous strategies flaviviruses use to circumvent this control (Lazear et al., 2016Lazear H.M. Govero J. Smith A.M. Platt D.J. Fernandez E. Miner J.J. Diamond M.S. A Mouse Model of Zika Virus Pathogenesis.Cell Host Microbe. 2016; 19: 720-730Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar, Quicke and Suthar, 2013Quicke K.M. Suthar M.S. The innate immune playbook for restricting West Nile virus infection.Viruses. 2013; 5: 2643-2658Crossref PubMed Scopus (33) Google Scholar). ZIKV infection stimulates the production of type I (α, β), type II (γ), and type III (λ) interferon (IFN) and numerous IFN-stimulated genes (ISGs) that limit infection (Bayer et al., 2016Bayer A. Lennemann N.J. Ouyang Y. Bramley J.C. Morosky S. Marques Jr., E.T. Cherry S. Sadovsky Y. Coyne C.B. Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection.Cell Host Microbe. 2016; 19: 705-712Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, Hamel et al., 2015Hamel R. Dejarnac O. Wichit S. Ekchariyawat P. Neyret A. Luplertlop N. Perera-Lecoin M. Surasombatpattana P. Talignani L. Thomas F. et al.Biology of zika virus infection in human skin cells.J. Virol. 2015; 89: 8880-8896Crossref PubMed Scopus (833) Google Scholar, Quicke et al., 2016Quicke K.M. Bowen J.R. Johnson E.L. McDonald C.E. Ma H. O'Neal J.T. Rajakumar A. Wrammert J. Rimawi B.H. Pulendran B. et al.Zika Virus Infects Human Placental Macrophages.Cell Host Microbe. 2016; 20: 83-90Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar). While the ISGs IFITM3 and, to a lesser degree, IFITM1 have been shown to inhibit ZIKV at an early stage of the replication cycle (Savidis et al., 2016Savidis G. Perreira J.M. Portmann J.M. Meraner P. Guo Z. Green S. Brass A.L. The IFITMs Inhibit Zika Virus Replication.Cell Rep. 2016; 15: 2323-2330Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar), the activity and mechanism of the repertoire of ISGs stimulated by ZIKV have not yet been cataloged. The NS5 polymerase of ZIKV was shown to degrade STAT2 in a proteasome-dependent manner (Grant et al., 2016Grant A. Ponia S.S. Tripathi S. Balasubramaniam V. Miorin L. Sourisseau M. Schwarz M.C. Sánchez-Seco M.P. Evans M.J. Best S.M. García-Sastre A. Zika virus targets human stat2 to inhibit type i interferon signaling.Cell Host Microbe. 2016; 19: 882-890Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar), and while the mechanisms differ in some respects, a similar process to limit IFN signaling has been described for DENV. The species-specific nature of this immune evasion mechanism likely contributes to the inability of ZIKV to replicate robustly and to cause disease in immunocompetent mice (Mysorekar and Diamond, 2016Mysorekar I.U. Diamond M.S. Modeling zika virus infection in pregnancy.N. Engl. J. Med. 2016; 375: 481-484Crossref PubMed Scopus (81) Google Scholar). The cellular immune response to flavivirus infection may contribute to both protection and pathogenesis, as supported by the linkage of HLA alleles and susceptibility to disease in humans (Screaton et al., 2015Screaton G. Mongkolsapaya J. Yacoub S. Roberts C. New insights into the immunopathology and control of dengue virus infection.Nat. Rev. Immunol. 2015; 15: 745-759Crossref PubMed Scopus (236) Google Scholar, Weiskopf et al., 2013Weiskopf D. Angelo M.A. de Azeredo E.L. Sidney J. Greenbaum J.A. Fernando A.N. Broadwater A. Kolla R.V. De Silva A.D. de Silva A.M. et al.Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells.Proc. Natl. Acad. Sci. USA. 2013; 110: E2046-E2053Crossref PubMed Scopus (398) Google Scholar). Very little has been published about cellular immunity to ZIKV; the role of this arm of the immune response can only be inferred from studies of related flaviviruses. Studies in mouse models of several flaviviruses defined a protective role for CD8+ T cells; CD8- or MHC-class-I-deficient animals have a reduced capacity for viral clearance, and adoptively transferred cells may be protective (Shrestha and Diamond, 2004Shrestha B. Diamond M.S. Role of CD8+ T cells in control of West Nile virus infection.J. Virol. 2004; 78: 8312-8321Crossref PubMed Scopus (323) Google Scholar). CD8+ T cell responses in humans are readily detectable after flavivirus infection and target both virus type-specific (TS) and cross-reactive (CR) determinants (Bukowski et al., 1989Bukowski J.F. Kurane I. Lai C.J. Bray M. Falgout B. Ennis F.A. Dengue virus-specific cross-reactive CD8+ human cytotoxic T lymphocytes.J. Virol. 1989; 63: 5086-5091Crossref PubMed Google Scholar, Mongkolsapaya et al., 2003Mongkolsapaya J. Dejnirattisai W. Xu X.N. Vasanawathana S. Tangthawornchaikul N. Chairunsri A. Sawasdivorn S. Duangchinda T. Dong T. Rowland-Jones S. et al.Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever.Nat. Med. 2003; 9: 921-927Crossref PubMed Scopus (645) Google Scholar, Screaton et al., 2015Screaton G. Mongkolsapaya J. Yacoub S. Roberts C. New insights into the immunopathology and control of dengue virus infection.Nat. Rev. Immunol. 2015; 15: 745-759Crossref PubMed Scopus (236) Google Scholar). Multiple lineages of CD4+ T cells have been shown to contribute to protection via their capacity to produce pro-inflammatory cytokines and support the maturation of the antibody response. DENV-reactive cytotoxic CD4+ T cells were recently demonstrated in humans, particularly those with a history of multiple infections (Weiskopf et al., 2015Weiskopf D. Bangs D.J. Sidney J. Kolla R.V. De Silva A.D. de Silva A.M. Crotty S. Peters B. Sette A. Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity.Proc. Natl. Acad. Sci. USA. 2015; 112: E4256-E4263Crossref PubMed Scopus (192) Google Scholar). That these cells were commonly restricted to a protective HLA allele suggests a role for effector CD4+ T cells in protection that merits further study. A role for γδ T cells and NK cells in flavivirus immunity has also been proposed (Wang and Welte, 2013Wang T. Welte T. Role of natural killer and Gamma-delta T cells in West Nile virus infection.Viruses. 2013; 5: 2298-2310Crossref PubMed Scopus (27) Google Scholar). A recent study of four ZIKV-immune subjects detected ZIKV NS1- and E-reactive memory CD4+ T cells with little capacity to cross-react with DENV (Stettler et al., 2016Stettler K. Beltramello M. Espinosa D.A. Graham V. Cassotta A. Bianchi S. Vanzetta F. Minola A. Jaconi S. Mele F. et al.Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection.Science. 2016; 353: 823-826Crossref PubMed Scopus (554) Google Scholar), but the extent of cross-reactivity with other flavivirus T cell epitopes and their potential role in pathogenesis will require more extensive studies. The antigenic structure of ZIKV is similar to other flaviviruses, as predicted by the considerable conservation of the E protein at the amino acid level and early serological studies (Fagbami et al., 1987Fagbami A.H. Halstead S.B. Marchette N.J. Larsen K. Cross-infection enhancement among African flaviviruses by immune mouse ascitic fluids.Cytobios. 1987; 49: 49-55PubMed Google Scholar). Studies of other flaviviruses demonstrate that the structural proteins of the virion (prM and E) and the secreted non-structural protein 1 (NS1) are targeted frequently by antibodies (Heinz and Stiasny, 2012Heinz F.X. Stiasny K. Flaviviruses and their antigenic structure.J. Clin. Virol. 2012; 55: 289-295Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, Muller and Young, 2013Muller D.A. Young P.R. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker.Antiviral Res. 2013; 98: 192-208Crossref PubMed Scopus (343) Google Scholar). Analysis of monoclonal antibodies (mAbs) from ZIKV-infected humans (Stettler et al., 2016Stettler K. Beltramello M. Espinosa D.A. Graham V. Cassotta A. Bianchi S. Vanzetta F. Minola A. Jaconi S. Mele F. et al.Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection.Science. 2016; 353: 823-826Crossref PubMed Scopus (554) Google Scholar) and mice (Zhao et al., 2016Zhao H. Fernandez E. Dowd K.A. Speer S.D. Platt D.J. Gorman M.J. Govero J. Nelson C.A. Pierson T.C. Diamond M.S. Fremont D.H. Structural basis of zika virus-specific antibody protection.Cell. 2016; 166: 1016-1027Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar) indicates that this is also true for ZIKV, although additional mapping and structural studies are required. ZIKV-specific antibodies bind TS epitopes unique to ZIKV or to CR epitopes shared among flaviviruses and may contribute to protection via their capacity to directly neutralize infection or via effector functions mediated by the Fc portion of the heavy chain. While the functional properties of antibodies may vary considerably, both TS and CR antibodies may potently neutralize infection (Stettler et al., 2016Stettler K. Beltramello M. Espinosa D.A. Graham V. Cassotta A. Bianchi S. Vanzetta F. Minola A. Jaconi S. Mele F. et al.Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection.Science. 2016; 353: 823-826Crossref PubMed Scopus (554) Google Scholar). Epitope accessibility on the intact virion is a key determinant of neutralization potency (Dowd and Pierson, 2011Dowd K.A. Pierson T.C. Antibody-mediated neutralization of flaviviruses: a reductionist view.Virology. 2011; 411: 306-315Crossref PubMed Scopus (139) Google Scholar). The neutralization potency of recently described E-DIII-reactive murine mAbs correlated well with the predicted exposure of their epitopes on the mature virion. As observed with WNV-specific mAbs (Nybakken et al., 2005Nybakken G.E. Oliphant T. Johnson S. Burke S. Diamond M.S. Fremont D.H. Structural basis of West Nile virus neutralization by a therapeutic antibody.Nature. 2005; 437: 764-769Crossref PubMed Scopus (297) Google Scholar), antibodies that recognize an accessible epitope on the lateral ridge of E-DIII potently neutralize infection in vitro at a post-attachment step and are protective in vivo (Zhao et al., 2016Zhao H. Fernandez E. Dowd K.A. Speer S.D. Platt D.J. Gorman M.J. Govero J. Nelson C.A. Pierson T.C. Diamond M.S. Fremont D.H. Structural basis of zika virus-specific antibody protection.Cell. 2016; 166: 1016-1027Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). In contrast, antibodies that bind the highly conserved E-DII fusion loop have incomplete neutralizing activity consistent with the limited accessibility of this structure on the mature virion (Barba-Spaeth et al., 2016Barba-Spaeth G. Dejnirattisai W. Rouvinski A. Vaney M.C. Medits I. Sharma A. Simon-Lorière E. Sakuntabhai A. Cao-Lormeau V.M. 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