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Summary Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals that develop high titers of anti-ZIKV antibodies we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with preexisting reactivity to DENV1 in humans.

The rat zinc-finger antiviral protein (ZAP) was recently identified as a host protein conferring resistance to retroviral infection. We analyzed ZAP's ability to inhibit viruses from other families and found that ZAP potently inhibits the replication of multiple members of the Alphavirus genus within the Togaviridae, including Sindbis virus, Semliki Forest virus, Ross River virus, and Venezuelan equine encephalitis virus. However, expression of ZAP did not induce a broad-spectrum antiviral state as some viruses, including vesicular stomatitis virus, poliovirus, yellow fever virus, and herpes simplex virus type 1, replicated to normal levels in ZAP-expressing cells. We determined that ZAP expression inhibits Sindbis virus replication after virus penetration and entry, but before the amplification of newly synthesized plus strand genomic RNA. Using a temperature-sensitive Sindbis virus mutant expressing luciferase, we further showed that translation of incoming viral RNA is blocked by ZAP expression. Elucidation of the antiviral mechanism by which ZAP inhibits Sindbis virus translation may lead to the development of agents with broad activity against alphaviruses.A previously unknown rat protein, designated zinc-finger antiviral protein (ZAP), was recently found to exhibit antiviral activity against Moloney murine leukemia virus (MMLV), a member of the Retroviridae. When challenged with an ecotropic MMLV carrying a luciferase reporter, cells expressing ZAP expressed 30 times less luciferase than did control cells. Expression of either the full-length rat ZAP or the aminoterminal one-third fused to the product of the zeocin resistance gene (NZAP-Zeo) was inhibitory, and the mechanism of the block was found to be a dramatic and specific loss of viral mRNAs from the cytoplasm, but not the nuclei, of cells (5). In our effort to better understand virus-host interactions, we tested ZAP's ability to inhibit infection by other viruses. Our studies indicate that, in addition to inhibiting MMLV replication, ZAP's range of targets also includes multiple members of the Alphavirus genus of the Togaviridae.Alphaviruses cause significant morbidity and mortality worldwide (reviewed in reference 7). The broad host range for these viruses includes vertebrates and invertebrates, with arthropods being the usual vectors of transmission to mammals. Infection with Sindbis virus (SIN), the type alphavirus, can lead to a painful polyarthritis, while disease caused by Venezuelan equine encephalitis virus (VEE) ranges from a mild influenzatype illness to fatal encephalitis. Alphaviruses are small, enveloped RNA viruses with an icosahedral nucleocapsid (reviewed in reference 22). The SIN genome consists of a single, capped, positive-sense RNA molecule of approximately 11.7 kb and contains a 5Ј untranslated region (UTR) as well as a 3Ј UTR and a poly(A) tail. The 5Ј-terminal two-thirds of the genomic 49S RNA is directly translated to produce the four nonstructural proteins (nsPs), while the structural proteins are encoded by a subgenomic 26S ...

Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.

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