buy Tenofovir Disoproxil The in vivo replication kinetics of

The in vivo replication kinetics of ZIKV in natural human infections remains elusive. The neurotropic nature of ZIKV has been evidenced by mouse experiments (Cugola et al., 2016) and clinical investigations (Carteaux et al., 2016). Our necropsy data from two animals demonstrate that the contemporary ZIKV strain can invade and replicate within the CNS system of macaques following s.c. inoculation, despite no neurological signs developed. However, the viral loads in CNS tissues are quite lower than other major target organs. In our experiments, few viral RNA or proteins was detected in the genital organs except buy Tenofovir Disoproxil and testis on day 5 p.i. (Fig. 3), and no obvious pathological changes were seen in these organs. We are not able to collected semen samples due to technical reasons. High levels of positive- and negative-strand ZIKV RNAs were detectable in potential target organs at different stages of infection (day 5 or day 10 p.i.), and infectious ZIKV can be directly recovered from selected organs with high viral load. Unexpectedly, our results suggest that the parotid gland, besides intestinal tracts and spleen, represents potential major target tissues of ZIKV. The parotid gland serves as the viral replication site and exit portal for the highly neurotropic rabies virus into saliva (Boonsriroj et al., 2016). Although the biological importance of ZIKV replication in parotid gland remains unknown, a probable connection to the persistent excretion of viral RNA in saliva is highly suspected. Since our results are only from two animals dissected at different time, the in vivo kinetic of ZIKV replication deserves extensive investigation in the future. In addition, the non-human primate model described here could be used to evaluate ZIKV vaccine or antiviral candidates. The reduction of body temperature increase, viremia, and excretion of viral RNA in various body fluids upon ZIKV infection could serve as endpoints for protection in vaccine or antiviral efficacy test. A large panel of ZIKV vaccine candidates is being developed in an expedited manner by using existing flavivirus vaccine platforms, e.g., chimeric live attenuated strains, killed virons, recombinant subunit viral proteins, subviral particles, or DNA plasmids, and clinical trials are highly expected in the near future (Weaver et al., 2016). The non-human primate model described here could serve as a gatekeeper for advancing vaccine candidates into clinics. Any candidate ZIKV vaccine is supposed to induce protective immune response and confer protection against contemporary ZIKV strain challenge in non-human primate model.
Competing Interests
Author Contributions
Acknowledgments & Funding We thank the veterinarians from Laboratory Animal Center, Academy of Military Medical Science, for their excellent technical support; and Drs. Jing An, Zhiheng Xu, Xia Jia, and Bo Zhang for helpful discussion. This work was supported by the State Key Laboratory of Pathogen and Biosecurity (no. SKLPBS1601), the Guangzhou Science and Technology Program for Public Wellbeing (no. 201508020263, and no. 2014Y2-00550), the Beijing Nova Program (no. 2016110, and no. 2010B041), and the National Key Research and Development Project of China (no. 2016YFD0500304). CFQ was supported by the Excellent Young Scientist Program from the NSFC of China (no. 81522025) and the Newton Advanced Fellowship from the Academy of Medical Sciences, UK and the NSFC of China (No. 81661130162). PYS was partially supported by NIH grant AI087856, and a grant from Pan-American Health Organization and World Health Organization. All authors declared no conflicts of interest.
Introduction With 390 million people infected every year, dengue is now a global concern [1]. Over the past decades, the virus has spread from South East Asia to regions across the world with climates favorable for breeding of the transmitting vector, the Aedes or “tiger” mosquito. In Singapore, where this study was conducted, dengue is endemic and approximately half the adult population is seropositive, providing an excellent opportunity to compare primary and secondary (memory) responses. The dengue virus (DENV) complex comprises four antigenically related viruses (DENV-1 to 4) from the flavivirus family, and infection with one serotype generates both serotype-specific and cross-reactive antibodies [2]. During heterotypic re-infection, the antibody response is dominated by cross-reactive antibodies binding to regions in the viral proteins that are conserved across all serotypes [3,4]. At the same time, neutralizing antibodies against the serotype of the previous infection are often amplified more efficiently than antibodies against the new infecting serotype, which can result in increased disease severity when an individual is re-infected with a different serotype, a phenomenon previously described as original antigenic sin [5,6].