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Title: Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives

Abstract

The exceptionally high virulence of the West Nile NY99 strain makes its suitability in the development of a live WN vaccine uncertain. The aim of this study is to investigate the immunogenicity of noninfectious virus derivatives carrying pseudolethal mutations, which preclude virion formation without affecting preceding steps of the viral infectious cycle. When administered using DNA immunization, such constructs initiate an infectious cycle but cannot lead to a viremia. While the magnitude of the immune response to a noninfectious replication-competent construct was lower than that of virus or infectious DNA, its overall quality and the protective effect were similar. In contrast, a nonreplicating construct of similar length induced only a marginally detectable immune response in the dose range used. Thus, replication-competent noninfectious constructs derived from infectious DNA may offer an advantageous combination of the safety of noninfectious formulations with the quality of the immune response characteristic of infectious vaccines.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [2]
  1. Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045 (United States)
  2. Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045 (United States). E-mail: yaximik@ku.edu
Publication Date:
OSTI Identifier:
20850580
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 356; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.virol.2006.07.038; PII: S0042-6822(06)00517-4; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; DNA; IMMUNE REACTIONS; MICE; MUTATIONS; VACCINES; VIRULENCE; VIRUSES

Citation Formats

Seregin, Alexey, Nistler, Ryan, Borisevich, Victoria, Yamshchikov, Galina, Chaporgina, Elena, Kwok, Chun Wai, and Yamshchikov, Vladimir. Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives. United States: N. p., 2006. Web. doi:10.1016/j.virol.2006.07.038.
Seregin, Alexey, Nistler, Ryan, Borisevich, Victoria, Yamshchikov, Galina, Chaporgina, Elena, Kwok, Chun Wai, & Yamshchikov, Vladimir. Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives. United States. doi:10.1016/j.virol.2006.07.038.
Seregin, Alexey, Nistler, Ryan, Borisevich, Victoria, Yamshchikov, Galina, Chaporgina, Elena, Kwok, Chun Wai, and Yamshchikov, Vladimir. Wed . "Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives". United States. doi:10.1016/j.virol.2006.07.038.
@article{osti_20850580,
title = {Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives},
author = {Seregin, Alexey and Nistler, Ryan and Borisevich, Victoria and Yamshchikov, Galina and Chaporgina, Elena and Kwok, Chun Wai and Yamshchikov, Vladimir},
abstractNote = {The exceptionally high virulence of the West Nile NY99 strain makes its suitability in the development of a live WN vaccine uncertain. The aim of this study is to investigate the immunogenicity of noninfectious virus derivatives carrying pseudolethal mutations, which preclude virion formation without affecting preceding steps of the viral infectious cycle. When administered using DNA immunization, such constructs initiate an infectious cycle but cannot lead to a viremia. While the magnitude of the immune response to a noninfectious replication-competent construct was lower than that of virus or infectious DNA, its overall quality and the protective effect were similar. In contrast, a nonreplicating construct of similar length induced only a marginally detectable immune response in the dose range used. Thus, replication-competent noninfectious constructs derived from infectious DNA may offer an advantageous combination of the safety of noninfectious formulations with the quality of the immune response characteristic of infectious vaccines.},
doi = {10.1016/j.virol.2006.07.038},
journal = {Virology},
number = 1-2,
volume = 356,
place = {United States},
year = {Wed Dec 20 00:00:00 EST 2006},
month = {Wed Dec 20 00:00:00 EST 2006}
}
  • West Nile (Sarafend) virus [WN(S)V] has been shown to egress by budding at the plasma membrane of infected cells. However, the region influencing this mode of virus release remains to be deciphered. In this study, we have constructed three chimeric clones in which specific regions of West Nile (Wengler) virus [WN(W)V] were replaced for the corresponding regions of WN(S)V in the full-length infectious clone of WN(S)V to define the region responsible for the cis-mode of WN(S)V maturation. The WN(W)V matures by the trans-mode. All of the resulting chimeric viruses were found to be infective. Transmission electron microscopy analyses performed inmore » Vero cells infected with these chimeric viruses disclosed that the 5' end of the WN(S)V genome plays a major role in influencing the process of maturation at the plasma membrane.« less
  • Direct attenuation of West Nile (WN) virus strain NY99 for the purpose of vaccine development is not feasible due to its high virulence and pathogenicity. Instead, we created highly attenuated chimeric virus W1806 with the serological identity of NY99. To further attenuate W1806, we investigated effects of mutations found in Japanese encephalitis virus vaccine SA14-14-2. WN viruses carrying all attenuating mutations lost infectivity in mammalian, but not in mosquito cells. No single reversion restored infectivity in mammalian cells, although increased infectivity in mosquito cells was observed. To identify a subset of mutations suitable for further attenuation of W1806, we analyzedmore » effects of E{sub 138}K and K{sub 279}M changes on virulence, growth properties, and immunogenicity of derivatized W956, from which chimeric W1806 inherited its biological properties and attenuation profile. Despite strong dominant attenuating effect, introduction of only two mutations was not sufficient for attenuating W1806 to the safety level acceptable for human use. - Highlights: • Further attenuation of a WN vaccine precursor is outlined. • Effect of SA14-14-2 attenuating mutations is tested. • Mechanism of attenuation is proposed and illustrated. • The need for additional attenuating mutations is justified.« less
  • Abstract not provided.
  • In transplanted SV 40 hamster tumors spontaneous development of infectious virus occurs only in an occasional cell out of many millions that carry the viral genome in a noninfectious state, more frequently in older tumors than in those that have grown for less than four weeks No infectious nucleic acid capable of producing complete SV 40 virus in susceptible Cercopithecus cells was found in the tumor cells. Induction of a greater frequency of synthesis of infectious virus in tumor cells has now been demonstrated by three procedures - propagation of the tumor cells in vitro --more frequently in rolled thanmore » in stationary cultures, although the latter are more suitable for optimum growth of the tumor cells; by association of viable tumor cells with susceptible cells under certain conditions of contact which do not require either proliferation or persistence of the tumor cells; by an x-ray effect on a very small proportion of the tumor cells. SV 40 tumors transplanted in newborn hamsters yield a satisfactory complement-fixing antigen which reacts specifically only with the sera of hamsters bearing SV 40 tumors but not with sera of hamsters bearing either polyoma tumors or Fortner fibrosarcoma no. 3 tumors. Hamsters bearing transplanted SV 40 tumors for four weeks or longer also develop complement-fixing antibody for an antigen present in BS-C -1 Cercopithecus cells infected with SV 40 virus, although these sera contain no neutralizing antibodies. Adult hamsters inoculated with large doses of SV 46 virus, which induces a specific resistence to transplantation of SV 40 tumor cells, possess no antibody for the antigen in the tumor or the antigen in the SV 40 virus-infected Cercopithecus cells. The available data are not sufffcient for a conclusion that the noninfectious viral genome in the SV 40 tumor cells carries information for the synthesis of at least a part of the viral antigen, although it gives rise to antigens that are specific for the SV 40 virus. The data on induction of infectious virus in the SV 40 tumor cells provide a new approach to the search for etiologically significant, dormant viruses in human cancers.« less