Teaching New Tricks to an Old Foe: Murinizing Hepatitis C Virus

Autor: Gisa Gerold, Alexander Ploss, Charles M. Rice
Rok vydání: 2010
Předmět:
Zdroj: PLoS Pathogens
ISSN: 0270-9139
Popis: Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
Author Summary The hepatitis C virus (HCV) infects only humans and chimpanzees, which has hampered development of suitable animal models. The inability of HCV to penetrate non-human cells is primarily due to inefficient usage of non-human CD81 and occludin. In this study we adapted HCV to mouse CD81. Efficient utilization of mouse CD81 is conferred by a combination of three mutations in the viral glycoproteins. These changes also permit entry via rat or hamster CD81, and lower viral dependence on additional HCV entry factors. Strikingly, mouse CD81 adapted HCV glycoproteins mediate entry into mouse cells in the absence of human entry factors. The adaptive mutations are not resident in viral domains implicated in direct CD81 binding. Nevertheless, they enhance binding to human CD81, increase susceptibility to different neutralizing antibodies and facilitate induction of viral cell fusion by low pH. This suggests that structural changes accompanied by exposure of the CD81 binding site and neutralizing epitopes have “unlocked” the viral envelope protein complex facilitating infection through non-human entry factors. These results highlight mechanisms of HCV receptor usage and tropism. They also demonstrate that HCV can be adapted to using non-human host factors, which may ultimately facilitate the development of small animal models.
Databáze: OpenAIRE
Externí odkaz: