Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs- HSV vectors for dendritic cell-mediated immunotherapy.
Herpes simplex virus (HSV) infects dendritic cells (DC) efficiently but with minimal replication. HSV, therefore, appears to have evolved the ability to enter DC even though they are nonpermissive for virus growth. This provides a potential utility for HSV in delivering genes to DC for vaccination purposes and also suggests that the life cycle of HSV usually includes the infection of DC. However, DC infected with HSV usually lose the ability to become activated following infection (M. Salio, M. Cella, M. Suter, and A. Lanzavecchia, Eur. J. Immunol. 29:3245-3253, 1999; M. Kruse, O. Rosorius, F. Kratzer, G. Stelz, C. Kuhnt, G. Schuler, J. Hauber, and A. Steinkasserer, J. Virol. 74:7127-7136, 2000). We report that for DC to retain the ability to become activated following HSV infection, the virion host shutoff protein (vhs) must be deleted. vhs usually functions to destabilize mRNA in favor of the production of HSV proteins in permissive cells. We have found that it also plays a key role in the inactivation of DC and is therefore likely to be important for immune evasion by the virus. Here, vhs would be anticipated to prevent DC activation in the early stages of infection of an individual with HSV, reducing the induction of cellular immune responses and thus preventing virus clearance during repeated cycles of virus latency and reactivation. Based on this information, replication-incompetent HSV vectors with vhs deleted which allow activation of DC and the induction of specific T-cell responses to delivered antigens have been constructed. These responses are greater than if DC are loaded with antigen by incubation with recombinant protein.
Samady
Laila
L
Department of Immunology and Molecular Pathology, University College London, London W1P 6DB. BioVex Ltd., Oxford OX14 4RX, United Kingdom.
Costigliola
Emanuela
E
MacCormac
Luci
L
McGrath
Yvonne
Y
Cleverley
Steve
S
Lilley
Caroline E
CE
Smith
Jill
J
Latchman
David S
DS
Chain
Benny
B
Coffin
Robert S
RS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D017353:Gene Deletion; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D012260:Ribonucleases; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
C050678:IE1 protein, Human herpesvirus 1; D017874:Immediate-Early Proteins; D014764:Viral Proteins; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases