Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector.
Herpes simplex virus (HSV) recombinants induce durable immune responses in rhesus macaques and mice and have induced partial protection in rhesus macaques against mucosal challenge with virulent simian immunodeficiency virus (SIV). In this study, we evaluated the properties of a new generation HSV vaccine vector, an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes. Because several of the HSV IE genes have been implicated in immune evasion, inactivation of the genes encoding these proteins was expected to result in enhanced immunogenicity. The d106 virus expresses few HSV gene products and shows minimal cytopathic effect in cultured cells. When d106 was inoculated into mice, viral DNA accumulated at high levels in draining lymph nodes, consistent with an ability to transduce dendritic cells and activate their maturation and movement to lymph nodes. A d106 recombinant expressing Escherichia coli beta-galactosidase induced durable beta-gal-specific IgG and CD8(+) T cell responses in naive and HSV-immune mice. Finally, d106-based recombinants have been constructed that express simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein for several days in cultured cells. Thus, d106 shows many of the properties desirable in a vaccine vector: limited expression of HSV gene products and cytopathogenicity, high level expression of transgenes, ability to induce durable immune responses, and an ability to transduce dendritic cells and induce their maturation and migration to lymph nodes.
Watanabe
Daisuke
D
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Brockman
Mark A
MA
Ndung'u
Thumbi
T
Mathews
Lydia
L
Lucas
William T
WT
Murphy
Cynthia G
CG
Felber
Barbara K
BK
Pavlakis
George N
GN
Deluca
Neal A
NA
Knipe
David M
DM
D000818:Animals; D002522:Chlorocebus aethiops; D003673:Defective Viruses / Q000235:genetics*; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D005822:Genetic Vectors / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D022301:Herpes Simplex Virus Vaccines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D011995:Recombination, Genetic; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology; D014709:Vero Cells
D022301:Herpes Simplex Virus Vaccines; D011993:Recombinant Fusion Proteins