High-level expression of glycoprotein D by a dominant-negative HSV-1 virus augments its efficacy as a vaccine against HSV-1 infection.
Using the T-REx (Invitrogen, Carlsbad, CA) gene switch technology, we previously generated a dominant-negative herpes simplex virus (HSV)-1 recombinant, CJ83193, capable of inhibiting its own replication as well as that of wild-type HSV-1 and HSV-2. It has been further demonstrated that CJ83193 is an effective vaccine against HSV-1 infection in a mouse ocular model. To ensure its safety and augment its efficacy, we generated an improved CJ83193-like HSV-1 recombinant, CJ9-gD, which contains a deletion in an HSV-1 essential gene and encodes an extra copy of gene-encoding glycoprotein D (gD) driven by the tetO-bearing human cytomegalovirus major immediate-early promoter. Unlike CJ83193, which exhibits limited plaque-forming capability in Vero cells and expresses little gD in infected cells, CJ9-gD is completely replication defective, yields high-level expression of gD following infection, and cannot establish detectable infection in mouse trigeminal ganglia following intranasal and ocular inoculation. Mice immunized with CJ9-gD produced 3.5-fold higher HSV-1 neutralizing antibody titer than CJ83193-immunized mice, and were completely protected from herpetic ocular disease following corneal challenge with wild-type HSV-1. Moreover, immunization of mice with CJ9-gD elicited a strong HSV-1-specific T-cell response and led to an 80% reduction in latent infection by challenge wild-type HSV-1 compared with the mock-immunized control.
Lu
Zheming
Z
Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Brans
Richard
R
Akhrameyeva
Natali V
NV
Murakami
Nao
N
Xu
Ximing
X
Yao
Feng
F
D000818:Animals; D000914:Antibodies, Viral / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000235:genetics; D016896:Treatment Outcome; D012668:Trigeminal Ganglion / Q000473:pathology / Q000821:virology; D014709:Vero Cells / Q000473:pathology / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D014765:Viral Vaccines / Q000235:genetics / Q000627:therapeutic use*; D014779:Virus Replication / Q000235:genetics
D000914:Antibodies, Viral; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C039447:glycoprotein D, Human herpesvirus 1