IL-12 delivery from recombinant vaccinia virus attenuates the vector and enhances the cellular immune response against HIV-1 Env in a dose-dependent manner.
To develop vaccination strategies against HIV-1 infection aimed to specifically enhance the cell-mediated immunity (CMI), we have engineered vaccinia virus (VV) recombinants expressing HIV-1 Env (rVVenv) and murine IL-12 (rVVlucIL-12) genes or coexpressing both genes (rVVenvIL-12). In mice inoculated with rVVlucIL-12 there is a rapid clearance of the virus, and this correlates with the induction of high levels of IL-12 and IFN-gamma in serum and spleen early after infection. Enzyme-linked immunospot analysis of mice inoculated with rVVlucIL-12, revealed a nearly 2-fold increase in the number of specific anti-VV CD8+ T cells compared with that in mice given control rVV, and the serum Ab response was biased in favor of a Th1 response. An enhancement of about 2-fold in the number of anti-gp160 IFN-gamma-secreting CD8+ T cells was observed in mice inoculated with rVVenvIL-12, when a dose of 1 x 107 PFU/mouse was used, but this enhancement was not observed when mice were given 5 x 107 PFU. This variation with virus dosage was confirmed in mice immunized simultaneously with different multiplicities of rVV expressing singly the env or IL-12 genes. The highest specific CMI was obtained in mice coadministered a low dose (2 x 104 PFU) of rVVlucIL-12 and 1 x 107 PFU of rVVenv. Our findings provide evidence for specific enhancement of the CMI to HIV-1 Env by the differential expression of IL-12 and env genes delivered from VV recombinants. This approach can be of wide vaccination interest as a means to improve immune responses to other Ags.
Gherardi
M M
MM
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Campus Universidad Autónoma, Madrid, Spain.
Ramirez
J C
JC
Rodríguez
D
D
Rodríguez
J R
JR
Sano
G
G
Zavala
F
F
Esteban
M
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D015686:Gene Products, env / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D007111:Immunity, Cellular / Q000235:genetics; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016207:Cytokines; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D018664:Interleukin-12; D007371:Interferon-gamma