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Virological and immunological characterization of novel NYVAC-based HIV/AIDS vaccine candidates expressing clade C trimeric soluble gp140(ZM96) and Gag(ZM96)-Pol-Nef(CN54) as virus-like particles.
- Source :
-
Journal of virology [J Virol] 2015 Jan 15; Vol. 89 (2), pp. 970-88. Date of Electronic Publication: 2014 Oct 29. - Publication Year :
- 2015
-
Abstract
- Unlabelled: The generation of vaccines against HIV/AIDS able to induce long-lasting protective immunity remains a major goal in the HIV field. The modest efficacy (31.2%) against HIV infection observed in the RV144 phase III clinical trial highlighted the need for further improvement of HIV vaccine candidates, formulation, and vaccine regimen. In this study, we have generated two novel NYVAC vectors, expressing HIV-1 clade C gp140(ZM96) (NYVAC-gp140) or Gag(ZM96)-Pol-Nef(CN54) (NYVAC-Gag-Pol-Nef), and defined their virological and immunological characteristics in cultured cells and in mice. The insertion of HIV genes does not affect the replication capacity of NYVAC recombinants in primary chicken embryo fibroblast cells, HIV sequences remain stable after multiple passages, and HIV antigens are correctly expressed and released from cells, with Env as a trimer (NYVAC-gp140), while in NYVAC-Gag-Pol-Nef-infected cells Gag-induced virus-like particles (VLPs) are abundant. Electron microscopy revealed that VLPs accumulated with time at the cell surface, with no interference with NYVAC morphogenesis. Both vectors trigger specific innate responses in human cells and show an attenuation profile in immunocompromised adult BALB/c and newborn CD1 mice after intracranial inoculation. Analysis of the immune responses elicited in mice after homologous NYVAC prime/NYVAC boost immunization shows that recombinant viruses induced polyfunctional Env-specific CD4 or Gag-specific CD8 T cell responses. Antibody responses against gp140 and p17/p24 were elicited. Our findings showed important insights into virus-host cell interactions of NYVAC vectors expressing HIV antigens, with the activation of specific immune parameters which will help to unravel potential correlates of protection against HIV in human clinical trials with these vectors.<br />Importance: We have generated two novel NYVAC-based HIV vaccine candidates expressing HIV-1 clade C trimeric soluble gp140 (ZM96) and Gag(ZM96)-Pol-Nef(CN54) as VLPs. These vectors are stable and express high levels of both HIV-1 antigens. Gag-induced VLPs do not interfere with NYVAC morphogenesis, are highly attenuated in immunocompromised and newborn mice after intracranial inoculation, trigger specific innate immune responses in human cells, and activate T (Env-specific CD4 and Gag-specific CD8) and B cell immune responses to the HIV antigens, leading to high antibody titers against gp140. For these reasons, these vectors can be considered vaccine candidates against HIV/AIDS and currently are being tested in macaques and humans.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- AIDS Vaccines administration & dosage
AIDS Vaccines genetics
Animals
CD8-Positive T-Lymphocytes immunology
Cells, Cultured
Chickens
HIV Antibodies blood
Mice
Microscopy, Electron, Transmission
Vaccines, Virus-Like Particle administration & dosage
Vaccines, Virus-Like Particle genetics
Vaccines, Virus-Like Particle ultrastructure
env Gene Products, Human Immunodeficiency Virus genetics
gag Gene Products, Human Immunodeficiency Virus genetics
nef Gene Products, Human Immunodeficiency Virus genetics
AIDS Vaccines immunology
Vaccination methods
Vaccines, Virus-Like Particle immunology
env Gene Products, Human Immunodeficiency Virus immunology
gag Gene Products, Human Immunodeficiency Virus immunology
nef Gene Products, Human Immunodeficiency Virus immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 89
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 25355891
- Full Text :
- https://doi.org/10.1128/JVI.02469-14