Abstract
BackgroundThe highly attenuated vaccinia virus strain NYVAC expressing HIV-1 components has been evaluated as a vaccine candidate in preclinical and clinical trials with encouraging results. We have previously described that the presence of C7L in the NYVAC genome prevents the induction of apoptosis and renders the vector capable of replication in human and murine cell lines while maintaining an attenuated phenotype in mice.Methodology/Principal FindingsIn an effort to improve the immunogenicity of NYVAC, we have developed a novel poxvirus vector by inserting the VACV host-range C7L gene into the genome of NYVAC-B, a recombinant virus that expresses four HIV-1 antigens from clade B (Env, Gag, Pol and Nef) (referred as NYVAC-B-C7L). In the present study, we have compared the in vitro and in vivo behavior of NYVAC-B and NYVAC-B-C7L. In cultured cells, NYVAC-B-C7L expresses higher levels of heterologous antigen than NYVAC-B as determined by Western blot and fluorescent-activated cell sorting to score Gag expressing cells. In a DNA prime/poxvirus boost approach with BALB/c mice, both recombinants elicited robust, broad and multifunctional antigen-specific T-cell responses to the HIV-1 immunogens expressed from the vectors. However, the use of NYVAC-B-C7L as booster significantly enhanced the magnitude of the T cell responses, and induced a more balanced cellular immune response to the HIV-1 antigens in comparison to that elicited in animals boosted with NYVAC-B.Conclusions/SignificanceThese findings demonstrate the possibility to enhance the immunogenicity of the highly attenuated NYVAC vector by the insertion of the host-range gene C7L and suggest the use of this modified vector as an improved vaccine candidate against HIV/AIDS.
Highlights
AIDS is one of the greatest pandemics of our time, affecting the health and the social and economic foundations of countries worldwide
In an effort to further improve the immunogenicity of NYVAC based vaccine candidates against human immunodeficiency virus (HIV)/AIDS, we have generated a new vector by inserting the Vaccinia Virus (VACV) C7L host range gene in the attenuated NYVAC-B recombinant which expresses four HIV-1 antigens from clade B (Env, Gag, Pol and Nef)
Different viral vectors of RNA and DNA origin are being considered as HIV/AIDS vaccine candidates, but to date only the poxvirus vector ALVAC in combination with a purified gp-120 prime boost has shown some efficacy in a phase III clinical trial [6]
Summary
AIDS is one of the greatest pandemics of our time, affecting the health and the social and economic foundations of countries worldwide. Appropriate designed envelope immunogens able to induce broad and potent neutralizing antibodies remained a major goal for vaccine development and vaccines directed to elicit virus specific cellular immune responses have been more readily developed, but their role in protection remains to be established In this regard the recent observations of limited protection against HIV-1 infection, about 31%, in a phase III Thai clinical trial with a combination of a recombinant canarypoxvirus and the protein gp-120, points in the direction that both humoral and cellular immune responses might be needed for protection against HIV/AIDS, the specific T cell and neutralizing antibody responses in the trial were low [6]. We have previously described that the presence of C7L in the NYVAC genome prevents the induction of apoptosis and renders the vector capable of replication in human and murine cell lines while maintaining an attenuated phenotype in mice
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