Vaccinia virus recombinants expressing chimeric proteins of human immunodeficiency virus and gamma interferon are attenuated for nude mice.

Abstract

We have developed a method for attenuating vaccinia virus recombinants by expressing a fusion protein of a lymphokine and an immunogen. Chimeric genes were constructed that coded for y interferon (IFN-y) and structural proteins of the human immunodeficiency virus type 1 (HIV-1).In this study, we describe the biological and immunological properties of vaccinia virus recombinants expressing chimeric genes of murine or human IFN-y with glycoprotein gpl20, gag, and a fragment of gp4l. Afl fusion proteins retained the antigenic characteristics of both IFN-y and HIV as shown by immunoblot analysis. However, the antiviral activity of IFN-y could be demonstrated only for the IUFN-,y-gag fusion protein.In contrast, the attenuating activity of IFN-yfor nude mice was retained by all of the recombinants, albeit at various rates. Unlike the antiviral activity, the attenuating activity of IFN-y was not species specific. Implications for the development of attenuated live recombinant vaccines for AIDS are discussed.

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

“…The HuIFNγ gene was in- cluded to enhance safety for individuals vaccinating livestock. In our previous studies, we have shown that replication-competent VACV can be attenuated by more than a million-fold by this method (34,35,38).…”

“…Our laboratory has extensive experience in developing rVACVs for the control of a number of human and animal diseases (17,18,22,24,34,35). Multiple approaches have been used to enhance the safety of poxviruses, including deletion or insertional inactivation of genes that enhance virulence, expression of cytokines, development of replication-deficient VACVs, such as MVA and NYVAC, or host cell-restricted vectors, such as canarypox and fowlpox (39)(40)(41)(42).…”

“…Replication-deficient vectors, however, are difficult to propagate to high titers and are often poorly immunogenic, especially when used as heterologous vaccine vectors. To address these issues, we have developed a number of rVACV with deletions in virulence and immunomodulating genes and expressing cytokines (34,35,38). These rVACVs are highly attenuated, immunogenic, and replicate to high titers in vitro.…”

Preferential Replication of Vaccinia Virus in the Ovaries is Independent of Immune Regulation Through IL-10 and TGF-β

“…3d). As experiments in mice have demonstrated that the forced expression of IFN-c can strongly enhance VACV clearance and promote immune responses (20)(21)(22), this suggested that concomitant induction of IL-10 and/or TGF-b might limit the activity of CD8 T-cell-derived IFN-c, which would antagonize the clearance of the virus from the ovary.…”

Poxvirus-Based Vaccine Platforms: Getting at Those Hard-To-Reach Places

“…In mice, these complexes have been found to enhance envelope-specific cellular and humoral immune responses [43]. In addition, several cytokines, such as IL-15 and IFN-γ, have been incorporated into anti-HIV poxvirus vaccines in an attempt to promote TH1-specific responses and induce memory [44,45].…”