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HIV/AIDS vaccine candidates based on replication-competent recombinant poxvirus NYVAC-C-KC expressing trimeric gp140 and Gag-derived VLPs or lacking the viral molecule B19 that inhibits type I interferon activate relevant HIV-1-specific B and T cell immune functions in non-human primates.

HIV/AIDS vaccine candidates based on replication-competent recombinant poxvirus NYVAC-C-KC expressing trimeric gp140 and Gag-derived VLPs or lacking the viral molecule B19 that inhibits type I interferon activate relevant HIV-1-specific B and T cell immune functions in non-human primates.
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García-Arriaza J, Perdiguero B, Heeney JL, Seaman MS, Montefiori DC, Yates NL, Tomaras GD, Ferrari G, Foulds KE, Roederer M, Self SG, Borate B, Gottardo R, Phogat S, Tartaglia J, Barnett SW, Burke B, Cristillo AD, Weiss DE, Lee C, Kibler KV, Jacobs BL, Wagner R, Ding S, Pantaleo G, Esteban M,


García-Arriaza J, Perdiguero B, Heeney JL, Seaman MS, Montefiori DC, Yates NL, Tomaras GD, Ferrari G, Foulds KE, Roederer M, Self SG, Borate B, Gottardo R, Phogat S, Tartaglia J, Barnett SW, Burke B, Cristillo AD, Weiss DE, Lee C, Kibler KV, Jacobs BL, Wagner R, Ding S, Pantaleo G, Esteban M, (click to view)

García-Arriaza J, Perdiguero B, Heeney JL, Seaman MS, Montefiori DC, Yates NL, Tomaras GD, Ferrari G, Foulds KE, Roederer M, Self SG, Borate B, Gottardo R, Phogat S, Tartaglia J, Barnett SW, Burke B, Cristillo AD, Weiss DE, Lee C, Kibler KV, Jacobs BL, Wagner R, Ding S, Pantaleo G, Esteban M,

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Journal of virology 2017 02 08() pii 10.1128/JVI.02182-16

Abstract

The non-replicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120), Gag-Pol-Nef antigens (NYVAC-C) showed in phase I clinical trials limited immunogenicity. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4(+) and CD8(+) T cells, here we compared the HIV-1-specific immunogenicity elicited in non-human primates immunized with two replicating NYVAC vectors that have been modified by the insertion of K1L and C7L vaccinia viral host-range genes and express clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4), and booster doses with NYVAC-C-KC vectors plus clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced an enhanced and similar HIV-1-specific CD4(+) and CD8(+) T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4(+) and CD8(+) T cells, induction of some cytokines and in the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions.IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia B19 protein, an inhibitor of type I interferon response. Immunization of non-human primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited a high level of T cell and humoral immune responses, with the vector containing the deletion in B19R inducing a trend to higher magnitude of CD4(+) and CD8(+) T cells and neutralization of some HIV-1 strains. These poxvirus vectors could be considered as HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

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