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

Juan García-Arriaza, Beatriz Perdiguero, Jonathan L. Heeney, Michael S. Seaman, David C. Montefiori, Nicole L. Yates, Georgia D. Tomaras, Guido Ferrari, Kathryn E. Foulds, Mario Roederer, Steven G. Self, Bhavesh Borate, Raphael Gottardo, Sanjay Phogat, Jim Tartaglia, Susan W. Barnett, Brian Burke, Anthony D. Cristillo, Deborah E. Weiss, Carter LeeKaren Kibler, Bertram Jacobs, Ralf Wagner, Song Ding, Giuseppe Pantaleo, Mariano Esteban

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. 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 nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gagderived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of 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 the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and 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, the induction of some cytokines, and 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.

Original languageEnglish (US)
Article numbere02182-16
JournalJournal of Virology
Volume91
Issue number9
DOIs
StatePublished - May 1 2017

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Keywords

  • B19R
  • Cellular responses
  • HIV-1
  • Humoral responses
  • Immunogenicity
  • Nonhuman primates
  • NYVAC
  • Poxvirus

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

García-Arriaza, J., Perdiguero, B., Heeney, J. L., Seaman, M. S., Montefiori, D. C., Yates, N. L., Tomaras, G. D., Ferrari, G., Foulds, K. E., Roederer, M., Self, S. G., Borate, B., Gottardo, R., Phogat, S., Tartaglia, J., Barnett, S. W., Burke, B., Cristillo, A. D., Weiss, D. E., ... Esteban, M. (2017). HIV/AIDS vaccine candidates based on replication-competent recombinant poxvirus NYVAC-C-KC expressing trimeric gp140 and Gag-derived virus-like particles or lacking the viral molecule B19 that inhibits type I interferon activate relevant HIV-1-specific B and T cell immune functions in nonhuman primates. Journal of Virology, 91(9), [e02182-16]. https://doi.org/10.1128/JVI.02182-16