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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.
- Source :
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Journal of virology [J Virol] 2017 Apr 13; Vol. 91 (9). Date of Electronic Publication: 2017 Apr 13 (Print Publication: 2017). - Publication Year :
- 2017
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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 <superscript>+</superscript> and CD8 <superscript>+</superscript> 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 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 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 <superscript>+</superscript> and CD8 <superscript>+</superscript> 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 <superscript>+</superscript> and CD8 <superscript>+</superscript> 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. 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 virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4 <superscript>+</superscript> and CD8 <superscript>+</superscript> T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.<br /> (Copyright © 2017 American Society for Microbiology.)
- Subjects :
- AIDS Vaccines genetics
Animals
Antibodies, Neutralizing immunology
Antibody-Dependent Cell Cytotoxicity immunology
HIV Antibodies immunology
HIV Antigens immunology
HIV Infections prevention & control
Interferon Type I genetics
Macaca mulatta
Male
Receptors, Interferon genetics
Receptors, Interferon immunology
Vaccination
Vaccinia virus genetics
env Gene Products, Human Immunodeficiency Virus genetics
AIDS Vaccines immunology
Antibodies, Neutralizing blood
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
HIV Antibodies blood
HIV Envelope Protein gp120 immunology
Vaccines, Virus-Like Particle immunology
env Gene Products, Human Immunodeficiency Virus metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 91
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 28179536
- Full Text :
- https://doi.org/10.1128/JVI.02182-16