Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques

Lucas Gonzalez-Nieto, Isabelle M. Castro, Georg F. Bischof, Young C. Shin, Michael J. Ricciardi, Varian K. Bailey, Christine M. Dang, Nuria Pedreño-Lopez, Diogo M. Magnani, Keisuke Ejima, David B. Allison, Hwi Min Gil, David T. Evans, Eva G. Rakasz, Jeffrey D. Lifson, Ronald C. Desrosiers, Mauricio A. Martins

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Abstract

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)-a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.

Original languageEnglish (US)
Article numbere1008015
JournalPLoS pathogens
Volume15
Issue number9
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Gonzalez-Nieto, L., Castro, I. M., Bischof, G. F., Shin, Y. C., Ricciardi, M. J., Bailey, V. K., Dang, C. M., Pedreño-Lopez, N., Magnani, D. M., Ejima, K., Allison, D. B., Gil, H. M., Evans, D. T., Rakasz, E. G., Lifson, J. D., Desrosiers, R. C., & Martins, M. A. (2019). Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. PLoS pathogens, 15(9), [e1008015]. https://doi.org/10.1371/journal.ppat.1008015