Alphavirus replicon particles as candidate HIV vaccines

Nancy L. Davis, Ande West, Elizabeth Reap, Gene MacDonald, Martha Collier, Sergey Dryga, Maureen Maughan, Mary Connell, Chris Walker, Kathryn McGrath, Chad Cecil, Li Hua Ping, Jeff Frelinger, Robert Olmsted, Paula Keith, Ronald Swanstrom, Carolyn Williamson, Philip Johnson, David Montefiori, Robert E. Johnston

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Replicon particles based on Venezuelan equine encephalitis virus (VEE) contain a self-replicating RNA encoding the VEE replicase proteins and expressing a gene of interest in place of the viral structural protein genes. Structural proteins for packaging of replicon RNA into VEE replicon particles (VRPs) are expressed from separate helper RNAs. Aspects of the biology of VEE that are exploited in VRP vaccines include 1) expression of very high levels of immunogen, 2) expression of immunizing proteins in cells in the draining lymph node, and 3) the ability to induce mucosal immunity from a parental inoculation. Results of experiments with VRPs expressing green fluorescent protein or influenza virus hemagglutinin (HA) demonstrated that specific mutations in the VRP envelope glycoproteins affect both targeting in the draining lymph node and efficiency of the immune response in mice. VRPs expressing either the matrix-capsid portion of Gag, the full-length envelope gp160, or the secreted gp140 of cloned SIV sm H-4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIV sm H-4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIV sm E660 was given at 5 months. A vaccine effect was seen in reduced peak virus loads, reduced virus loads both at set point and at 41 weeks postchallenge, and preserved or increased CD4 counts compared to controls. A candidate VRP HIV vaccine expressing Clade C Gag contains a sequence that is very close to the South African Clade C consensus and was selected from a recent seroconverter in the Durban cohort to represent currently circulating genotypes in South Africa. A GMP lot of this vaccine has been manufactured and tested for a phase I trial in the first months of 2002.

Original languageEnglish (US)
Pages (from-to)209-211
Number of pages3
JournalIUBMB Life
Volume53
Issue number4-5
DOIs
StatePublished - Jul 16 2002
Externally publishedYes

Keywords

  • Dendritic cell targeting in vivo
  • Mucosal SIV challenge in macaques
  • SIV sm E660 intrarectal challenge
  • Venezuelan equine encephalitis virus replicon particles

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Davis, N. L., West, A., Reap, E., MacDonald, G., Collier, M., Dryga, S., Maughan, M., Connell, M., Walker, C., McGrath, K., Cecil, C., Ping, L. H., Frelinger, J., Olmsted, R., Keith, P., Swanstrom, R., Williamson, C., Johnson, P., Montefiori, D., & Johnston, R. E. (2002). Alphavirus replicon particles as candidate HIV vaccines. IUBMB Life, 53(4-5), 209-211. https://doi.org/10.1080/15216540212657