Alphavirus replicon particles as candidate HIV vaccines.
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 SIVsm H-4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIVsm H-4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIVsm 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.
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA. joiner@med.unc.edu
Nancy L
NL
Davis
Ande
A
West
Elizabeth
E
Reap
Gene
G
MacDonald
Martha
M
Collier
Sergey
S
Dryga
Maureen
M
Maughan
Mary
M
Connell
Chris
C
Walker
Kathryn
K
McGrath
Chad
C
Cecil
Li-Hua
LH
Ping
Jeff
J
Frelinger
Robert
R
Olmsted
Paula
P
Keith
Ronald
R
Swanstrom
Carolyn
C
Williamson
Philip
P
Johnson
David
D
Montefiori
Robert E
RE
Johnston
D016915:AIDS Vaccines / Q000235:genetics*; D000818:Animals; D002986:Clinical Trials as Topic; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D015683:Gene Products, gag / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins; D019302:HIV Envelope Protein gp160 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control*; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D013019:South Africa; D013997:Time Factors
D016915:AIDS Vaccines; C033904:GP 140; D015683:Gene Products, gag; D006023:Glycoproteins; D019302:HIV Envelope Protein gp160; D006388:Hemagglutinins; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins