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301 Herpes Simplex Virus 2 Recombinants as AIDS Vaccine Vectors
W. T. Lucas1, C. G. Murphy1, R. C. Desrosiers2, G. N. Pavlakis3, and D. M. Knipe*1
1Harvard Med. Sch., Boston, MA, USA; 2New England Regional Primate Res. Ctr., Southborough, MA, USA; and 3NCI-FCRDC, Frederick, MD< USA
Background: We have previously constructed herpes simplex virus 1 (HSV-1) recombinants that express SIV env and nef proteins as AIDS vaccine vectors. Rhesus macaques immunized with these vectors developed long-lasting immune responses to the SIV antigens, and 3 of 7 animals were protected from challenge with pathogenic SIVmac239.
Methods: To improve antigen delivery in macaques, we analyzed the ability of various strains of HSV-1 and HSV-2 to replicate in primary rhesus cells. HSV-2 strain 186 was found to replicate far better than the HSV-1 strain chosen for our initial studies. We then tested the levels of env and gag expression from HSV-2 and HSV-1 vectors using wild-type and rev-independent env and gag genes.
Results: Expression of env from rev-independent constructs was approximately 40-fold greater than from our original constructs, and the use of a rev-independent gag gene also resulted in a high level of protein expression. Additionally, we have generated HSV vectors that express a fusion protein consisting of the SIV rev, tat, and a mutant nef protein that cannot down-regulate MHC. Initial results from macaques immunized with the second generation vectors using HSV-2 strain 186 and rev-independent env and gag genes have shown enhanced and durable immune responses from these recombinants.
Conclusions: HSV-2 vectors containing rev-independent SIV env and gag genes show high level expression in rhesus fibroblasts and induce enhanced and durable immune responses in rhesus macaques.
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