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302 Helper Virus-Free Herpes Simplex Virus-1 (HSV-1) Amplicon Vectors Expressing HIV-1 gp120 Elicit Potent Cellular and Humoral Immune Responses
P. K. Hocknell1, R. Wiley1, X. Wang1, W. J. Bowers1, T. G. Evans2, T. Hanke3, H. J. Federoff1, and S. Dewhurst*1
1Univ. of Rochester, NY, USA; 2Univ. of California-Davis, USA; and 3Oxford Univ., UK
Background: HSV-1 infects dendritic cells. Thus, HSV-1 amplicons may elicit potent immune responses to vectored antigens. To test this hypothesis, we constructed an HSV-1 amplicon plasmid encoding codon-optimized HIV-1 gp120 (HSV:gp120) and examined T-cell and antibody responses to helper virus-free amplicon preparations derived from this construct, following injection of packaged amplicons into BALB/c mice.
Methods: Cellular immune responses to gp120 were analyzed by interferon-gamma ELISPOT and cytotoxicity assays (JAM) using a class-I restricted peptide (RGPGRAFVTI). Humoral responses were examined by gp160 ELISA.
Results: We first examined immune responses to a single intramuscular (I.M.) injection of 1 ( 106 infectious units of helper virus-free HSV:gp120 amplicon particles. Potent cellular and humoral responses to gp120 were detected. Follow-up experiments examined the durability of these responses, as well as the effectiveness of different routes of inoculation and different amplicon doses. These studies revealed that gp120-specific T-cell responses persisted at a high level for over 5 months, following a single I.M. inoculation of HSV:gp120. In addition, inoculation of amplicon particles via the tail-base or I.M. routes were found to elicit superior responses, as compared with the intraperitoneal route. Analysis of different amplicon doses is ongoing. Finally, the effect of pre-existing immunity to HSV-1 on immune responses to HSV:gp120 amplicon particles was examined. These experiments revealed that HSV:gp120 amplicon particles elicited strong cellular immune responses, even in mice previously infected with HSV-1.
Conclusions: These findings show that helper-free HSV-1 amplicon particles can elicit strong and long-lasting cellular immune responses to HIV-1 gp120. Furthermore, immune responses to gp120 were successfully elicited even in animals that had pre-existing immunity to HSV-1.
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