Early reports on administration to animals of AAV vectors expressing some neoantigenic transgenes demonstrated the long-term durability of transgene expression in the muscle and showed that the use of AAV vectors did not result necessarily in an immune response against the vector-encoded transgene (54,55,287,288). However, other studies in mice showed that under certain conditions both humoral and antigen-specific T cell responses to the transgene protein could be observed. Production of these immune responses probably depends on several parameters that include the nature of the neoantigen and its level of expression and localization within transduced cells, the mouse strain used, and the vector dose. Transgene-specific immune responses have been observed in mice following administration of AAV vectors expressing genes encoding Escherichia coli p-galactosidase (203,289,290), ovalbumin (199), HSV-2 glycoproteins B (gB) and D (gD) (204), influenza virus hemagglutinin, and HIV-1 Env (290-292), human alpha-1-antitrypsin (97), and clotting factor IX (206).

The ability to elicit immune responses implies that there is no general mechanism by which AAV blunts the immune system. Although the mechanism of antigen presentation following administration of recombinant AAV vectors to the muscle is not clear, one report suggests that activation of T cells in the draining lymph nodes occurs exclusively through cross-presentation by antigen-presenting cells rather than by direct transduction of dendritic cells (DCs) (289). Whether cross-presentation is a phenomena occurring for all transgenes in the context of recombinant AAV vectors is unknown, but it suggests a possible role for these vectors as vehicles for prophylactic or therapeutic vaccines. For example, one study demonstrated that a recombinant AAV vector expressing a secreted HSV-2 gB led to the activation of gB-specific CTL, which were most likely activated via cross-presentation of the secreted protein by DC (195). In contrast, mice injected intramuscularly with an AAV vector expressing ovalbumin developed a robust humoral response to the transgene product but only a minimal ovalbumin-specific CTL response (199).

The use of AAV to stimulate an antihuman immunodeficiency virus (HIV-1) response has been tested in mice. A single, intramuscular injection of an AAV vector encoding the HIV-1 env, tat, and rev genes (AAV-HIV) induced robust, long-term production of HIV-1-specific serum IgG and MHC class I-restricted CTL activity (292). HIV-specific cell-mediated immunity was enhanced strongly by coadministration with an AAV vector encoding interleukin-12, whereas boosting with AAV-HIV resulted in rapid and strong HIV-1-spe-cific humoral responses. When AAV-HIV was administered orally, a strong systemic and regional HIV-specific humoral immunity and MHC class I-restricted CTL response was induced, which significantly reduced viral load after intrarectal challenge with a recombinant vaccinia virus expressing the HIV-1 env gene (293).

In rhesus macaques, a single-dose, intramuscular administration of an AAV vector expressing the simian immunodeficiency virus (SIV) major structural genes resulted in long-term CD8 +, antigen-specific CTL responses against multiple SIV protein epitopes that were similar to responses observed in monkeys directly infected with pathogenic SIV. Neutralizing antibody responses were also robust and persisted for more than 1 year. More recent studies have begun to test the efficacy of AAV-SIV vaccines in an SIV-macaque challenge model. The data so far strongly suggest that immunized macaques have significantly lower virus burden at peak (2 weeks) and set point (10 weeks) after intravenous challenge with SIV than do mock-vaccinated control animals (294).

AAV vectors are also being examined as potential vehicles for tumor vaccines. In one study, an AAV-based tumor vaccine was developed by constructing a chimeric gene containing a human papillomavirus (HPV) type 16 E7 CTL epitope fused to a heat shock protein. When administered intramuscularly, this vaccine was able to eliminate tumor cells in synge-neic animals in a manner that was dependent on CD4+ and CD8+ cells. This suggests that vaccination with this gene could be a therapeutic treatment for cervical cancer containing HPV-16 E7 (295)

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