Lawlor, J

Lawlor, J. the prime. The primary response to an AdC7 vaccine differed from that generated by AAVs in that the peak effector response evolved into populations of Gag-specific T cells expressing high levels of Pseudoginsenoside-F11 cytokines, including IL-2, and with effector memory and central memory phenotypes. A number of mechanisms could be considered to explain the aberrant activation of CD8+ T cells by AAV, including insufficient inflammatory responses, CD4 help, and/or chronic antigen expression and T-cell exhaustion. Interestingly, the B-cell response to AAV-encoded Gag was quite vibrant and easily boosted with AdC7. Pseudoginsenoside-F11 A number of vaccine strategies have been developed for preventing and treating human immunodeficiency virus type 1 (HIV-1)-related diseases. These have ranged from protein adjuvant formulations to inactivated HIV-1 to a variety of genetic vaccines based on DNA and recombinant viruses (5, 15, 24). Unique properties of the HIV-1 envelope have confounded the successful development of a vaccine that elicits long-lasting and broadly cross-reactive neutralizing antibodies (34). More success has been achieved in activating CD8+ T cells against HIV-1 antigens by methods such as recombinant adenovirus vectors (7, 31, 32, 35). Merck has developed vaccines based on human adenovirus serotype 5 that have progressed to phase II clinical trials. These studies have been encouraging in that individuals without significant preexisting immunity to the vector have demonstrated a high frequency of responses in terms of antigen-specific T cells ( One problem, however, is that vaccine efficacy is diminished in some individuals with preexisting immunity to adenovirus serotype 5, which in the United States occurs at a frequency of 30 to 50% (11), and in many developing countries at 90% (M. Cleveland et al., presented at AIDS Vaccine 2005, Montreal, Quebec, Canada, 2005). An alternative platform for genetic vaccines is based on adeno-associated viruses (AAVs). This group of parvoviruses was identified over 30 years ago as contaminants in laboratory preparations of adenoviruses (1, 3, 4, 16, 17, 25, 28). Six JWS serotypes of AAV were identified. The initial application of vectors based on these viruses was for gene therapy. In these studies, impressive results were achieved following in vivo administration of vector in terms of the efficiency and stability of transgene expression without significant toxicity. A number of investigators have pursued the use of AAV type 2 (AAV2) as a vaccine carrier. Manning et al. demonstrated T- and B-cell responses to herpes simplex virus type 2 glycoproteins B and D following intramuscular (i.m.) injection in mice (22). AAV2 expressing human papillomavirus E7 eliminated human papillomavirus-expressing tumors in a syngeneic mouse model (21). Intranasal administration of AAV2 expressing HA from influenza virus resulted in protection against a challenge with influenza virus (41). A number of investigators have demonstrated encouraging results with AAV2-based vaccines administered orally. AAV2 expressing a receptor to a neurotransmitter found in the brain was shown to induce autoantibodies that prevented clinical sequelae in experimentally induced stroke and epilepsy (10). AAV2 vectors have been evaluated as vaccine carriers for HIV-1 antigens as well. Xin et al., injected AAV2 vectors expressing HIV-1 Env, Tat, and Rev into muscles of BALB/c mice and showed persistent HIV antibodies based on an enzyme-linked immunosorbent assay (ELISA) and T cells based on cytotoxic T-lymphocyte (CTL) assays (41). Orally administered AAV2 expressing Pseudoginsenoside-F11 HIV-1 Env resulted in systemic and regional immunity and significantly reduced the viral load of a vaccinia virus expressing HIV-1 Env following rectal administration (40). Johnson and colleagues have shown detectable Gag-specific T cells by an.