Adeno-Associated Virus (AAV) has shown great promise as a potential vaccine and gene therapy vector in small animal models and non-human primates. One of AAV's most desirable qualities is the sustained expression of its genetic payload over the course of many months, leading to the suggestion that it might be used to make a "one shot" vaccine. However, at recent conferences it has been revealed that the immunogenicity of AAV-based HIV vaccine candidates in phase I human trials has been extremely disappointing. Results using AAV as a gene therapy in humans have also not lived up to expectations. In the online first section of Nature Medicine, researchers now report that they may have identified the problem. It appears that, unlike the animals used in preclinical experiments, humans have CD8 T cell responses targeting the AAV capsid. Furthermore, these T cell responses are capable of recognizing capsids from multiple different AAV serotypes. These findings suggest that it will be extremely difficult - perhaps impossible - to alter current AAV vectors to evade the human CD8 T cell response.
Nature Medicine, Advance online publication
Brief Communication
Published online: 18 March 2007; | doi:10.1038/nm1549
CD8+ T-cell responses to adeno-associated virus capsid in humans
Federico Mingozzi, Marcela V Maus, Daniel J Hui, Denise E Sabatino, Samuel L Murphy, John E J Rasko, Margaret V Ragni, Catherine S Manno, 6, Jurg Sommer, Haiyan Jiang, Glenn F Pierce, Hildegund C J Ertl & Katherine A High
Hepatic adeno-associated virus (AAV)-serotype 2 mediatedgene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid–specific memory CD8+ T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid–specific CD8+ T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.
Comments