Today (May 18) is HIV Vaccine Awareness Day and, with an eye for a PR opportunity, Nature Medicine has just published a study of a novel approach to immunization against HIV infection. Philip Johnson and colleagues describe their use of an adeno-associated virus (AAV) vector to persistently express antibody-like “immunoadhesins” that can inhibit a particular SIV variant called SIVmac316. They report that delivery of the AAV vector to rhesus macaques produced sustained circulating levels of immunoadhesins that protected 6/9 animals from a subsequent intravenous SIVmac316 challenge.
The paper has garnered a fair amount of media coverage today. While the approach is novel and the results are somewhat encouraging, there are some important caveats to be borne in mind. Firstly, it is as yet unclear whether AAV can be engineered to produce similar sustained protein expression in humans. While it’s not mentioned in the paper, a previous AAV vector - developed by Philip Johnson and manufactured by Targeted Genetics - was designed to encode HIV proteins with the goal of triggering the development of HIV-specific T cell responses. This AAV vector proved dismally immunogenic in phase I human trials, inducing detectable HIV-specific T cell responses in fewer than 1 in 5 participants.
Although this new study obviously represents a different use of the vector, the lack of immunogenicity in prior trials suggests that it was not efficient at producing proteins in the human body. The results echo the disappointments of other research groups who have attempted to use AAV as a gene transfer vehicle. As reported on the blog previously, the explanation may be that many people have pre-existing CD8 T cell responses against the AAV capsid, which can cross-react with capsids from different AAV serotypes. Killing of AAV-infected cells by these CD8 T cells would limit the ability of the vector to encode its protein payload. Macaques (and other animals used in preclinical studies) do not have pre-existing AAV-specific CD8 T cell responses.
The other major caveat regarding the approach is the potential for the induction of immune responses against the antibody or immunoadhesin being produced by the vector. The three immunized macaques that became SIV-infected in Johnson’s study all showed evidence of antibody responses against the immunoadhesin. However, it is perhaps encouraging to note that a human trial that administered a combination of broadly neutralizing monoclonal antibodies (2G12, 4E10 and 2F5) against HIV did not detect the generation of an immune response against the antibodies, at least in the setting of extant HIV infection (to the best of my knowledge, the antibodies have not been administered to HIV-negative volunteers).
The overall idea of genetically engineered immunity is certainly novel, and timely given the struggles involved in persuading the adaptive immune system to make a response that protects against HIV infection. An excellent description of the approaches under study, including Johnson’s, can be found in an article by Andreas von Bubnoff from the July-August 2008 issue of IAVI Report. What remains unclear, despite these new data, is whether AAV can work as a vehicle for delivering antibodies in humans.
Published online: 17 May 2009 | doi:10.1038/nm.1967
Philip R Johnson1, Bruce C Schnepp1, Jianchao Zhang2, Mary J Connell1, Sean M Greene1, Eloisa Yuste3, Ronald C Desrosiers3 & K Reed Clark2
1. The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
2. The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
3. New England Primate Research Center and Harvard Medical School, Southborough, Massachusetts, USA.
The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.