David Baltimore of the California Institute of Technology in Pasadena, California, and colleagues have a new approach that is part vaccine, part gene therapy. They turn muscles into factories that churn out potent antibodies against HIV. Because muscle isn’t on HIV’s hitlist, it will continue to generate antibodies even after an HIV infection, making the strategy potentially better than one which tweaks the immune system to produce the antibodies.
Genetically altered mice were able to resist 100 times the level of HIV that would normally cause an infection.
“We produce a similar effect to a vaccine, but without ever calling on the immune system to do any of the work,” says Alejandro Balazs, a member of Baltimore’s team also at Caltech.
The team loaded a harmless, cold-related virus called adeno-associated virus (AAV) with genes that make potent antibodies to HIV. Then they used them to “infect” the leg muscles of mice with genes that pump out the antibodies.
“The idea here is to basically supply the body with its own factory for making anti-HIV antibodies,” says Baltimore.
The mice continued to make the antibodies throughout their lives, and stayed healthy despite the researchers’ best efforts to overwhelm them with HIV.
“We expected that at some dose, the antibodies would fail to protect the mice, but there was no infection even when we gave mice 100 times more HIV than would be needed to infect seven out of eight mice,” says Balaz
Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.