PURPOSE OF THE STUDY.
A large majority of new HIV infection results from transmission across mucosal barriers. HIV vaccine clinical trials have failed to illicit protective immunity to infection. Furthermore, pre-exposure and postexposure prophylaxis regimens have had limited success, primarily due to nonadherence to the prescribed regimens. Protection with currently available vaccines to mucosal infections, such as human papilloma virus and influenza virus, correlate with systemic neutralizing antibodies. The purpose of this study was to evaluate a new strategy for prevention of HIV transmission, “vectored immunoprophylaxis,” a specific form of gene transfer therapy in which the gene for a modified broadly neutralizing antibody is directed into muscle cells via an adeno-associated virus vector. This technique results in an episomally replicating construct that produces the neutralizing antibody that enters the systemic circulation.
Genetic immunodeficient mice that had been reconstituted with a human immune system, BLT (bone marrow-liver-thymus) mice, were used to study mucosal HIV infection. These mice exhibit extensive engraftment of immune cells in mucosal tissues.
BLT mice were administered adeno-associated virus vectors containing genes either for a control protein or for a broadly neutralizing monoclonal immunoglobulin (Ig)G antibody. These mice were then challenged intravenously with infectious HIV. In addition, mice were challenged weekly with low-dose, nonabrasive vaginal HIV challenge to mimic mucosal exposure.
The initial antibody tested, VRC01, was shown to reduce HIV transmission of a diverse range of HIV strains. This antibody also reduced vaginal transmission of HIV. All control animals were infected after a mean of 4.25 vaginal challenges; 2 VRC01-expressing mice became infected after 13 and 15 challenges, respectively. A second antibody, VRC07G54W, was selected for additional study with the repetitive challenge model. None of the mice expressing VRC07G54W exhibited detectible virus in the plasma despite 21 consecutive weekly challenges.
Providing broadly neutralizing monoclonal antibody with vector immunoprophylaxis protects humanized mice against mucosal HIV challenge.
“Protective” immunologic responses to virus infection differ when considering prevention of new infection versus control of chronic infection. Neutralizing antibody seems to be necessary and sufficient for the former, CD8+ cytotoxic T cells for the later. Early HIV vaccines were designed to enhance CD8+ T-cell responses and were ineffective in preventing new HIV infection. Even for viruses transmitted through mucosal surfaces, neutralizing antibody levels provide the best surrogate marker for protection in humans. Importantly, the view that the dominant antibody in vaginal secretions is of the IgA isotype is incorrect; IgG that is actively transported across vaginal epithelium via Fcn receptors is the predominant antibody isotype in this location. This at least in part explains the efficacy of systemic immunizations against human papillomavirus. Unfortunately, the generation of broadly neutralizing antibodies against HIV occurs naturally only in the context of chronic infection and with selection of effective antibodies only after many cycles of B-cell affinity maturation. Creating an immunogen that replicates this process will be exceptionally challenging. Vectored immunoprophylaxis uses gene transfer technology to generate a systemic monoclonal antibody that provides the desired neutralizing response. Although it will require additional studies in higher animal models, vectored immunoprophylaxis may offer an alternative to standard immunizing techniques.
- Copyright © 2014 by the American Academy of Pediatrics