Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys

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Abstract

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.

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Figure 1: Schematic representation of immunoadhesin constructs.
Figure 2: Neutralization of SIV in vitro.
Figure 3: Serum concentration of immunoadhesins or antibodies after gene transfer and SIV challenge.
Figure 4: Detection of SIV in plasma after challenge.
Figure 5: Immunoadhesin antibodies in immunized monkeys.

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Acknowledgements

We thank A. Hessell and D. Burton (The Scripps Research Institute) for providing the SIV Fab molecular clones, D. McCarty (The Research Institute at Nationwide Children's Hospital) for the self-complementary AAV vector genome, R. Doms (University of Pennsylvania) for purified SIVmac gp120, J. Bixby and E. Mackenzie for technical assistance and M. Piatek and J. Lifson for SIV viral load data. We also thank J. Hoxie and S. Douglas for helpful comments on the manuscript. Funding for this work was provided by grants from the US National Institutes of Health National Institute of Allergy and Infectious Diseases Division of AIDS (P.R.J. and R.C.D.), National Institutes of Health National Center for Research Resources (R.C.D.) and support from The Children's Hospital of Philadelphia.

Author information

Project planning was performed by P.R.J., B.C.S. and K.R.C.; experimental work was performed by B.C.S., J.Z., M.J.C., S.M.G. and E.Y.; data analysis was performed by P.R.J., K.R.C., R.C.D., B.C.S., J.Z., M.J.C. and S.M.G.; and the manuscript was composed by P.R.J., R.C.D., B.C.S. and K.R.C.

Correspondence to Philip R Johnson.

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