AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges
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Author
Gardner, Matthew R.
Kattenhorn, Lisa M.
Kondur, Hema R.
von Schaewen, Markus
Dorfman, Tatyana
Haworth, Kevin G.
Decker, Julie M.
Bailey, Charles C.
Neale, Ernest S.
Fellinger, Christoph H.
Joshi, Vinita R.
Fuchs, Sebastian P.
Martinez-Navio, Jose M.
Quinlan, Brian D.
Yao, Annie Y.
Mouquet, Hugo
Gorman, Jason
Zhang, Baoshan
Poignard, Pascal
Nussenzweig, Michel C.
Burton, Dennis R.
Kwong, Peter D.
Piatak, Michael
Lifson, Jeffrey D.
Gao, Guangping
Evans, David T.
Hahn, Beatrice H.
Ploss, Alexander
Cannon, Paula M.
Farzan, Michael
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature14264Metadata
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Gardner, M. R., L. M. Kattenhorn, H. R. Kondur, M. von Schaewen, T. Dorfman, J. J. Chiang, K. G. Haworth, et al. 2015. “AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.” Nature 519 (7541): 87-91. doi:10.1038/nature14264. http://dx.doi.org/10.1038/nature14264.Abstract
Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)1,2. However even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (IC80 > 5 μg/ml), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3–6. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC50 < 0.05 μg/ml). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and SIV isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17 to 77 μg/ml of fully functional rhesus eCD4-Ig for 40 weeks, and these macaques were protected from multiple infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352131/pdf/Terms of Use
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