Gardner, Matthew R.Kattenhorn, Lisa M.Kondur, Hema R.von Schaewen, MarkusDorfman, TatyanaChiang, JessicaHaworth, Kevin G.Decker, Julie M.Alpert, MichaelBailey, 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, HugoGorman, JasonZhang, BaoshanPoignard, PascalNussenzweig, Michel C.Burton, Dennis R.Kwong, Peter D.Piatak, MichaelLifson, Jeffrey D.Gao, GuangpingDesrosiers, RonaldEvans, David T.Hahn, Beatrice H.Ploss, AlexanderCannon, Paula M.Seaman, MichaelFarzan, Michael2015-10-012015Gardner, 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/nature14264.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:22856832Long-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.en-USJournal Article2015-10-0110.1038/nature14264