AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

Matthew R. Gardner, Lisa M. Kattenhorn, Hema R. Kondur, Markus Von Schaewen, Tatyana Dorfman, Jessica J. Chiang, Kevin G. Haworth, Julie M. Decker, Michael D. Alpert, Charles C. Bailey, Ernest S. Neale, Christoph H. Fellinger, Vinita R. Joshi, Sebastian P. Fuchs, Jose M. Martinez-Navio, Brian D. Quinlan, Annie Y. Yao, Hugo Mouquet, Jason Gorman, Baoshan ZhangPascal Poignard, Michel C. Nussenzweig, Dennis R. Burton, Peter D. Kwong, Michael Piatak, Jeffrey D. Lifson, Guangping Gao, Ronald C. Desrosiers, David T. Evans, Beatrice H. Hahn, Alexander Ploss, Paula M. Cannon, Michael S. Seaman, Michael Farzan

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

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). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 μg ml1), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. 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 half-maximum inhibitory concentration (IC50) < 0.05 μg ml1). 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 simian immunodeficiency virus 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 17-77 μg ml1 of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several 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.

Original languageEnglish (US)
Pages (from-to)87-91
Number of pages5
JournalNature
Volume519
Issue number7541
DOIs
StatePublished - Mar 5 2015

ASJC Scopus subject areas

  • General

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