1. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.
- Author
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Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, Chiang JJ, Haworth KG, Decker JM, Alpert MD, Bailey CC, Neale ES Jr, Fellinger CH, Joshi VR, Fuchs SP, Martinez-Navio JM, Quinlan BD, Yao AY, Mouquet H, Gorman J, Zhang B, Poignard P, Nussenzweig MC, Burton DR, Kwong PD, Piatak M Jr, Lifson JD, Gao G, Desrosiers RC, Evans DT, Hahn BH, Ploss A, Cannon PM, Seaman MS, and Farzan M
- Subjects
- AIDS Vaccines genetics, AIDS Vaccines immunology, Animals, Antibodies, Neutralizing immunology, CCR5 Receptor Antagonists immunology, CD4 Antigens genetics, Female, Genetic Therapy, HIV Antibodies immunology, HIV-1 immunology, HIV-2 immunology, Immunoglobulins genetics, Macaca mulatta, Male, Neutralization Tests, Receptors, CCR5 metabolism, Simian Acquired Immunodeficiency Syndrome virology, CD4 Antigens immunology, Dependovirus genetics, Immunoglobulins immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology, Virus Internalization
- 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 ml(-1)), 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 ml(-1)). 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 ml(-1) 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.
- Published
- 2015
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