Journal Article

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

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

2015

Overview

The new entry inhibitor eCD4-Ig, consisting of the immunoadhesin form of CD4 (CD4-Ig) fused to a small CCR5-mimetic sulfopeptide, avidly binds two highly conserved sites of the HIV-1 Env protein; the inhibitor has high potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1 viruses, and when delivered to macaques using an adeno-associated virus vector, it can provide effective long-term protection from multiple challenges with simian/human immunodeficiency virus. HIV-1 entry inhibitors with vaccine-like action This study describes a novel class of highly potent HIV-1 entry inhibitors that can be delivered with a gene-therapy vector to provide an effective alternative to conventional vaccines for HIV-1. To enter cells, HIV-1 first binds its cellular receptor CD4, then the co-receptor CCR5 or CXCR4 The new entry inhibitor consists of the immunoadhesin CD4-Ig fused to a sulfopeptide mimicking CCR5. This fusion, called eCD4-Ig, avidly binds the Env protein of HIV-1 and irreversibly inactivates it. Michael Farzan and colleagues show that this inhibitor has exceptional potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1. When delivered to macaques using an adeno-associated virus, it can protect them from multiple challenges with virus. 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 (80% inhibitory concentration (IC 80 ) > 5 μg ml −1 ), suggesting that high concentrations of these antibodies would be necessary to achieve general protection 3 , 4 , 5 , 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 half-maximum inhibitory concentration (IC 50 ) < 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/44 / 631/326/590/2294 / 631/326/596 / 82/1 / AIDS Vaccines - genetics / AIDS Vaccines - immunology / Analysis / Animals / Antibodies, Neutralizing - immunology / Binding sites / CCR5 Receptor Antagonists - immunology / CD4 Antigens - genetics / CD4 Antigens - immunology / Dependovirus - genetics / Dependoviruses / Female / Gene expression / Genetic Therapy / Genetic vectors / Glycoproteins / HIV / HIV (Viruses) / HIV Antibodies - immunology / HIV-1 - immunology / HIV-2 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Immunoglobulins / Immunoglobulins - genetics / Immunoglobulins - immunology / letter / Macaca mulatta / Male / Medical research / multidisciplinary / Neutralization / Neutralization Tests / Primates / Receptors, CCR5 - metabolism / Science / Simian Acquired Immunodeficiency Syndrome - immunology / Simian Acquired Immunodeficiency Syndrome - prevention & control / Simian Acquired Immunodeficiency Syndrome - virology / Simian Immunodeficiency Virus - immunology / Studies / Vaccines / Virus Internalization