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 Zhang; Pascal 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

doi:10.1038/nature14264

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

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241 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 language	English (US)
Pages (from-to)	87-91
Number of pages	5
Journal	Nature
Volume	519
Issue number	7541
DOIs	https://doi.org/10.1038/nature14264
State	Published - Mar 5 2015

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Gardner, M. R., Kattenhorn, L. M., Kondur, H. R., Von Schaewen, M., Dorfman, T., Chiang, J. J., Haworth, K. G., Decker, J. M., Alpert, M. D., Bailey, C. C., Neale, E. S., Fellinger, C. H., Joshi, V. R., Fuchs, S. P., Martinez-Navio, J. M., Quinlan, B. D., Yao, A. Y., Mouquet, H., Gorman, J., ... Farzan, M. (2015). AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature, 519(7541), 87-91. https://doi.org/10.1038/nature14264

@article{6b5495ddfff141e282c1563eff7465d5,

title = "AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = mar,

day = "5",

doi = "10.1038/nature14264",

language = "English (US)",

volume = "519",

pages = "87--91",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7541",

}

Gardner, MR, Kattenhorn, LM, Kondur, HR, Von Schaewen, M, Dorfman, T, Chiang, JJ, Haworth, KG, Decker, JM, Alpert, MD, Bailey, CC, Neale, ES, 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, Lifson, JD, Gao, G, Desrosiers, RC, Evans, DT, Hahn, BH, Ploss, A, Cannon, PM, Seaman, MS & Farzan, M 2015, 'AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges', Nature, vol. 519, no. 7541, pp. 87-91. https://doi.org/10.1038/nature14264

TY - JOUR

T1 - AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

AU - Gardner, Matthew R.

AU - Kattenhorn, Lisa M.

AU - Kondur, Hema R.

AU - Von Schaewen, Markus

AU - Dorfman, Tatyana

AU - Chiang, Jessica J.

AU - Haworth, Kevin G.

AU - Decker, Julie M.

AU - Alpert, Michael D.

AU - Bailey, Charles C.

AU - Neale, Ernest S.

AU - Fellinger, Christoph H.

AU - Joshi, Vinita R.

AU - Fuchs, Sebastian P.

AU - Martinez-Navio, Jose M.

AU - Quinlan, Brian D.

AU - Yao, Annie Y.

AU - Mouquet, Hugo

AU - Gorman, Jason

AU - Zhang, Baoshan

AU - Poignard, Pascal

AU - Nussenzweig, Michel C.

AU - Burton, Dennis R.

AU - Kwong, Peter D.

AU - Piatak, Michael

AU - Lifson, Jeffrey D.

AU - Gao, Guangping

AU - Desrosiers, Ronald C.

AU - Evans, David T.

AU - Hahn, Beatrice H.

AU - Ploss, Alexander

AU - Cannon, Paula M.

AU - Seaman, Michael S.

AU - Farzan, Michael

PY - 2015/3/5

Y1 - 2015/3/5

N2 - 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.

AB - 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.

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IS - 7541

ER -

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

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