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

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Overview

related to degree

  • Fellinger, Christoph, Ph.D. in Virology, Scripps Research , Transferred from Harvard University 2012 - 2018

authors

  • 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 Jr., E. S.
  • Fellinger, Christoph
  • Joshi, V. R.
  • Fuchs, S. P.
  • Martinez-Navio, J. M.
  • Quinlan, B. D.
  • Yao, A. Y.
  • Mouquet, H.
  • Gorman, J.
  • Zhang, B.
  • Poignard, Pascal
  • Nussenzweig, M. C.
  • Burton, Dennis
  • Kwong, P. D.
  • Piatak Jr., M.
  • Lifson, J. D.
  • Gao, G.
  • Desrosiers, R. C.
  • Evans, D. T.
  • Hahn, B. H.
  • Ploss, A.
  • Cannon, P. M.
  • Seaman, M. S.
  • Farzan, Michael

publication date

  • March 2015

journal

  • Nature  Journal

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.

subject areas

  • AIDS Vaccines
  • Animals
  • Antibodies, Neutralizing
  • Antigens, CD4
  • CCR5 Receptor Antagonists
  • Dependovirus
  • Female
  • Genetic Therapy
  • HIV Antibodies
  • HIV-1
  • HIV-2
  • Immunoglobulins
  • Macaca mulatta
  • Male
  • Neutralization Tests
  • Receptors, CCR5
  • Simian Acquired Immunodeficiency Syndrome
  • Simian Immunodeficiency Virus
  • Virus Internalization
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Identity

PubMed Central ID

  • PMC4352131

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature14264

PubMed ID

  • 25707797
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Additional Document Info

start page

  • 87

end page

  • 91

volume

  • 519

issue

  • 7541

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