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AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

  1. Author:
    Gardner, Matthew R [ORCID]
    Fellinger, Christoph H [ORCID]
    Kattenhorn, Lisa M
    Davis-Gardner, Meredith E [ORCID]
    Weber, Jesse A
    Alfant, Barnett [ORCID]
    Zhou, Amber S [ORCID]
    Prasad, Neha R
    Kondur, Hema R [ORCID]
    Newton, Wendy A [ORCID]
    Weisgrau, Kimberly L
    Rakasz, Eva G [ORCID]
    Lifson,Jeffrey [ORCID]
    Gao, Guangping [ORCID]
    Schultz-Darken, Nancy [ORCID]
    Farzan, Michael [ORCID]

  2. Author Address

    Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA. mgardner@scripps.edu., Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA., Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715 USA., AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA., Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.,
    1. Year: 2019
    2. Date: Jul 24
  2. Journal: Science translational medicine
    1. 11
    2. 502
    3. Pages: pii: eaau5409
  4. Type of Article: Article
  5. Article Number: eaau5409
  6. ISSN: 1946-6234
  1. Abstract:

    A number of simian and simian human immunodeficiency viruses (SIV and SHIV, respectively) have been used to assess the efficacy of HIV-1 vaccine strategies. Among these, SIVmac239 is considered among the most stringent because, unlike SHIV models, its full genome has coevolved in its macaque host and its tier 3 envelope glycoprotein (Env) is exceptionally hard to neutralize. Here, we investigated the ability of eCD4-Ig, an antibody-like entry inhibitor that emulates the HIV-1 and SIV receptor and coreceptor, to prevent SIVmac239 infection. We show that rh-eCD4-IgI39N expressed by recombinant adeno-associated virus (AAV) vectors afforded four rhesus macaques complete protection from high-dose SIVmac239 challenges that infected all eight control macaques. However, rh-eCD4-IgI39N-expressing macaques eventually succumbed to serial escalating challenge doses that were 2, 8, 16, and 32 times the challenge doses that infected the control animals. Despite receiving greater challenge doses, these macaques had significantly lower peak and postpeak viral loads than the control group. Virus isolated from three of four macaques showed evidence of strong immune pressure from rh-eCD4-IgI39N, with mutations located in the CD4-binding site, which, in one case, exploited a point-mutation difference between rh-eCD4-IgI39N and rhesus CD4. Other escape pathways associated with clear fitness costs to the virus. Our data report effective protection of rhesus macaques from SIVmac239. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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External Sources

  1. View Full Text
  2. DOI: 10.1126/scitranslmed.aau5409
  3. PMID: 31341061
  4. View record in Web of Science®
  5. WOS: 000479138200003
  6. PII : 11/502/eaau5409

Library Notes

  1. Fiscal Year: FY2018-2019
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