Blocking α4β7 integrin binding to SIV does not improve virologic control
An antibody is not the antidote
An HIV therapeutic that would give long-term remission without sustained antiretroviral therapy (ART) is a long-term goal. Byrareddy et al. [Science354, 197 (2016)] reported that treating simian immunodeficiency virus (SIV)–positive macaques with an antibody against integrin α4β7 during and after ART results in sustained virologic control after stopping all treatment. Three studies in this issue question the reproducibility of that result. Di Mascio et al. sequenced the virus used in the 2016 study and found that it was a variant with a stop codon in the nef gene rather than a wild-type virus. Abbink et al. used the same antibody for α4β7 as before but tested control of a more commonly used pathogenic virus. Iwamato et al. used the same nef-stop virus as in the earlier paper but combined the antibody against the integrin with an antibody against the SIV envelope glycoprotein, which also blocks viral binding of the integrin. None of these three new studies found that treating with the antibody had any effect on virologic control after stopping ART treatment.
Abstract
A study in nonhuman primates reported that infusions of an antibody against α4β7 integrin, in combination with antiretroviral therapy, showed consistent, durable control of simian immunodeficiency virus (SIV) in rhesus macaques. The antibody used has pleiotropic effects, so we set out to gain insight into the underlying mechanism by comparing this treatment to treatment with non-neutralizing monoclonal antibodies against the SIV envelope glycoprotein that only block α4β7 binding to SIV Env but have no other host-directed effects. Similar to the initial study, we used an attenuated strain of SIV containing a stop codon in nef. The study used 30 macaques that all began antiretroviral therapy and then were divided into five groups to receive different antibody treatments. Unlike the published report, we found no sustained virologic control by these treatments in vivo.
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Supplementary Material
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Materials and Methods
Figs. S1 to S4
Table S1
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References and Notes
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Volume 365 | Issue 6457
6 September 2019
6 September 2019
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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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Received: 1 February 2019
Accepted: 26 June 2019
Published in print: 6 September 2019
Acknowledgments
We thank J. P. Todd, A. Taylor, and D. Scorpio for veterinary and animal logistics support; M. Lewis and staff at BioQual, Inc. for expert animal assistance; D. Finzi for coordinating acquisition of reagents; F. Villinger for providing the virus challenge stock; members of the ImmunoTechnology Section for critical discussion and support; the Nonhuman Primate Immunogenicity Core (VRC) for assistance with specimen processing; the Flow Cytometry Core (VRC) for expert cytometry assistance; the Quantitative Molecular Diagnostics Core (ACVP/FNLCR) and Viral Evolution Core (VEC/FNLCR) for viral load measurements and viral sequence analysis; and J. Mascola, R. Koup, D. Douek, C. Dieffenbach, C. Lane, D. Barouch, and A. Fauci for support, advice, and critical feedback. Funding: This work was supported by the Intramural Research Programs of the Vaccine Research Center and the National Institute of Allergy and Infectious Diseases, National Institutes of Health; in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HSN261200800001E; and by the NHP Reagent Resource grants OD010976 and AI126683. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of any trade names, commercial products, or organizations imply endorsement by the U.S. government. Author contributions: Conceptualization: M.R.; Data Curation: N.I., R.D.M., J.A., C.C., S.M., H.A.D.K., P.D.K., J.D.L., B.F.K., M.R.; Formal analysis: N.I., R.D.M., J.G., J.A., C.C., H.A.D.K., P.D.K., J.D.L., B.F.K., M.R.; Funding acquisition: J.A., J.D.L., M.R.; Investigation: N.I., R.D.M., K.S., J.G., H.W., J.A., C.C., S.M., A.J.B., H.A.D.K., K.E.F.; Methodology: N.I., R.D.M., K.S., J.G., J.A., C.C., K.E.F.; Project administration: N.I., M.R.; Resources: R.D.M., H.W., J.A., C.C., K.A.R., K.E.F.; Supervision: M.R.; Validation: N.I., J.D.L., B.F.K., M.R.; Visualization: N.I., J.A., B.F.K., M.R.; Writing – original draft: N.I., M.R.; Writing – Review & editing: all authors. Competing interests: The authors declare no competing financial interests. Data and materials availability: Sequences are deposited in GenBank. All data are available in the manuscript or supplementary materials, or by request to M.R.
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