HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G

Terumasa Ikeda, Menelaos Symeonides, John S. Albin, Ming Li, Markus Thali, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


HIV-1 replication normally requires Vif-mediated neutralization of APOBEC3 antiviral enzymes. Viruses lacking Vif succumb to deamination-dependent and -independent restriction processes. Here, HIV-1 adaptation studies were leveraged to ask whether viruses with an irreparable vif deletion could develop resistance to restrictive levels of APOBEC3G. Several resistant viruses were recovered with multiple amino acid substitutions in Env, and these changes alone are sufficient to protect Vif-null viruses from APOBEC3G-dependent restriction in T cell lines. Env adaptations cause decreased fusogenicity, which results in higher levels of Gag-Pol packaging. Increased concentrations of packaged Pol in turn enable faster virus DNA replication and protection from APOBEC3G-mediated hypermutation of viral replication intermediates. Taken together, these studies reveal that a moderate decrease in one essential viral activity, namely Env-mediated fusogenicity, enables the virus to change other activities, here, Gag-Pol packaging during particle production, and thereby escape restriction by the antiviral factor APOBEC3G. We propose a new paradigm in which alterations in viral homeostasis, through compensatory small changes, constitute a general mechanism used by HIV-1 and other viral pathogens to escape innate antiviral responses and other inhibitions including antiviral drugs.

Original languageEnglish (US)
Article numbere1007010
JournalPLoS pathogens
Issue number4
StatePublished - Apr 2018

Bibliographical note

Funding Information:
This work was supported by a JSPS Postdoctoral Fellowship for Research Abroad to TI and by grants from the National Institutes of Health to RSH (NIAID R37 AI064046 and NCI R21 CA206309) and to MT (NIAID R01 AI080302 and NIGMS R01 GM117839). MS was supported in part by the Graduate Program in Cell and Molecular Biology. RSH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are thankful to B. Anderson, M. Carpenter, A. Land, and C. Richards for helpful comments on the manuscript, E. Freed for discussion and sharing results prior to publication, D. Mundt for technical assistance, and several colleagues in the HIV-1 molecular virology field including B. Berkhout, B. Hahn, J. Hoxie, S. Hughes, M. Malim, S. Saffarian, W. Sundquist, and A. Telesnitsky for thoughtful and encouraging comments on our APOBEC resistance studies over the years.

Publisher Copyright:
© 2018 Ikeda et al.


Dive into the research topics of 'HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G'. Together they form a unique fingerprint.

Cite this