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Editor's Pick Research Article | Host-Microbe Biology

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

Gurvani B. Singh, Hyewon Byun, Almas F. Ali, Frank Medina, Dennis Wylie, Haridha Shivram, Andrea K. Nash, Mary M. Lozano, Jaquelin P. Dudley
Jaisri R. Lingappa, Editor
Gurvani B. Singh
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Hyewon Byun
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Almas F. Ali
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Frank Medina
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Dennis Wylie
bComputational Biology and Bioinformatics and Center for Biomedical Research Support, The University of Texas at Austin, Austin, Texas, USA
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Haridha Shivram
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Andrea K. Nash
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Mary M. Lozano
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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Jaquelin P. Dudley
aDept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
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  • ORCID record for Jaquelin P. Dudley
Jaisri R. Lingappa
University of Washington
Roles: Editor
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Welkin Johnson
Boston College
Roles: Solicited external reviewer
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Tatyana Golovkina
University of Chicago
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DOI: 10.1128/mBio.01678-19
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ABSTRACT

Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.

IMPORTANCE Complex retroviruses, such as human immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

  • Copyright © 2019 Singh et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus
Gurvani B. Singh, Hyewon Byun, Almas F. Ali, Frank Medina, Dennis Wylie, Haridha Shivram, Andrea K. Nash, Mary M. Lozano, Jaquelin P. Dudley
mBio Aug 2019, 10 (4) e01678-19; DOI: 10.1128/mBio.01678-19

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A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus
Gurvani B. Singh, Hyewon Byun, Almas F. Ali, Frank Medina, Dennis Wylie, Haridha Shivram, Andrea K. Nash, Mary M. Lozano, Jaquelin P. Dudley
mBio Aug 2019, 10 (4) e01678-19; DOI: 10.1128/mBio.01678-19
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KEYWORDS

AID inhibitor
Apobec3
activation-induced cytidine deaminase
mouse mammary tumor virus
retroviruses

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