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

Research output: Contribution to journalArticle

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-virusinduced 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 AIDinsufficient 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-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.

Original languageEnglish (US)
Article numbere01678-19
JournalmBio
Volume10
Issue number4
DOIs
StatePublished - Jan 1 2019

Fingerprint

Mouse mammary tumor virus
Retroviridae
Proteins
Proviruses
Mutation
Virus Replication
vif Gene Products
AICDA (activation-induced cytidine deaminase)
B-Lymphocytes
Lymphocytes
Breast Neoplasms
Immune Evasion
Immunologic Factors
Human Mammary Glands
Innate Immunity
Mutagenesis
Virion
Antiviral Agents
Transfection
HIV-1

Keywords

  • AID inhibitor
  • Activation-induced cytidine deaminase
  • Apobec3
  • Mouse mammary tumor virus
  • Retroviruses

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

A protein antagonist of activation-induced cytidine deaminase encoded by a complex mouse retrovirus. / Singh, Gurvani B.; Byun, Hyewon; Ali, Almas F.; Medina, Frank; Wylie, Dennis; Shivram, Haridha; Nash, Andrea K.; Lozano, Mary M.; Dudley, Jaquelin P.

In: mBio, Vol. 10, No. 4, e01678-19, 01.01.2019.

Research output: Contribution to journalArticle

Singh, GB, Byun, H, Ali, AF, Medina, F, Wylie, D, Shivram, H, Nash, AK, Lozano, MM & Dudley, JP 2019, 'A protein antagonist of activation-induced cytidine deaminase encoded by a complex mouse retrovirus', mBio, vol. 10, no. 4, e01678-19. https://doi.org/10.1128/mBio.01678-19
Singh GB, Byun H, Ali AF, Medina F, Wylie D, Shivram H et al. A protein antagonist of activation-induced cytidine deaminase encoded by a complex mouse retrovirus. mBio. 2019 Jan 1;10(4). e01678-19. https://doi.org/10.1128/mBio.01678-19
Singh, Gurvani B. ; Byun, Hyewon ; Ali, Almas F. ; Medina, Frank ; Wylie, Dennis ; Shivram, Haridha ; Nash, Andrea K. ; Lozano, Mary M. ; Dudley, Jaquelin P. / A protein antagonist of activation-induced cytidine deaminase encoded by a complex mouse retrovirus. In: mBio. 2019 ; Vol. 10, No. 4.
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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-virusinduced 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 AIDinsufficient 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-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.",
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AU - Wylie, Dennis

AU - Shivram, Haridha

AU - Nash, Andrea K.

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