PMID- 31409681 OWN - NLM STAT- MEDLINE DCOM- 20200505 LR - 20231214 IS - 2150-7511 (Electronic) VI - 10 IP - 4 DP - 2019 Aug 13 TI - A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus. LID - 10.1128/mBio.01678-19 [doi] LID - e01678-19 AB - 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-pathogenic 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-pathogenic 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. CI - Copyright (c) 2019 Singh et al. FAU - Singh, Gurvani B AU - Singh GB AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Byun, Hyewon AU - Byun H AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Ali, Almas F AU - Ali AF AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Medina, Frank AU - Medina F AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Wylie, Dennis AU - Wylie D AD - Computational Biology and Bioinformatics and Center for Biomedical Research Support, The University of Texas at Austin, Austin, Texas, USA. FAU - Shivram, Haridha AU - Shivram H AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Nash, Andrea K AU - Nash AK AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Lozano, Mary M AU - Lozano MM AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA. FAU - Dudley, Jaquelin P AU - Dudley JP AUID- ORCID: 0000-0002-1581-1098 AD - Dept. of Molecular Biosciences, LaMontagne Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA jdudley@austin.utexas.edu. LA - eng GR - R01 AI131660/AI/NIAID NIH HHS/United States GR - R01 CA167053/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190813 PL - United States TA - mBio JT - mBio JID - 101519231 RN - 0 (Viral Regulatory and Accessory Proteins) RN - EC 3.5.4.- (AICDA (activation-induced cytidine deaminase)) RN - EC 3.5.4.5 (Apobec3 protein, mouse) RN - EC 3.5.4.5 (Cytidine Deaminase) SB - IM MH - Animals MH - Cytidine Deaminase/*antagonists & inhibitors/genetics/metabolism MH - Female MH - Immunity, Innate MH - Male MH - Mammary Neoplasms, Experimental/immunology/virology MH - Mammary Tumor Virus, Mouse/*genetics/physiology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Mutant Strains MH - Mutation MH - Proviruses/*genetics/physiology MH - Retroviridae Infections/immunology/virology MH - Tumor Virus Infections/immunology/virology MH - Viral Load/genetics MH - Viral Regulatory and Accessory Proteins/*genetics/metabolism MH - Virus Replication PMC - PMC6692512 OTO - NOTNLM OT - AID inhibitor OT - Apobec3 OT - activation-induced cytidine deaminase OT - mouse mammary tumor virus OT - retroviruses EDAT- 2019/08/15 06:00 MHDA- 2020/05/06 06:00 PMCR- 2019/08/13 CRDT- 2019/08/15 06:00 PHST- 2019/08/15 06:00 [entrez] PHST- 2019/08/15 06:00 [pubmed] PHST- 2020/05/06 06:00 [medline] PHST- 2019/08/13 00:00 [pmc-release] AID - mBio.01678-19 [pii] AID - mBio01678-19 [pii] AID - 10.1128/mBio.01678-19 [doi] PST - epublish SO - mBio. 2019 Aug 13;10(4):e01678-19. doi: 10.1128/mBio.01678-19.