A high rate of polymerization during synthesis of mouse mammary tumor virus DNA alleviates hypermutation by APOBEC3 proteins

Hagen, Benedikt; Kraase, Martin; Indikova, Ivana; Indik, Stanislav

doi:10.1371/journal.ppat.1007533

Cited by 16 publications

(16 citation statements)

References 64 publications

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“…Previous data from studies of mA3-insufficient mice indicated that MMTV replication and tumorigenesis are inhibited by members of the Apobec family of cytidine deaminases (12). No MMTV-specified inhibitors of these enzymes have been reported, including in a recent report that concluded on the basis of transfection experiments in 293T cells that MMTV does not encode an mA3 inhibitor (54). Our experiments are consistent with the need for Rem C-terminal sequences to antagonize the mutagenic effects of the Apobec cytidine deaminase AID during MMTV replication in lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

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

Singh

Byun

Ali

et al. 2019

mBio

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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.

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Section: Discussionmentioning

confidence: 99%

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

Singh

Byun

Ali

et al. 2019

mBio

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“…As described above, Vif is a well-studied viral protein that counteracts host APOBEC3 proteins. Other than Vif, some viral proteins such as HIV-1 protease [ 68 ] and RT [ 69 ], FIV protease [ 57 ], murine leukemia virus protease [ 70 ] and glycogag [ 71 ], human T-cell leukemia virus type I capsid [ 72 ], and mouse mammary tumor virus RT [ 73 ] potentially counteract host antiviral APOBEC3 proteins. These observations suggest that retroviruses have evolved a variety of strategies to counteract APOBEC3 proteins.…”

Section: Apobec3 Proteins and Non-retrovirusesmentioning

confidence: 99%

The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present

Uriu

Kosugi

Ito

et al. 2021

Viruses

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The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. APOBEC3 genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian APOBEC3 genes and viruses.

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“…In a second study, a different group suggested that MMTV evolved its reverse transcriptase for a high polymerization rate to escape mA3 hypermutation during cDNA synthesis [301]. Using cell culture and overexpression experiments, Hagen et al showed that MMTV packaged the same levels of human A3G or mA3 as HIV-1 lacking Vif expression (HIV-1-ΔVif).…”

Section: Betaretroviruses and Deamination-independent Apobec Activitymentioning

confidence: 99%

The Role of APOBECs in Viral Replication

Xu¹,

Byun²,

Dudley³

2020

Preprint

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Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to selection for viral variants.

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A high rate of polymerization during synthesis of mouse mammary tumor virus DNA alleviates hypermutation by APOBEC3 proteins

Cited by 16 publications

References 64 publications

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

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

The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present

The Role of APOBECs in Viral Replication

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