A role for gorilla APOBEC3G in shaping lentivirus evolution including transmission to humans

Nakano, Yoshiaki; Yamamoto, Keisuke; Ueda, Mahoko Takahashi; Soper, Andrew; Konno, Yoriyuki; Kimura, Izumi; Uriu, Keiya; Kumata, Ryuichi; Aso, Hirofumi; Misawa, Naoko; Nagaoka, Sumiharu; Shimizu, Soma; Mitsumune, Keito; Kosugi, Yusuke; Juarez-Fernandez, Guillermo; Ito, Jumpei; Nakagawa, So; Ikeda, Terumasa; Koyanagi, Yoshio; Harris, Reuben S.; Sato, Kei

doi:10.1371/journal.ppat.1008812

Cited by 19 publications

(16 citation statements)

References 48 publications

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“…Cellular restriction factors and their antagonization by viral effector proteins can act as decisive factors for cross-species transmission of viruses. This has extensively been studied for antiretroviral restriction factors like APOBEC3 deaminases which need to be degraded by adapted lentiviral vif proteins in order to allow cross-species infection [ 47 ]. In contrast, the mechanisms limiting cross-species infection of cytomegaloviruses are less well understood.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

Schweininger

Scherer²,

Rothemund³

et al. 2021

PLoS Pathog

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Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.

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Section: Discussionmentioning

confidence: 99%

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

Schweininger

Scherer²,

Rothemund³

et al. 2021

PLoS Pathog

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“…This observation suggests that gorilla APOBEC3G has played a role in restricting the cross-species transmission of SIVcpz from chimpanzees to gorillas as a species barrier and that SIVcpz Vif evolved into SIVgor Vif by acquiring the ability to counteract gorilla APOBEC3G. Intriguingly, Nakano et al recently demonstrated that a single amino acid mutation (M16E) enabled SIVcpz Vif to degrade and counteract gorilla APOBEC3G [ 50 ]. Methionine (M) at amino acid position 16 is highly conserved in SIVcpz Vif, while glutamic acid (E) is conserved in SIVgor Vif [ 50 ].…”

Section: Role Of Mammalian Apobec3 Proteins In Cross-species Lentimentioning

confidence: 99%

“…Intriguingly, Nakano et al recently demonstrated that a single amino acid mutation (M16E) enabled SIVcpz Vif to degrade and counteract gorilla APOBEC3G [ 50 ]. Methionine (M) at amino acid position 16 is highly conserved in SIVcpz Vif, while glutamic acid (E) is conserved in SIVgor Vif [ 50 ]. Second, SIVcpz Vif proteins cannot counteract human antiviral APOBEC3H, while HIV-1M Vif can [ 51 ].…”

Section: Role Of Mammalian Apobec3 Proteins In Cross-species Lentimentioning

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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“…APOBEC3 proteins are examples of host factors that restrict cross-species transmission of lentiviruses [reviewed by Nakano et al (2017a) ; Uriu et al (2021) ]. Interactions between mammalian A3 proteins and lentiviral Vifs are largely specific to viruses in their hosts ( Mariani et al, 2003 ; Compton et al, 2012 ; Etienne et al, 2015 ; Yamada et al, 2016 ; Zhang et al, 2016 ; Nakano et al, 2020 ). As examples, HIV-1 Vif can degrade A3G protein from humans but not from African green monkeys or rhesus macaques ( Bogerd et al, 2004 ; Schrofelbauer et al, 2004 ; Xu et al, 2004 ).…”

Section: Potential Utilization Of Vif-resistant A3 Proteins For An Hiv-1 Functional Curementioning

confidence: 99%

Potential Utilization of APOBEC3-Mediated Mutagenesis for an HIV-1 Functional Cure

et al. 2021

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The introduction of combination antiretroviral therapy (cART) has managed to control the replication of human immunodeficiency virus type 1 (HIV-1) in infected patients. However, a complete HIV-1 cure, including a functional cure for or eradication of HIV-1, has yet to be achieved because of the persistence of latent HIV-1 reservoirs in adherent patients. The primary source of these viral reservoirs is integrated proviral DNA in CD4+ T cells and other non-T cells. Although a small fraction of this proviral DNA is replication-competent and contributes to viral rebound after the cessation of cART, >90% of latent viral reservoirs are replication-defective and some contain high rates of G-to-A mutations in proviral DNA. At least in part, these high rates of G-to-A mutations arise from the APOBEC3 (A3) family proteins of cytosine deaminases. A general model has shown that the HIV-1 virus infectivity factor (Vif) degrades A3 family proteins by proteasome-mediated pathways and inactivates their antiviral activities. However, Vif does not fully counteract the HIV-1 restriction activity of A3 family proteins in vivo, as indicated by observations of A3-mediated G-to-A hypermutation in the proviral DNA of HIV-1-infected patients. The frequency of A3-mediated hypermutation potentially contributes to slower HIV-1/AIDS disease progression and virus evolution including the emergence of cytotoxic T lymphocyte escape mutants. Therefore, combined with other strategies, the manipulation of A3-mediated mutagenesis may contribute to an HIV-1 functional cure aimed at cART-free remission. In this mini-review, we discuss the possibility of an HIV-1 functional cure arising from manipulation of A3 mutagenic activity.

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A role for gorilla APOBEC3G in shaping lentivirus evolution including transmission to humans

Cited by 19 publications

References 48 publications

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

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

Potential Utilization of APOBEC3-Mediated Mutagenesis for an HIV-1 Functional Cure

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