Editorial

5 pages, 200 KiB

Open AccessEditorial

Special Issue “APOBECs and Virus Restriction”

by Linda Chelico

Viruses 2021, 13(8), 1613; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081613 - 15 Aug 2021

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The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [...] Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

Research

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14 pages, 5588 KiB

Open AccessArticle

Structural Characterization of a Minimal Antibody against Human APOBEC3B

by Heng Tang, Özlem Demir, Fredy Kurniawan, William L. Brown, Ke Shi, Nicholas H. Moeller, Michael A. Carpenter, Christopher Belica, Kayo Orellana, Guocheng Du, Aaron M. LeBeau, Rommie E. Amaro, Reuben S. Harris and Hideki Aihara

Viruses 2021, 13(4), 663; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040663 - 12 Apr 2021

Cited by 2 | Viewed by 3065

Abstract

APOBEC3B (A3B) is one of seven human APOBEC3 DNA cytosine deaminases that restrict viral infections as part of the overall innate immune response, but it also plays a major role in tumor evolution by mutating genomic DNA. Given the importance of A3B as [...] Read more.

APOBEC3B (A3B) is one of seven human APOBEC3 DNA cytosine deaminases that restrict viral infections as part of the overall innate immune response, but it also plays a major role in tumor evolution by mutating genomic DNA. Given the importance of A3B as a restriction factor of viral infections and as a driver of multiple human cancers, selective antibodies against A3B are highly desirable for its specific detection in various research and possibly diagnostic applications. Here, we describe a high-affinity minimal antibody, designated 5G7, obtained via a phage display screening against the C-terminal catalytic domain (ctd) of A3B. 5G7 also binds APOBEC3A that is highly homologous to A3Bctd but does not bind the catalytic domain of APOBEC3G, another Z1-type deaminase domain. The crystal structure of 5G7 shows a canonical arrangement of the heavy and light chain variable domains, with their complementarity-determining region (CDR) loops lining an antigen-binding cleft that accommodates a pair of α-helices. To understand the mechanism of A3Bctd recognition by 5G7, we used the crystal structures of A3Bctd and 5G7 as templates and computationally predicted the A3B-5G7 complex structure. Stable binding poses obtained by the simulation were further tested by site-directed mutagenesis and in vitro binding analyses. These studies mapped the epitope for 5G7 to a portion of C-terminal α6 helix of A3Bctd, with Arg374 playing an essential role. The same region of A3Bctd was used previously as a peptide antigen for generating a rabbit monoclonal antibody (mAb 5210-87-13), suggesting that this region is particularly immunogenic and that these antibodies from very different origins may share similar binding modes. Our studies provide a platform for the development of selective antibodies against A3B and other APOBEC3 family enzymes. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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25 pages, 31870 KiB

Open AccessArticle

Small-Angle X-ray Scattering Models of APOBEC3B Catalytic Domain in a Complex with a Single-Stranded DNA Inhibitor

by Fareeda M. Barzak, Timothy M. Ryan, Maksim V. Kvach, Harikrishnan M. Kurup, Hideki Aihara, Reuben S. Harris, Vyacheslav V. Filichev, Elena Harjes and Geoffrey B. Jameson

Viruses 2021, 13(2), 290; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020290 - 12 Feb 2021

Cited by 6 | Viewed by 2964

Abstract

In normal cells APOBEC3 (A3A-A3H) enzymes as part of the innate immune system deaminate cytosine to uracil on single-stranded DNA (ssDNA) to scramble DNA in order to give protection against a range of exogenous retroviruses, DNA-based parasites, and endogenous retroelements. However, some viruses [...] Read more.

In normal cells APOBEC3 (A3A-A3H) enzymes as part of the innate immune system deaminate cytosine to uracil on single-stranded DNA (ssDNA) to scramble DNA in order to give protection against a range of exogenous retroviruses, DNA-based parasites, and endogenous retroelements. However, some viruses and cancer cells use these enzymes, especially A3A and A3B, to escape the adaptive immune response and thereby lead to the evolution of drug resistance. We have synthesized first-in-class inhibitors featuring modified ssDNA. We present models based on small-angle X-ray scattering (SAXS) data that (1) confirm that the mode of binding of inhibitor to an active A3B C-terminal domain construct in the solution state is the same as the mode of binding substrate to inactive mutants of A3A and A3B revealed in X-ray crystal structures and (2) give insight into the disulfide-linked inactive dimer formed under the oxidizing conditions of purification. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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Review

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24 pages, 10423 KiB

Open AccessReview

Human APOBEC3 Variations and Viral Infection

by Shiva Sadeghpour, Saeideh Khodaee, Mostafa Rahnama, Hamzeh Rahimi and Diako Ebrahimi

Viruses 2021, 13(7), 1366; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071366 - 14 Jul 2021

Cited by 25 | Viewed by 4231

Abstract

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive [...] Read more.

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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20 pages, 1967 KiB

Open AccessReview

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

by Amit Gaba, Ben Flath and Linda Chelico

Viruses 2021, 13(6), 1084; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061084 - 07 Jun 2021

Cited by 13 | Viewed by 3886

Abstract

The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus [...] Read more.

The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (−)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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17 pages, 2202 KiB

Open AccessReview

Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein

by Benjamin Stupfler, Cédric Verriez, Sarah Gallois-Montbrun, Roland Marquet and Jean-Christophe Paillart

Viruses 2021, 13(4), 617; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040617 - 03 Apr 2021

Cited by 11 | Viewed by 3576

Abstract

The ubiquitin–proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary proteins from the (HIV-1) divert this system to its own advantage, notably to induce the degradation of cellular restriction factors. For [...] Read more.

The ubiquitin–proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary proteins from the (HIV-1) divert this system to its own advantage, notably to induce the degradation of cellular restriction factors. For instance, the HIV-1 viral infectivity factor (Vif) has been shown to specifically counteract several cellular deaminases belonging to the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 or A3) family (A3A to A3H) by recruiting an E3-ubiquitin ligase complex and inducing their polyubiquitination and degradation through the proteasome. Although this pathway has been extensively characterized so far, Vif has also been shown to impede A3s through degradation-independent processes, but research on this matter remains limited. In this review, we describe our current knowledge regarding the degradation-independent inhibition of A3s, and A3G in particular, by the HIV-1 Vif protein, the molecular mechanisms involved, and highlight important properties of this small viral protein. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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23 pages, 1842 KiB

Open AccessReview

Foamy Viruses, Bet, and APOBEC3 Restriction

by Ananda Ayyappan Jaguva Vasudevan, Daniel Becker, Tom Luedde, Holger Gohlke and Carsten Münk

Viruses 2021, 13(3), 504; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030504 - 18 Mar 2021

Cited by 6 | Viewed by 3229

Abstract

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic [...] Read more.

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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25 pages, 5664 KiB

Open AccessReview

Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions

by Xiaojiang S. Chen

Viruses 2021, 13(3), 497; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030497 - 17 Mar 2021

Cited by 11 | Viewed by 3390

Abstract

Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single-stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and [...] Read more.

Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single-stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and innate immunity, which are critical for restricting viral infection and endogenous retroelements. Dysregulation of their functions can cause undesired genomic mutations and RNA modification, leading to various associated diseases, such as hyper-IgM syndrome and cancer. This review focuses on the structural and biochemical data on the multimerization status of individual APOBECs and the associated functional implications. Many APOBECs form various multimeric complexes, and multimerization is an important way to regulate functions for some of these proteins at several levels, such as deaminase activity, protein stability, subcellular localization, protein storage and activation, virion packaging, and antiviral activity. The multimerization of some APOBECs is more complicated than others, due to the associated complex RNA binding modes. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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15 pages, 2273 KiB

Open AccessReview

APOBECs and Herpesviruses

by Adam Z. Cheng, Sofia N. Moraes, Nadine M. Shaban, Elisa Fanunza, Craig J. Bierle, Peter J. Southern, Wade A. Bresnahan, Stephen A. Rice and Reuben S. Harris

Viruses 2021, 13(3), 390; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030390 - 28 Feb 2021

Cited by 34 | Viewed by 4148

Abstract

The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and [...] Read more.

The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded (ss)DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes—APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new pathogen-host conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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11 pages, 748 KiB

Open AccessReview

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

by Keiya Uriu, Yusuke Kosugi, Jumpei Ito and Kei Sato

Viruses 2021, 13(1), 124; https://0-doi-org.brum.beds.ac.uk/10.3390/v13010124 - 17 Jan 2021

Cited by 28 | Viewed by 4837

Abstract

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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12 pages, 1056 KiB

Open AccessReview

Mouse APOBEC3 Restriction of Retroviruses

by Karen Salas-Briceno, Wenming Zhao and Susan R. Ross

Viruses 2020, 12(11), 1217; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111217 - 27 Oct 2020

Cited by 11 | Viewed by 2804

Abstract

Apolipoprotein B mRNA editing enzyme, catalytic peptide 3 (APOBEC3) proteins are critical host proteins that counteract and prevent the replication of retroviruses. Unlike the genome of humans and other species, the mouse genome encodes a single Apobec3 gene, which has undergone positive selection, [...] Read more.

Apolipoprotein B mRNA editing enzyme, catalytic peptide 3 (APOBEC3) proteins are critical host proteins that counteract and prevent the replication of retroviruses. Unlike the genome of humans and other species, the mouse genome encodes a single Apobec3 gene, which has undergone positive selection, as reflected by the allelic variants found in different inbred mouse strains. This positive selection was likely due to infection by various mouse retroviruses, which have persisted in their hosts for millions of years. While mouse retroviruses are inhibited by APOBEC3, they nonetheless still remain infectious, likely due to the actions of different viral proteins that counteract this host factor. The study of viruses in their natural hosts provides important insight into their co-evolution. Full article

(This article belongs to the Special Issue APOBECs and Virus Restriction)

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