scholarly journals The Role of APOBECs in Viral Replication

2020 ◽  
Vol 8 (12) ◽  
pp. 1899
Author(s):  
Wendy Kaichun Xu ◽  
Hyewon Byun ◽  
Jaquelin P. Dudley
Keyword(s):  
Viral Replication ◽  
Mammalian Species ◽  
Specific Gene ◽  
Viral Inhibition ◽  
Cytidine Deaminases ◽  
Catalytically Active ◽  
Antiviral Function ◽  
Selection For ◽  
Vif Protein ◽  
Hiv 1

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 HIV-1 Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to APOBEC selection for viral variants that enhance replication or avoid immune elimination.

scholarly journals The Role of APOBECs in Viral Replication

2020 ◽  
Author(s):  
Wendy K. Xu ◽  
Hyewon Byun ◽  
Jaquelin P. Dudley
Keyword(s):  
Viral Replication ◽  
Mammalian Species ◽  
Specific Gene ◽  
Viral Inhibition ◽  
Cytidine Deaminases ◽  
Catalytically Active ◽  
Antiviral Function ◽  
Selection For ◽  
Vif Protein ◽  
Hiv 1

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.

scholarly journals Divergence in dimerization and activity of primate APOBEC3C

2021 ◽  
Author(s):  
Amit Gaba ◽  
Mark A Hix ◽  
Sana Suhail ◽  
Ben Flath ◽  
Brock Boysan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
World Monkey ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Host Restriction ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Vif Protein ◽  
Hiv 1

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Multiple integrated analyses determined why rhA3C was not active against HIV-1 and how to increase this activity. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity also promoted dimerization. Although rhA3C shares a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C, establish the amino acid network for dimerization and increased activity, and track the loss and gain of A3C antiviral activity in primates. The coevolutionary analysis of the A3C dimerization interface provides a basis from which to analyze dimerization interfaces of other A3 family members.

scholarly journals Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Anjuman Ara ◽  
Robin P. Love ◽  
Tyson B. Follack ◽  
Khawaja A. Ahmed ◽  
Madison B. Adolph ◽  
...  
Keyword(s):  
Size Exclusion ◽  
Minus Strand ◽  
Cytidine Deaminases ◽  
Proviral Dna ◽  
Exclusion Chromatography ◽  
Viral Infectivity Factor ◽  
Biochemical Analyses ◽  
Vif Protein ◽  
Hiv 1

ABSTRACT The APOBEC3 (A3) enzymes, A3G and A3F, are coordinately expressed in CD4+ T cells and can become coencapsidated into HIV-1 virions, primarily in the absence of the viral infectivity factor (Vif). A3F and A3G are deoxycytidine deaminases that inhibit HIV-1 replication by inducing guanine-to-adenine hypermutation through deamination of cytosine to form uracil in minus-strand DNA. The effect of the simultaneous presence of both A3G and A3F on HIV-1 restriction ability is not clear. Here, we used a single-cycle infectivity assay and biochemical analyses to determine if coencapsidated A3G and A3F differ in their restriction capacity from A3G or A3F alone. Proviral DNA sequencing demonstrated that compared to each A3 enzyme alone, A3G and A3F, when combined, had a coordinate effect on hypermutation. Using size exclusion chromatography, rotational anisotropy, and in vitro deamination assays, we demonstrate that A3F promotes A3G deamination activity by forming an A3F/G hetero-oligomer in the absence of RNA which is more efficient at deaminating cytosines. Further, A3F caused the accumulation of shorter reverse transcripts due to decreasing reverse transcriptase efficiency, which would leave single-stranded minus-strand DNA exposed for longer periods of time, enabling more deamination events to occur. Although A3G and A3F are known to function alongside each other, these data provide evidence for an A3F/G hetero-oligomeric A3 with unique properties compared to each individual counterpart. IMPORTANCE The APOBEC3 enzymes APOBEC3F and APOBEC3G act as a barrier to HIV-1 replication in the absence of the HIV-1 Vif protein. After APOBEC3 enzymes are encapsidated into virions, they deaminate cytosines in minus-strand DNA, which forms promutagenic uracils that induce transition mutations or proviral DNA degradation. Even in the presence of Vif, footprints of APOBEC3-catalyzed deaminations are found, demonstrating that APOBEC3s still have discernible activity against HIV-1 in infected individuals. We undertook a study to better understand the activity of coexpressed APOBEC3F and APOBEC3G. The data demonstrate that an APOBEC3F/APOBEC3G hetero-oligomer can form that has unique properties compared to each APOBEC3 alone. This hetero-oligomer has increased efficiency of virus hypermutation, raising the idea that we still may not fully realize the antiviral mechanisms of endogenous APOBEC3 enzymes. Hetero-oligomerization may be a mechanism to increase their antiviral activity in the presence of Vif.

scholarly journals Association of Potent Human Antiviral Cytidine Deaminases with 7SL RNA and Viral RNP in HIV-1 Virions

2010 ◽  
Vol 84 (24) ◽  
pp. 12903-12913 ◽  
Author(s):  
Wenyan Zhang ◽  
Juan Du ◽  
Kevin Yu ◽  
Tao Wang ◽  
Xiong Yong ◽  
...  
Keyword(s):  
Rna Binding ◽  
Signal Recognition Particle ◽  
Viral Inhibition ◽  
Cytidine Deaminases ◽  
Amino Terminal ◽  
7Sl Rna ◽  
Rnp Complex ◽  
Rna Interaction ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT 7SL RNA promotes the formation of the signal recognition particle that targets secretory and membrane proteins to the endoplasmic reticulum. 7SL RNA is also selectively packaged by many retroviruses, including HIV-1. Here, we demonstrate that 7SL RNA is an integral component of the viral ribonucleoprotein (RNP) complex containing Gag, viral genomic RNA, and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathbf{tRNA}_{3}^{Lys}\) \end{document} . Only the potent anti-HIV-1 cytidine deaminases can bind to 7SL RNA and target to HIV-1 RNP. A conserved motif in the amino-terminal region of A3G is important for 7SL RNA interaction. The weak anti-HIV-1 A3C did not interact with 7SL RNA and failed to target to viral RNPs, despite efficient virion packaging. However, a chimeric construct of A3C plus the 7SL-binding amino terminus of A3G did target to viral RNPs and showed enhanced anti-HIV-1 activity. 7SL RNA binding is a conserved feature of human anti-HIV-1 cytidine deaminases. Thus, potent anti-HIV-1 cytidine deaminases have evolved to possess a unique RNA-binding ability for precise HIV-1 targeting and viral inhibition.

scholarly journals Structural features of antiviral DNA cytidine deaminases

2013 ◽  
Vol 394 (11) ◽  
pp. 1357-1370 ◽  
Author(s):  
Ananda Ayyappan Jaguva Vasudevan ◽  
Sander H.J. Smits ◽  
Astrid Höppner ◽  
Dieter Häussinger ◽  
Bernd W. Koenig ◽  
...  
Keyword(s):  
Cytidine Deaminase ◽  
Structural Features ◽  
Zinc Ion ◽  
Vital Role ◽  
Cytidine Deaminases ◽  
Innate Defense ◽  
Individual Structure ◽  
Vif Protein ◽  
Hiv 1 ◽  
Viral Reverse Transcription

Abstract The APOBEC3 (A3) family of cytidine deaminases plays a vital role for innate defense against retroviruses. Lentiviruses such as HIV-1 evolved the Vif protein that triggers A3 protein degradation. There are seven A3 proteins, A3A-A3H, found in humans. All A3 proteins can deaminate cytidines to uridines in single-stranded DNA (ssDNA), generated during viral reverse transcription. A3 proteins have either one or two cytidine deaminase domains (CD). The CDs coordinate a zinc ion, and their amino acid specificity classifies the A3s into A3Z1, A3Z2, and A3Z3. A3 proteins occur as monomers, dimers, and large oligomeric complexes. Studies on the nature of A3 oligomerization, as well as the mode of interaction of A3s with RNA and ssDNA are partially controversial. High-resolution structures of the catalytic CD2 of A3G and A3F as well as of the single CD proteins A3A and A3C have been published recently. The NMR and X-ray crystal structures show globular proteins with six α-helices and five β sheets arranged in a characteristic motif (α1-β1-β2/2′-α2-β3-α3-β4-α4-β5-α5-α6). However, the detailed arrangement and extension of individual structure elements and their relevance for A3 complex formation and activity remains a matter of debate and will be highlighted in this review.

scholarly journals Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids

2010 ◽  
Vol 84 (14) ◽  
pp. 7312-7324 ◽  
Author(s):  
Jörg Zielonka ◽  
Daniela Marino ◽  
Henning Hofmann ◽  
Naoya Yuhki ◽  
Martin Löchelt ◽  
...  
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Domestic Cat ◽  
Moderate Degree ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Immunodeficiency Virus ◽  
Specific Restriction ◽  
Species Specific ◽  
Vif Protein ◽  
Hiv 1

ABSTRACT To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Δvif FIV, felid A3Z2s did not show any antiviral activity against Δvif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether VifFIV can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1.VifFIV was constructed. This HIV-1.VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor.

scholarly journals Functional Neutralization of HIV-1 Vif Protein by Intracellular Immunization Inhibits Reverse Transcription and Viral Replication

2002 ◽  
Vol 277 (35) ◽  
pp. 32036-32045 ◽  
Author(s):  
Joao Goncalves ◽  
Frederico Silva ◽  
Acilino Freitas-Vieira ◽  
Mariana Santa-Marta ◽  
Rui Malhó ◽  
...  
Keyword(s):  
Viral Replication ◽  
Reverse Transcription ◽  
Intracellular Immunization ◽  
Vif Protein ◽  
Hiv 1

scholarly journals Endoribonuclease-Prepared Short Interfering RNAs Induce Effective and Specific Inhibition of Human Immunodeficiency Virus Type 1 Replication

2007 ◽  
Vol 81 (19) ◽  
pp. 10680-10686 ◽  
Author(s):  
Mireia Gimenez-Barcons ◽  
Bonaventura Clotet ◽  
Miguel Angel Martinez
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Escape ◽  
Viral Inhibition ◽  
Rnase Iii ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Short interfering RNAs (siRNAs) targeting viral or cellular genes can efficiently inhibit human immunodeficiency virus type 1 (HIV-1) replication. Nevertheless, optimal HIV-1 gene silencing by siRNA requires precise complementarity with most of the target sequence. The emergence of mutations in the targeted gene could lead to rapid viral escape from the siRNA. In the present study, Escherichia coli endoribonuclease III (RNase III) or mammalian Dicer was used to cleave double-stranded RNA into endoribonuclease-prepared siRNA (esiRNA). esiRNAs generate a variety of siRNAs which can efficiently and specifically target multiple sites in the cognate RNA. esiRNAs targeting the region encoding the HIV-1 reverse transcriptase (RT) reduced viral replication by 90%. The inhibition was dose dependent and sequence specific because several irrelevant esiRNAs did not inhibit HIV-1 replication. Importantly, esiRNAs obtained from the prototypic RT sequence of the HXB2 strain and from highly mutated RT sequences showed similar degrees of viral inhibition, suggesting that the heterogeneous population of esiRNAs could overcome individual mismatches in the RT sequence. Finally, esiRNAs generated by Dicer cleavage were five times more potent than those generated by bacterial RNase III digestion. These results show that esiRNAs are potent HIV-1 inhibitors. Moreover, sequence targets do not need to be highly conserved to reach a high level of viral replication inhibition.

scholarly journals Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture

2009 ◽  
Vol 54 (3) ◽  
pp. 1047-1054 ◽  
Author(s):  
Daniel A. Donahue ◽  
Richard D. Sloan ◽  
Björn D. Kuhl ◽  
Tamara Bar-Magen ◽  
Susan M. Schader ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Replication ◽  
Reverse Transcription ◽  
Antiretroviral Drugs ◽  
Proteolytic Processing ◽  
Viral Inhibition ◽  
Dependent Inhibition ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT Recent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data provide in vitro evidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.

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