Foamy Viruses, Bet, and APOBEC3 Restriction

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.

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Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

Current HIV Research ◽

10.2174/1570162x16666180817115830 ◽

2018 ◽

Vol 16 (3) ◽

pp. 184-207 ◽

Cited By ~ 9

Author(s):

Vanessa D`Urbano ◽

Elisa De Crignis ◽

Maria Carla Re

Keyword(s):

Mammalian Cells ◽

Viral Evolution ◽

Type I ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Immunodeficiency Virus ◽

Lentiviral Infection ◽

Specific Proteins ◽

Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

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The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates

Journal of Virology ◽

10.1128/jvi.00972-16 ◽

2016 ◽

Vol 90 (18) ◽

pp. 8085-8089 ◽

Cited By ~ 26

Author(s):

Ben Murrell ◽

Thomas Vollbrecht ◽

John Guatelli ◽

Joel O. Wertheim

Keyword(s):

Viral Infections ◽

Arms Race ◽

Restriction Factor ◽

Restriction Factors ◽

Arms Races ◽

Host Restriction ◽

Host Restriction Factor ◽

Novel Host ◽

Evolutionary Arms Race ◽

Hiv 1

ABSTRACTMolecular evolutionary arms races between viruses and their hosts are important drivers of adaptation. These Red Queen dynamics have been frequently observed in primate retroviruses and their antagonists, host restriction factor genes, such as APOBEC3F/G, TRIM5-α, SAMHD1, and BST-2. Host restriction factors have experienced some of the most intense and pervasive adaptive evolution documented in primates. Recently, two novel host factors, SERINC3 and SERINC5, were identified as the targets of HIV-1 Nef, a protein crucial for the optimal infectivity of virus particles. Here, we compared the evolutionary fingerprints of SERINC3 and SERINC5 to those of other primate restriction factors and to a set of other genes with diverse functions. SERINC genes evolved in a manner distinct from the canonical arms race dynamics seen in the other restriction factors. Despite their antiviral activity against HIV-1 and other retroviruses, SERINC3 and SERINC5 have a relatively uneventful evolutionary history in primates.IMPORTANCERestriction factors are host proteins that block viral infection and replication. Many viruses, like HIV-1 and related retroviruses, evolved accessory proteins to counteract these restriction factors. The importance of these interactions is evidenced by the intense adaptive selection pressures that dominate the evolutionary histories of both the host and viral genes involved in this so-called arms race. The dynamics of these arms races can point to mechanisms by which these viral infections can be prevented. Two human genes, SERINC3 and SERINC5, were recently identified as targets of an HIV-1 accessory protein important for viral infectivity. Unexpectedly, we found that these SERINC genes, unlike other host restriction factor genes, show no evidence of a recent evolutionary arms race with viral pathogens.

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Divergence in dimerization and activity of primate APOBEC3C

10.1101/2021.07.13.452235 ◽

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.

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Accessory Regulatory Proteins of HIV-1 and Host Restriction Factors Interactions

Biomedical Journal of Scientific & Technical Research ◽

10.26717/bjstr.2020.31.005120 ◽

2020 ◽

Vol 31 (4) ◽

Author(s):

Lopez Hernandez

Keyword(s):

Regulatory Proteins ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

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Cul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 and host restriction

10.21203/rs.3.rs-912958/v1 ◽

2021 ◽

Author(s):

Rongrong Li ◽

Iqbal Ahmad ◽

Sunan Li ◽

Silas Johnson ◽

Liangliang Sun ◽

...

Keyword(s):

Plasma Membrane ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Productive Infection ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factor ◽

Cullin 3 ◽

Golgi Network ◽

Hiv 1

Abstract HIV-1 must counteract various host restriction factors to establish productive infection. SERINC5 is a critical host restriction factor that potently blocks HIV-1 entry from virions, but its activity is counteracted by Nef. The SERINC5 and Nef activities are both initiated from the plasma membrane, where SERINC5 is packaged into virions and downregulated by Nef via lysosomal degradation. However, it is still unclear how SERINC5 is localized to the plasma membrane and how its expression is regulated on the plasma membrane. We now report that Cullin 3-KLHL20, a trans-Golgi network (TGN)-localized E3 ubiquitin ligase, polyubiquitinates SERINC5 at lysine 130 via K33- and K48-linked ubiquitin chains. The K130 polyubiquitination is required not only for the SERINC5 expression on the plasma membrane, but also the SERINC5 anti-HIV-1 activity and the Nef counteractive activity. Our study reveals an important role of K33/K48-branched ubiquitin chains in HIV-1 infection by regulating protein post-Golgi trafficking and degradation.

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Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses

Frontiers in Immunology ◽

10.3389/fimmu.2021.740713 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenying Gao ◽

Yajuan Rui ◽

Guangquan Li ◽

Chenyang Zhai ◽

Jiaming Su ◽

...

Keyword(s):

Viral Replication ◽

Ectopic Expression ◽

Specific Inhibitor ◽

Restriction Factors ◽

Deubiquitinating Enzymes ◽

Host Restriction ◽

Host Restriction Factors ◽

Virion Infectivity Factor ◽

Specific Protease ◽

Hiv 1

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host’s DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

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Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

Frontiers in Immunology ◽

10.3389/fimmu.2021.716927 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kumaraswami Chintala ◽

Krishnaveni Mohareer ◽

Sharmistha Banerjee

Keyword(s):

Innate Immunity ◽

Life Cycle ◽

Innate Immune ◽

Therapeutic Interventions ◽

Innate Immune Responses ◽

Restriction Factors ◽

Host Restriction ◽

Interferon Stimulated Genes ◽

Host Restriction Factors ◽

Hiv 1

Host restriction factors affect different phases of a viral life cycle, contributing to innate immunity as the first line of defense against viruses, including HIV-1. These restriction factors are constitutively expressed, but triggered upon infection by interferons. Both pre-integration and post-integration events of the HIV-1 life cycle appear to play distinct roles in the induction of interferon-stimulated genes (ISGs), many of which encode antiviral restriction factors. However, HIV-1 counteracts the mechanisms mediated by these restriction factors through its encoded components. Here, we review the recent findings of pathways that lead to the induction of ISGs, and the mechanisms employed by the restriction factors such as IFITMs, APOBEC3s, MX2, and ISG15 in preventing HIV-1 replication. We also reflect on the current understanding of the counter-mechanisms employed by HIV-1 to evade innate immune responses and overcome host restriction factors. Overall, this mini-review provides recent insights into the HIV-1-host cross talk bridging the understanding between intracellular immunity and research avenues in the field of therapeutic interventions against HIV-1.

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