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Viruses
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Viral Accessory Proteins
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Viral Accessory Proteins

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 13220

Special Issue Editor

Dr. Jimmy D. Dikeakos

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
Interests: HIV-1; Nef; Vpu; SARS-CoV-2; membrane trafficking; microscopy

Special Issue Information

Dear Colleagues,

A defining characteristic of complex retroviruses such as human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) is the expression of an array of accessory proteins. These accessory proteins typically mediate multiple aspects of adaptive and innate immune evasion and are key viral elements ensuring the virus can thrive in the harsh host environment. Accessory proteins for HIV and SIV include Nef, Vif, Vpr, Vpx, and Vpu. These proteins were originally termed accessory as they can often be dispensable for viral replication in certain in cellulo models. However, these proteins remain critical for the virus replication cycle when expressed within a host and are often critical mediators of viral pathogenesis. Moreover, accessory proteins can often antagonize the specific activity of host restriction factors that are expressed in response to viral infections, rendering the relationship between accessory proteins and restriction factors of particular importance.

In this Special Issue on “Viral Accessory Proteins”, we invite submissions on this exciting topic to highlight recent advances in this field. In addition, in light of the current global pandemic, and the continued study of SARS-CoV-2 open reading frames, we also invite submissions of research papers on SARS-CoV-2 accessory proteins to enhance our understanding of the SARS-CoV-2 genome.

Dr. Jimmy D. Dikeakos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Nef
  • Vpu
  • Vpr
  • Vif
  • SARS-CoV-2

Published Papers (6 papers)

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Research

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15 pages, 2851 KiB  
Article
A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation
by Claudia Firrito, Cinzia Bertelli, Annachiara Rosa, Ajit Chande, Swetha Ananth, Hannah van Dijk, Oliver T. Fackler, Charlotte Stoneham, Rajendra Singh, John Guatelli and Massimo Pizzato
Viruses 2023, 15(3), 652; https://doi.org/10.3390/v15030652 - 28 Feb 2023
Cited by 1 | Viewed by 1515
Abstract
The host transmembrane protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The lentiviral Nef protein counteracts SERINC5 by downregulating it from the cell surface and preventing its incorporation into virions. The ability of Nef to antagonize the host factor varies [...] Read more.
The host transmembrane protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The lentiviral Nef protein counteracts SERINC5 by downregulating it from the cell surface and preventing its incorporation into virions. The ability of Nef to antagonize the host factor varies in magnitude between different HIV-1 isolates. After having identified a subtype H nef allele unable to promote HIV-1 infectivity in the presence of SERINC5, we investigated the molecular determinants responsible for the defective counteraction of the host factor. Chimeric molecules with a subtype C Nef highly active against SERINC5 were constructed to locate Nef residues crucial for the activity against SERINC5. An Asn at the base of the C-terminal loop of the defective nef allele was found in place of a highly conserved acidic residue (D/E 150). The conversion of Asn to Asp restored the ability of the defective Nef to downregulate SERINC5 and promote HIV-1 infectivity. The substitution was also found to be crucial for the ability of Nef to downregulate CD4, but not for Nef activities that do not rely on the internalization of receptors from the cell surface, suggesting a general implication in promoting clathrin-mediated endocytosis. Accordingly, bimolecular fluorescence complementation revealed that the conserved acidic residue contributes to the recruitment of AP2 by Nef. Altogether, our results confirm that Nef downregulates SERINC5 and CD4 by engaging a similar machinery and indicates that, in addition to the di-leucine motif, other residues in the C-terminal flexible loop are important for the ability of the protein to sustain clathrin-mediated endocytosis. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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16 pages, 1479 KiB  
Article
The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi’s Sarcoma Tumors during Antiretroviral Therapy
by David J. Nolan, Rebecca Rose, Rongzhen Zhang, Alan Leong, Gary B. Fogel, Larissa L. S. Scholte, Jeffrey M. Bethony, Paige Bracci, Susanna L. Lamers and Michael S. McGrath
Viruses 2022, 14(12), 2774; https://doi.org/10.3390/v14122774 - 13 Dec 2022
Cited by 2 | Viewed by 1655
Abstract
Epidemic Kaposi’s sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, [...] Read more.
Epidemic Kaposi’s sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV env-nef found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180–250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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18 pages, 3420 KiB  
Article
Structural Dynamics and Activity of B19V VP1u during the pHs of Cell Entry and Endosomal Trafficking
by Renuk V. Lakshmanan, Joshua A. Hull, Luke Berry, Matthew Burg, Brian Bothner, Robert McKenna and Mavis Agbandje-McKenna
Viruses 2022, 14(9), 1922; https://doi.org/10.3390/v14091922 - 30 Aug 2022
Cited by 4 | Viewed by 2290
Abstract
Parvovirus B19 (B19V) is a human pathogen that is the causative agent of fifth disease in children. It is also known to cause hydrops in fetuses, anemia in AIDS patients, and transient aplastic crisis in patients with sickle cell disease. The unique N-terminus [...] Read more.
Parvovirus B19 (B19V) is a human pathogen that is the causative agent of fifth disease in children. It is also known to cause hydrops in fetuses, anemia in AIDS patients, and transient aplastic crisis in patients with sickle cell disease. The unique N-terminus of Viral Protein 1 (VP1u) of parvoviruses, including B19V, exhibits phospholipase A2 (PLA2) activity, which is required for endosomal escape. Presented is the structural dynamics of B19V VP1u under conditions that mimic the pHs of cell entry and endosomal trafficking to the nucleus. Using circular dichroism spectroscopy, the receptor-binding domain of B19V VP1u is shown to exhibit an α-helical fold, whereas the PLA2 domain exhibits a probable molten globule state, both of which are pH invariant. Differential scanning calorimetry performed at endosomal pHs shows that the melting temperature (Tm) of VP1u PLA2 domain is tuned to body temperature (37 °C) at pH 7.4. In addition, PLA2 assays performed at temperatures ranging from 25–45 °C show both a temperature and pH-dependent change in activity. We hypothesize that VP1u PLA2 domain differences in Tm at differing pHs have enabled the virus to “switch on/off” the phospholipase activity during capsid trafficking. Furthermore, we propose the environment of the early endosome as the optimal condition for endosomal escape leading to B19V infection. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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13 pages, 3409 KiB  
Article
Evolutionary Conservation of PP2A Antagonism and G2/M Cell Cycle Arrest in Maedi-Visna Virus Vif
by Adeline M. Luperchio, Stefán R. Jónsson and Daniel J. Salamango
Viruses 2022, 14(8), 1701; https://doi.org/10.3390/v14081701 - 01 Aug 2022
Cited by 1 | Viewed by 1571
Abstract
The canonical function of lentiviral Vif proteins is to counteract the mutagenic potential of APOBEC3 antiviral restriction factors. However, recent studies have discovered that Vif proteins from diverse HIV-1 and simian immunodeficiency virus (SIV) isolates degrade cellular B56 phosphoregulators to remodel the host [...] Read more.
The canonical function of lentiviral Vif proteins is to counteract the mutagenic potential of APOBEC3 antiviral restriction factors. However, recent studies have discovered that Vif proteins from diverse HIV-1 and simian immunodeficiency virus (SIV) isolates degrade cellular B56 phosphoregulators to remodel the host phosphoproteome and induce G2/M cell cycle arrest. Here, we evaluate the conservation of this activity among non-primate lentiviral Vif proteins using fluorescence-based degradation assays and demonstrate that maedi-visna virus (MVV) Vif efficiently degrades all five B56 family members. Testing an extensive panel of single amino acid substitution mutants revealed that MVV Vif recognizes B56 proteins through a conserved network of electrostatic interactions. Furthermore, experiments using genetic and pharmacologic approaches demonstrate that degradation of B56 proteins requires the cellular cofactor cyclophilin A. Lastly, MVV Vif-mediated depletion of B56 proteins induces a potent G2/M cell cycle arrest phenotype. Therefore, remodeling of the cellular phosphoproteome and induction of G2/M cell cycle arrest are ancient and conserved functions of lentiviral Vif proteins, which suggests that they are advantageous for lentiviral pathogenesis. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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16 pages, 1799 KiB  
Article
A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening
by Hirotaka Sato, Tomoyuki Murakami, Ryosuke Matsuura, Masako Abe, Seiji Matsuoka, Yoko Yashiroda, Minoru Yoshida, Hirofumi Akari, Yosuke Nagasawa, Masami Takei and Yoko Aida
Viruses 2022, 14(6), 1321; https://doi.org/10.3390/v14061321 - 16 Jun 2022
Cited by 2 | Viewed by 2544
Abstract
The human immunodeficiency virus type 1 (HIV-1) accessory protein, Vpr, arrests the cell cycle of the G2 phase, and this Vpr-mediated G2 arrest is implicated in an efficient HIV-1 spread in monocyte-derived macrophages. Here, we screened new candidates for Vpr-targeting HIV-1 inhibitors by [...] Read more.
The human immunodeficiency virus type 1 (HIV-1) accessory protein, Vpr, arrests the cell cycle of the G2 phase, and this Vpr-mediated G2 arrest is implicated in an efficient HIV-1 spread in monocyte-derived macrophages. Here, we screened new candidates for Vpr-targeting HIV-1 inhibitors by using fission yeast- and mammalian cell-based high-throughput screening. First, fission yeast strains expressing the HIV-1 Vpr protein were generated and then treated for 48 h with 20 μM of a synthetic library, including 140,000 chemical compounds. We identified 268 compounds that recovered the growth of Vpr-overexpressing yeast. The selected compounds were then tested in mammalian cells, and those displaying high cytotoxicity were excluded from further cell cycle analysis and imaging-based screening. A flow cytometry analysis confirmed that seven compounds recovered from the Vpr-induced G2 arrest. The cell toxicity and inhibitory effect of HIV-1 replication in human monocyte-derived macrophages (MDM) were examined, and three independent structural compounds, VTD227, VTD232, and VTD263, were able to inhibit HIV-1 replication in MDM. Furthermore, we showed that VTD227, but not VTD232 and VTD263, can directly bind to Vpr. Our results indicate that three new compounds and their derivatives represent new drugs targeting HIV-1 replication and can be potentially used in clinics to improve the current antiretroviral therapy. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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Review

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13 pages, 633 KiB  
Review
Antiretroviral Drug Discovery Targeting the HIV-1 Nef Virulence Factor
by Lori A. Emert-Sedlak, Haibin Shi, Colin M. Tice, Li Chen, John J. Alvarado, Sherry T. Shu, Shoucheng Du, Catherine E. Thomas, Jay E. Wrobel, Allen B. Reitz and Thomas E. Smithgall
Viruses 2022, 14(9), 2025; https://doi.org/10.3390/v14092025 - 13 Sep 2022
Cited by 3 | Viewed by 2882
Abstract
While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for [...] Read more.
While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for HIV-1 infection is therefore an essential goal of current AIDS research. This review is focused on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef is well known to enhance HIV-1 infectivity and replication, and to promote immune escape of HIV-infected cells by preventing cell surface MHC-I display of HIV-1 antigens. Recent progress shows that Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with latency reversal agents and therapeutic vaccines may provide a path to clearance of viral reservoirs. Full article
(This article belongs to the Special Issue Viral Accessory Proteins)
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