scholarly journals Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and cofactor required for A3 degradation

2020 ◽  
pp. jbc.RA120.015828
Author(s):  
Kirsten M. Knecht ◽  
Yingxia Hu ◽  
Diana Rubene ◽  
Matthew Cook ◽  
Samantha J Ziegler ◽  
...  
Keyword(s):  
Viral Infections ◽  
Zinc Ion ◽  
Binding Motif ◽  
Cytidine Deaminases ◽  
Visna Virus ◽  
Primate Lentiviruses ◽  
Maedi Visna Virus ◽  
Hiv 1

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called Vif, which recruits A3 proteins to Cullin-RING E3 ubiquitin ligases such as Cul5 for ubiquitylation and subsequent proteasomal degradation. While Vif proteins from primate lentiviruses like HIV-1 utilize the transcription factor CBFβ as a non-canonical cofactor to stabilize the complex, maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Since CBFβ and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that while some common motifs between HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.

scholarly journals Simultaneous Mutations in CA and Vif of Maedi-Visna Virus Cause Attenuated Replication in Macrophages and Reduced Infectivity In Vivo

2005 ◽  
Vol 79 (24) ◽  
pp. 15038-15042 ◽  
Author(s):  
Bjarki Gudmundsson ◽  
Stefán Ragnar Jónsson ◽  
Oddur Ólafsson ◽  
Gudrún Agnarsdóttir ◽  
Sigrídur Matthíasdóttir ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Differential Growth ◽  
Nucleotide Substitutions ◽  
Highly Pathogenic ◽  
Visna Virus ◽  
Primate Lentiviruses ◽  
The Central Nervous System ◽  
Growth Phenotype ◽  
Maedi Visna Virus

ABSTRACT Maedi-visna virus (MVV) is a lentivirus of sheep sharing several key features with the primate lentiviruses. The virus causes slowly progressive diseases, mainly in the lungs and the central nervous system of sheep. Here, we investigate the molecular basis for the differential growth phenotypes of two MVV isolates. One of the isolates, KV1772, replicates well in a number of cell lines and is highly pathogenic in sheep. The second isolate, KS1, no longer grows on macrophages or causes disease. The two virus isolates differ by 129 nucleotide substitutions and two deletions of 3 and 15 nucleotides in the env gene. To determine the molecular nature of the lesions responsible for the restrictive growth phenotype, chimeric viruses were constructed and used to map the phenotype. An L120R mutation in the CA domain, together with a P205S mutation in Vif (but neither alone), could fully convert KV1772 to the restrictive growth phenotype. These results suggest a functional interaction between CA and Vif in MVV replication, a property that may relate to the innate antiretroviral defense mechanisms in sheep.

scholarly journals ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 34
Author(s):  
Maria Pujantell ◽  
Eva Riveira-Muñoz ◽  
Edurne García-Vidal ◽  
Lucía Gutiérrez-Chamorro ◽  
Roger Badia ◽  
...  
Keyword(s):  
Genetic Association ◽  
Immune Activation ◽  
Viral Infections ◽  
Association Studies ◽  
Innate Immune ◽  
Viral Control ◽  
Innate Immune Activation ◽  
Hiv 1

Viral infection induces innate intracellular antiviral defenses, aimed at restricting virus replication and spread. Therefore, understanding the role and function of innate immune modulators can help to establish novel strategies for viral control. Here, we explore the role of ADAR1 as a regulator of the HIV, HCV, and HPV infections, both in vitro and in vivo, in a genetic association study. Depletion of ADAR1 induced innate immune activation, observed by a significant increase in IFNB1 mRNA and CXCL10 expression. Further characterization of ADAR1 knockdown also showed upregulation of the RNA sensors MDA5 and RIG-I, increased IRF7 expression, and phosphorylation of STAT1. ADAR1 deficiency had differential effects depending on the virus tested: siADAR1 cells showed a significant reduction in HIV-1 infection, whereas ADAR1 knockdown suggested a proviral role in HCV and HPV infections. In addition, genetic association studies were performed in a cohort of 155 HCV/HIV individuals with chronic coinfection, and a cohort of 173 HPV/HIV-infected individuals was followed for a median of six years (range 0.1–24). Polymorphisms within the ADAR1 gene were found to be significantly associated with poor clinical outcome of HCV therapy and advanced liver fibrosis in a cohort of HCV/HIV-1-coinfected patients. Moreover, we identified the low-frequency haplotype AACCAT to be significantly associated with recurrent HPV dysplasia, suggesting a role for ADAR1 in the outcome of HPV infection in HIV+ individuals. In conclusion, we show that ADAR1 regulates innate immune activation and plays a key role in susceptibility to viral infections by either limiting or enhancing viral replication. Overall, ADAR1 could be a potential target for designing immune-modulating therapeutic strategies.

scholarly journals Inositol hexakisphosphate (IP6) and inositol pentakisphosphate (IP5) are required for viral particle release of retroviruses belonging to the primate lentivirus genus

2020 ◽  
Author(s):  
Clifton L Ricana ◽  
Terri D Lyddon ◽  
Robert A Dick ◽  
Marc C Johnson
Keyword(s):  
Particle Production ◽  
Virus Production ◽  
Virus Release ◽  
Inositol Hexakisphosphate ◽  
Infectious Particle ◽  
Fold Reduction ◽  
Primate Lentiviruses ◽  
Hiv 1

AbstractInositol hexakisphosphate (IP6) potently stimulates HIV-1 particle assembly in vitro and infectious particle production in vivo. However, knockout cells lacking the enzyme inositol-pentakisphosphate 2-kinase (IPPK-KO), which adds the final phosphate to inositol pentakisphosphate (IP5) to produce IP6, were still able to produce infectious HIV-1 particles at a greatly reduced rate. HIV-1 in vitro assembly can also be stimulated to a lesser extent with IP5, but it was not known if IP5 could also function in promoting assembly in vivo. IPPK-KO cells expressed no detectable IP6 but elevated IP5 levels and displayed a 20-100-fold reduction in infectious particle production, correlating with lost virus release. Transient transfection of an IPPK expression vector stimulated infectious particle production and release in IPPK-KOs but not in wildtype cells. Several attempts to make an IP6 and IP5 deficient stable cell line were not successful, but transient expression of multiple inositol polyphosphate phosphatase-1 (MINPP1) into IPPK-KOs resulted in the near ablation of IP6 and IP5. Under these conditions, HIV-1 infectious particle production and virus release were essentially abolished (1000-fold reduction). However, other retroviruses including a Gammaretrovirus, a Betaretrovirus, and two non-primate Lentiviruses displayed only a modest (3-fold) reduction in infectious particle production from IPPK-KOs and were not significantly altered by expression of IPPK or MINPP1. The only other retrovirus found that showed a clear IP6/IP5 dependence was the primate (macaque) Lentivirus Simian Immunodeficiency Virus (SIV-mac), which displayed similar sensitivity to IP6/IP5 levels as HIV-1. Finally, we found that loss of IP6/IP5 in viral target cells had no effect on permissiveness to HIV-1 infection. However, because it was not possible to generate viral particles devoid of IP6 and IP5, we were not able to determine if IP6 or IP5 derived from the virus producer cells is required at additional steps beyond assembly.Author SummaryInositol hexakisphosphate (IP6) is a co-factor required for efficient production of infectious HIV-1 particles. The HIV-1 structural protein Gag forms a hexagonal lattice structure. The negatively charged IP6 sits in the middle of the hexamer and stabilizes a ring of positively charged lysines. Previously described results show that depletion of IP6 reduces, but does not eliminate, infectious virus production. This depletion was achieved through knock-out of inositol-pentakisphosphate 2-kinase (IPPK-KO), the enzyme responsible for adding the sixth and final phosphate to the molecule. Whether IP6 is required, another inositol phosphate can substitute, or IP6 is simply acting as an enhancer for virus production was unknown. Here, we show that loss of IP6 and inositol pentakisphosphate (IP5) abolishes infectious HIV-1 production from cells. We do this through a cell-based system using transiently expressed proteins to restore or deplete IP6 and IP5 in the IPPK-KO cell line. We further show that the IP6 and IP5 requirement is a feature of primate lentiviruses, but not all retroviruses, and that IP6 and IP5 is required in the producer but not the target cell for HIV-1 infection.

scholarly journals The vif gene of maedi-visna virus is essential for infectivity in vivo and in vitro

Virology ◽  
2004 ◽  
Vol 318 (1) ◽  
pp. 350-359 ◽  
Author(s):  
Helga Bryndı́s Kristbjörnsdóttir ◽  
Valgerdur Andrésdóttir ◽  
Vilhjálmur Svansson ◽  
Sigurbjörg Torsteinsdóttir ◽  
Sigrı́dur Matthı́asdóttir ◽  
...  
Keyword(s):  
Visna Virus ◽  
Maedi Visna Virus

scholarly journals African and Asian Medicinal Plants as a Repository for Prospective Antiviral Metabolites Against HIV-1 and SARS CoV-2: A Mini Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Godwin Anywar ◽  
Muhammad Akram ◽  
Muhammad Amjad Chishti
Keyword(s):  
Medicinal Plants ◽  
Plant Species ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Natural Compounds ◽  
Drug Candidates ◽  
Novel Coronavirus ◽  
Hiv 1

Introduction: The worldwide burden of viral infections has triggered a resurgence in the search for new and more efficient antiviral drugs. Scientists are also repurposing existing natural compounds such as the antimalarial drug artemisinin from Artemesia annua L. as potential drug candidates for some of the emerging and re-emerging viral infections such as covid-19Aim: The aim of this review was to analyse the existing literature to explore the actual or potential natural antiviral compounds from African and Asian medicinal plants as lead compounds in the drug discovery process.Methods: We searched the literature on African and Asian medicinal plant species as antiviral agents for HIV-1 and the novel coronavirus (SARS-CoV-2) in various databases and search engines such as Web of Science, Google Scholar and PubMed. The search was limited to in vitro, in vivo, and clinical studies and excluded in silico studies.Results: We present 16 plant species with actual or potential antiviral activity against HIV-1 and SARS-CoV-2. These plant species span the continents of Africa and Asia where they are widely used for treating several other ailments.Conclusion: Natural compounds from plants can play a significant role in the clinical management of HIV/AIDS and the covid-19 pandemic. More research needs to be conducted to investigate the potential toxicities of the various compounds and their efficacies in clinical settings.

scholarly journals 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1997 ◽  
Vol 41 (5) ◽  
pp. 1082-1093 ◽  
Author(s):  
S M Daluge ◽  
S S Good ◽  
M B Faletto ◽  
W H Miller ◽  
M H St Clair ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Bioavailability ◽  
Human Peripheral Blood ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Carbocyclic Nucleoside ◽  
Hiv 1 ◽  
In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

scholarly journals G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission

2021 ◽  
Vol 22 (16) ◽  
pp. 8366
Author(s):  
Ignacio Relaño-Rodríguez ◽  
María de la Sierra Espinar-Buitrago ◽  
Vanessa Martín-Cañadilla ◽  
Rafael Gómez-Ramírez ◽  
María Ángeles Muñoz-Fernández
Keyword(s):  
T Cells ◽  
Developed Countries ◽  
Main Role ◽  
Viral Particles ◽  
Carbosilane Dendrimer ◽  
Science Community ◽  
New Compounds ◽  
Hiv 1

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

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