1,721,032 research outputs found
Virion Background and Efficiency of Virion Incorporation Determine Susceptibility of Simian Immunodeficiency Virus Env-Driven Viral Entry to Inhibition by IFITM Proteins
No full textABSTRACT
Interferon-induced transmembrane proteins (IFITMs) can inhibit the cellular entry of several enveloped viruses, including simian immunodeficiency virus (SIV). The blockade of SIV by IFITMs is isolate specific, raising the question of which parameters impact sensitivity to IFITM. We show that the virion context in which SIV-Env is presented and the efficiency of virion incorporation determine Env susceptibility to inhibition by IFITMs. Thus, determinants other than the nature of the envelope protein can impact the IFITM sensitivity of viral entry.
IMPORTANCE
The host cell-encoded IFITM proteins can block viral entry and are an important component of the innate defenses against viral infection. However, the determinants controlling whether a virus is susceptible to blockade by IFITM proteins are incompletely understood. Our study shows that the amount of envelope proteins incorporated into virions as well as the nature of the virion particle itself can impact the sensitivity of viral entry to IFITMs. These results show for the first time that determinants other than the viral envelope protein can impact sensitivity to IFITM and have implications for the interpretation of previously published data on inhibition of viruses by IFITM proteins. Moreover, our findings might help to define the mechanism underlying the antiviral activity of IFITM proteins.Leibniz-Gemeinschaft https://doi.org/10.13039/50110000166
SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination
No full textSearching for Novel Antiviral Agents as COVID19 Treatments: Guanidino Diaryl Thioureas
No full textThe COVID‐19 pandemic highlighted the urgent need for effective antiviral treatments targeting SARS‐CoV‐2. TMPRSS2, a serine protease essential for viral entry into host cells, represents a promising therapeutic target, and this study explores guanidino diaryl thioureas as potential TMPRSS2 inhibitors. Initial screening identified a “hit‐compound” ( 1 ) with reversible inhibitory activity against TMPRSS2. Computational studies, including docking and molecular dynamics simulations, were conducted to optimize derivatives of compound 1 . Twenty‐five derivatives were synthesized, and their pharmacokinetic properties and cytotoxicity assessments indicated favorable drug‐likeness and minimal toxicity. However, biochemical studies revealed that none of the derivatives improved TMPRSS2 inhibitory activity compared to the original “hit‐compound”. The findings suggest that reversible inhibitors may be suboptimal for TMPRSS2 targeting, as camostat and nafamostat exert their effects through irreversible covalent binding. Future efforts should focus on developing irreversible TMPRSS2 inhibitors to enhance antiviral efficacy against SARS‐CoV‐2.Science Foundation Ireland https://doi.org/10.13039/50110000160
Probing scaffold size effects on multivalent lectin-glycan binding affinity, thermodynamics and antiviral properties using polyvalent glycan-gold nanoparticles
No full textMultivalent lectin-glycan interactions (MLGIs) are pivotal for viral infection and immune regulation. Their structural and biophysical data are thus highly valuable, not only for understanding their basic mechanisms but also for designing potent glycoconjugate therapeutics against target MLGIs. However, such information for some important MGLIs remain poorly understood, which has greatly limited the research progress. We have recently developed densely glycosylated nanoparticles, e.g., ~4 nm quantum dot (QD) or ~5 nm gold nanoparticle (GNP), as mechanistic probes for MLGIs. Using two important model lectin viral receptors, DC-SIGN and DC-SIGNR, we have shown these probes not only can offer sensitive fluorescence assays for quantifying MLGI affinities, but also reveal key structural information (e.g., binding site orientation and binding mode) useful for MLGI targeting. However, the small sizes of the previous scaffolds may not be optimal for maximising MLGI affinity and targeting specificity. Herein, using -manno--1,2-biose (DiMan) functionalised GNP (GNP-DiMan) probes, we have systematically studied how GNP scaffold size (e.g., 5, 13, and 27 nm) and glycan density (e.g., 100, 75, 50 and 25%) determine their MLGI affinities, thermodynamics, and antiviral properties. We have developed a new GNP fluorescence quenching assay format to minimise the possible interference of GNP’s strong inner filter effect in MLGI affinity quantification, revealing that increasing GNP size is highly beneficial for enhancing MLGI affinity. We have further determined the MLGI thermodynamics by combining temperature-dependent affinity and Van’t Hoff analyses, revealing that GNP-DiMan-DC-SIGN/R binding is enthalpy driven and their favourable binding Gibbs free energy changes (G0) being enhanced with the increasing GNP size. Finally, we show that increasing GNP size significantly enhances their antiviral potency. Notably, the DiMan coated 27 nm GNP potently and robustly blocks both DC-SIGN and DC-SIGNR mediated pseudo-Ebola virus cellular entry with an EC50 of ~23 and ~49 pM, respectively, making it the most potent glycoconjugate inhibitor against DC-SIGN/R-mediated Ebola cellular infections. Our results have established GNP-glycans as a new tool for quantifying MLGI biophysical parameters and revealed that increasing GNP scaffold size significantly enhances their MLGI affinities and antiviral potencies
Role of rhesus macaque IFITM3(2) in simian immunodeficiency virus infection of macaques
No full textThe experimental infection of rhesus macaques (rh) with simian immunodeficiency virus (SIV) is an important model for human immunodeficiency virus (HIV) infection of humans. The interferon-induced transmembrane protein 3 (IFITM3) inhibits HIV and SIV infection at the stage of host cell entry. However, it is still unclear to what extent the antiviral activity of IFITM3 observed in cell culture translates into inhibition of HIV/SIV spread in the infected host. We have shown previously that although rhIFITM3 inhibits SIV entry into cultured cells, polymorphisms in the rhIFITM3 gene are not strongly associated with viral load or disease progression in SIV infected macaques. Here, we examined whether rhIFITM3(2), which is closely related to rhIFITM3 at the sequence level, exerts antiviral activity and whether polymorphisms in the rhIFITM3(2) gene impact the course of SIV infection. We show that expression of rhIFITM3(2) is interferon-inducible and inhibits SIV entry into cells, although with reduced efficiency as compared to rhIFITM3. We further report the identification of 19 polymorphisms in the rhIFITM3(2) gene. However, analysis of a well characterized cohort of SIV infected macaques revealed that none of the polymorphisms had a significant impact upon the course of SIV infection. These results and our previous work suggest that polymorphisms in the rhIFITM3 and rhIFITM3(2) genes do not strongly modulate the course of SIV infection in macaques.</div
The glycoprotein of vesicular stomatitis virus promotes release of virus-like particles from tetherin-positive cells.
No full textVesicular stomatitis virus (VSV) release from infected cells is inhibited by the interferon (IFN)-inducible antiviral host cell factor tetherin (BST-2, CD317). However, several viruses encode tetherin antagonists and it is at present unknown whether residual VSV spread in tetherin-positive cells is also promoted by a virus-encoded tetherin antagonist. Here, we show that the viral glycoprotein (VSV-G) antagonizes tetherin in transfected cells, although with reduced efficiency as compared to the HIV-1 Vpu protein. Tetherin antagonism did not involve alteration of tetherin expression and was partially dependent on a GXXXG motif in the transmembrane domain of VSV-G. However, mutation of the GXXXG motif did not modulate tetherin sensitivity of infectious VSV. These results identify VSV-G as a tetherin antagonist in transfected cells but fail to provide evidence for a contribution of tetherin antagonism to viral spread
Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5
Full text linkDeutsches Zentrum für Infektionsforschung (German Center for Infection Research) https://doi.org/10.13039/100009139EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj) https://doi.org/10.13039/501100008530Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) https://doi.org/10.13039/501100002347Niedersächsische Ministerium für Wissenschaft und Kultur (Lower Saxony Ministry of Science and Culture) https://doi.org/10.13039/100011937European Commission (EC) https://doi.org/10.13039/501100000780Deutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/50110000165
Humoral immunity after mRNA SARS-CoV-2 omicron JN.1 vaccination
No full text501100023651 European Social Fund for Germany100006479 Cordis Corporation501100001659 German Research Foundation501100010570 Niedersächsisches Ministerium für Wissenschaft und Kultur100011937 Lower Saxony State Ministry of Science and Cultur
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