ABSTRACT Macrophages are thought to represent one of the first cell types in body be infected during early stage human immunodeficiency virus type 1 (HIV-1) transmission and a potential viral reservoir vivo. Thus, an understanding HIV-1 attachment these cells is fundamental development novel anti-HIV-1 therapies. Although major targets vivo—CD4 + T lymphocytes—express high CD4 levels, other such as macrophages do not. We asked this study whether low level on sufficient support or surface...

Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well its influence intracellular Cyp levels was investigated a randomized, double-blind, placebo-controlled study. Mean hepatitis decreased significantly by 3.6 log(10) after 14-day treatment 1200 mg twice daily (P < 0.0001) against the 3 genotypes (1, 3, and 4) represented In addition, absence of rebound during indicates that has high barrier for selection...

Cyclosporine A and nonimmunosuppressive cyclophilin (Cyp) inhibitors such as Debio 025, NIM811, SCY-635 block hepatitis C virus (HCV) replication in vitro. This effect was recently confirmed HCV-infected patients where 025 treatment dramatically decreased HCV viral load, suggesting that Cyps represent a novel class of anti-HCV agents. However, it remains unclear how these compounds control replication. Recent studies suggest are important for profound disagreement currently exists to the...

DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and vivo. It currently being evaluated phase II clinical trials. DEB025 binds to CypA, peptidyl-prolyl cis-trans isomerase which crucial cofactor for HCV replication. Here we report that it was very difficult select resistant replicons (genotype 1b) DEB025, requiring an average of 20 weeks (four independent experiments), compared the typically <2 protease or...

Although the transport of human immunodeficiency virus type 1 (HIV-1) through epithelium is critical for HIV-1 colonization, mechanisms controlling this process remain obscure. In present study, we investigated transcellular migration as a cell-free primary genital epithelial cells (PGECs). The absence CD4 on PGECs implicates an unusual entry pathway HIV-1. We found that syndecans are abundantly expressed and promote initial attachment subsequent PGECs. CXCR4 CCR5 do not contribute to...

Dendritic cells (DCs) efficiently capture HIV-1 and mediate transmission to T cells, but the underlying molecular mechanism is still being debated. The C-type lectin DC-SIGN important in by DCs. However, various studies strongly suggest that another receptor on DCs involved of HIV-1. Here we have identified syndecan-3 as a major attachment Syndecan-3 DC-specific heparan sulfate (HS) proteoglycan captures through interaction with envelope glycoprotein gp120. stabilizes captured virus,...

There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in search against this virus, we explored use human tracheal airway epithelial cells (HtAEC) and small (HsAEC) grown at air-liquid interface (ALI). These cultures were infected apical side with one two different isolates. Each virus was shown to replicate high titers extended periods time (at least 8 days) and, particular an isolate D614G spike (S) protein did so more efficiently 35 °C...

We have analyzed tolerance-related clonal deletion of Mls-and I-E-reactive thymocytes at the RNA level using a multi-V beta probe RNAse protection assay, and used this phenomenon to identify maturation stage abnormally expanded CD4-8-, TCR-alpha/beta + subset in lpr gld homozygous mice, phenotypically similar minor thymocyte found normal mice. Essentially complete V deletions were detected cells all appropriate background strains. Substantial, but not complete, also CD4-8- Since expression...

Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. lack of effects compared to that was demonstrated both in vitro and vivo. For three cyclosporines, the potential PPIase activity quantitatively correlated human immunodeficiency virus type 1 (HIV-1) replication. selectively inhibited replication HIV-1 CD4+ cell line peripheral blood mononuclear cells: potent...

Cyclophilins are a diverse family of peptidyl-prolyl isomerases (PPIases) importance in variety essential cellular functions. We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease mice under western-diet and carbon tetrachloride (CCl 4 ) non-alcoholic steatohepatitis (NASH) model. CRV431 inhibits several cyclophilin isoforms, among which A (CypA) B (CypB) most abundant. It is not known whether simultaneous inhibition multiple members necessary...

ABSTRACT As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, myelin damage in AIDS patients. To gain access to brain, HIV-1 must migrate through microvascular endothelial cells (BMECs), which compose blood-brain barrier (BBB). Given that BMECs lack entry receptor CD4, use receptors distinct from CD4 enter these cells. We previously reported cell surface proteoglycans serve as major on primary In this study, we examined...

In the absence of an effective vaccine, there is urgent need for safe and antiviral agents to prevent transmission HIV. Here, we report that amphipathic α-helical peptide derived from hepatitis C virus NS5A anchor domain (designated C5A in this article) has been shown be virocidal (HCV) also potent activity against exhibits a broad range HIV isolates, it prevents infection three vivo targets HIV: CD4 + T lymphocytes, macrophages, dendritic cells by disrupting integrity viral membrane capsid...

ABSTRACT The nonimmunosuppressive cyclophilin (Cyp) inhibitor SCY-635 blocks hepatitis C virus (HCV) replication both in vitro and vivo represents a novel potent anti-HCV agent. However, its mechanism of action remains to be fully elucidated. A growing body evidence suggests that (CypA) is absolutely necessary for HCV the nonstructural 5A (NS5A) protein serves as main viral ligand CypA. In this study, we examined effect on replication. Specifically, asked whether by targeting CypA-NS5A...

ABSTRACT Although the mechanisms of action (MoA) nonstructural protein 3 inhibitors (NS3i) and NS5B (NS5Bi) are well understood, MoA cyclophilin (CypI) NS5A (NS5Ai) not fully defined. In this study, we examined whether CypI NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis replication complexes (RCs) or an earlier step HCV replication, creation double-membrane vesicles (DMVs) essential for replication. contrast to NS5Bi, both do block by way RCs, suggesting that they exert their...

Cyclophilins are host factors required for hepatitis C virus replication. Cyclophilin inhibitors such as alisporivir have shown strong anti-hepatitis activity in vitro and clinical studies. However, little is known about whether hepatocyte cyclophilins involved the B (HBV) life cycle. We investigated effects of 2 cyclophilin (alisporivir NIM811) on HBV replication surface antigen (HBsAg) production cell lines.Liver-derived lines producing full-length HBsAg particles, owing to stable...

Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in experimental models. However, no drug with inhibition as the primary mode of action has advanced completely through clinical development market. In this study, we present findings on inhibitor, CRV431, highlight its potential a candidate for chronic liver diseases. CRV431 was found potently inhibit all isoforms tested—A, B, D, G. Inhibitory...

HIV-1 has maximized its utilization of syndecans. It uses them as in cis receptors to infect macrophages and trans T-lymphocytes. In this study, we investigated at a molecular level the mechanisms that control HIV-1-syndecan interactions. We found single conserved arginine (Arg-298) V3 region gp120 governs binding an amine group on side chain residue is necessary for syndecan by HIV-1. Furthermore, showed binds syndecans via 6-O sulfation, demonstrating not result random interactions between...

ABSTRACT Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins a group naturally occurring cyclophilin binding polyketides that structurally distinct from the cyclosporines and produced by microorganism amenable to biosynthetic engineering lead optimization large-scale production fermentation. Preclinical characterization potential utility this class compounds treatment HCV revealed natural sanglifehrins A D...

Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression HBV replication, but treatments rarely eradicate from Similar for human immunodeficiency type-1 (HIV-1) hepatitis C (HCV) patients, improved therapies will require combination multiple drugs which target distinct steps life cycle. In this study, we tested potential cyclophilin...

An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted evaluate in vitro SARS-CoV-2 antiviral and virucidal (irreversible) activity astodrimer sodium, dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses vivo models, that is marketed for antibacterial applications. We report sodium...

In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address issue, sought viruses for independence using Debio-025, cyclosporine A (CsA) analog disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even presence of drug. Sequencing analyses revealed these encode capsid substitutions within CypA-binding site (V86P/H87Q/I91V/M96I). When introduced into normally rely on replication,...

The TRIM5alpha (tripartite motif 5alpha protein) has been linked to the cross-species restriction in human immunodeficiency virus type 1 (HIV-1) infection of non-human cells, but mechanism by which this occurs remains be fully elucidated. Here we demonstrate that capsid (CA) protein HIV-1 is more rapidly degraded cells expressing monkey than TRIM5alpha. Other proteins encoded Gag and Pol are not subject TRIM5alpha-mediated accelerated degradation. CA degradation apparently via a...

ABSTRACT Alisporivir is the most advanced host-targeting antiviral cyclophilin (Cyp) inhibitor in phase III studies and has demonstrated a great deal of promise decreasing hepatitis C virus (HCV) viremia infected patients. In an attempt to further elucidate mechanism action alisporivir, HCV replicons resistant drug were selected. Interestingly, mutations constantly arose domain II NS5A. To demonstrate that these are responsible for resistance, they reintroduced into parental genome,...