Simian Immunodeficiency Virus Is Susceptible to Inhibition by Carbohydrate-Binding Agents in a Manner Similar to That of HIV: Implications for Further Preclinical Drug Development

François, Katrien O.; Auwerx, Johan; Schols, Dominique; Balzarini, Jan

doi:10.1124/mol.108.047621

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…The lectins HHA, GNA and UDA have a broad spectrum antiviral activity against HIV [46], SIV [54], HCV [47], HCMV [49], [55] and DENV but not against parainfluenza-3, vesicular stomatitis virus, respiratory syncytial virus or herpes simplex virus [47]. This may be because of differences in carbohydrate structures on the glycoproteins of the viral envelope of different viruses grown in different host cells.…”

Section: Discussionmentioning

confidence: 99%

Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells

et al. 2011

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BackgroundDendritic cells (DC), present in the skin, are the first target cells of dengue virus (DENV). Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) is present on DC and recognizes N-glycosylation sites on the E-glycoprotein of DENV. Thus, the DC-SIGN/E-glycoprotein interaction can be considered as an important target for inhibitors of viral replication. We evaluated various carbohydrate-binding agents (CBAs) against all four described serotypes of DENV replication in Raji/DC-SIGN+ cells and in monocyte-derived DC (MDDC).Methodology/Principal FindingsA dose-dependent anti-DENV activity of the CBAs Hippeastrum hybrid (HHA), Galanthus nivalis (GNA) and Urtica dioica (UDA), but not actinohivin (AH) was observed against all four DENV serotypes as analyzed by flow cytometry making use of anti-DENV antibodies. Remarkably, the potency of the CBAs against DENV in MDDC cultures was significantly higher (up to 100-fold) than in Raji/DC-SIGN+ cells. Pradimicin-S (PRM-S), a small-size non-peptidic CBA, exerted antiviral activity in MDDC but not in Raji/DC-SIGN+ cells. The CBAs act at an early step of DENV infection as they bind to the viral envelope of DENV and subsequently prevent virus attachment. Only weak antiviral activity of the CBAs was detected when administered after the virus attachment step. The CBAs were also able to completely prevent the cellular activation and differentiation process of MDDC induced upon DENV infection.Conclusions/SignificanceThe CBAs exerted broad spectrum antiviral activity against the four DENV serotypes, laboratory-adapted viruses and low passage clinical isolates, evaluated in Raji/DC-SIGN+ cells and in primary MDDC.

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Section: Discussionmentioning

confidence: 99%

Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells

et al. 2011

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“…These N-linked glycosylation sites play an important function in entry, folding and modulating the immune response. GNA lectin has been shown antiviral activities against many enveloped viruses by blocking entry such as HIV [21,22], Simian immunodeficiency virus (SIV)[23], HCMV and influenza virus. Our data verified that GNA inhibit HCVpp and HCV whole genome entry in a dose-dependent manner and resulted in 50% reduction of virus at 1 ± 2 μg concentration (Figure 3a and 3b).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis C Virus 3a genotype entry through Glanthus Nivalis Agglutinin

Ashfaq

Masoud

Khaliq

et al. 2011

Virol J

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BackgroundHepatitis C Virus (HCV) has two envelop proteins E1 and E2 which is highly glycosylated and play an important role in cell entry. Inhibition of virus at entry step is an important target to find antiviral drugs against HCV. Glanthus Nivalis Agglutinin (GNA) is a mannose binding lectin which has tendency for specific recognition and reversible binding to the sugar moieties of a wide variety of glycoproteins of enveloped viruses.ResultsIn the present study, HCV pseudoparticles (HCVpp) for genotype 3a were produced to investigate the ability of GNA to block the HCV entry. The results demonstrated that GNA inhibit the infectivity of HCVpp and HCV infected serum in a dose-dependent manner and resulted in 50% reduction of virus at 1 ± 2 μg concentration. Molecular docking of GNA and HCV glycoproteins (E1 and E2) showed that GNA inhibit HCV entry by binding N-linked glycans.ConclusionThese results demonstrated that targeting the HCV glycans is a new approach to develop antiviral drugs against HCV.

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“…While our work was in progress, Francois et al published the sequence of two gp120 clones from a lab-adapted, HHA-selected SIVmac251 population (14). Both sequences lacked three N-linked carbohydrate attachment sites in gp120, two of which correspond to the sites described here.…”

Section: Discussionmentioning

confidence: 99%

“…GNA and HHA inhibit the replication of HIV-1 and SIVmac251, and uncloned, resistant populations of virus have been selected (3,14). In this report, we define two N-linked sites in the external surface glycoprotein gp120 and one in the transmembrane glycoprotein gp41 whose mutation imparts high-level resistance to the inhibitory effects of GNA and HHA to cloned SIVmac239.…”

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“…In contrast, resistance to GNA and HHA was conferred in SIVmac239 variants that lacked only three N-linked sites in Env, only two of which were in gp120. Selection using the SIVmac239-related, uncloned, lab-adapted SIVmac251 with HHA resulted in the elimination of three N-linked carbohydrate attachment sites in gp120 (14). To determine if differences in the content of high-mannose carbohydrate can be consistently demonstrated in head-to-head comparisons, the GNA binding capacities of recombinant HIV-1 and SIVmac/sm gp120 proteins produced from HEK293 cells were determined.…”

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Fundamental Difference in the Content of High-Mannose Carbohydrate in the HIV-1 and HIV-2 Lineages

Stansell

Desrosiers

2010

J Virol

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The virus-encoded envelope proteins of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) typically contain 26 to 30 sites for N-linked carbohydrate attachment. N-linked carbohydrate can be of three major types: high mannose, complex, or hybrid. The lectin proteins from Galanthus nivalis (GNA) and Hippeastrum hybrid (HHA), which specifically bind high-mannose carbohydrate, were found to potently inhibit the replication of a pathogenic cloned SIV from rhesus macaques, SIVmac239. Passage of SIVmac239 in the presence of escalating concentrations of GNA and HHA yielded a lectin-resistant virus population that uniformly eliminated three sites (of 26 total) for N-linked carbohydrate attachment (Asn-X-Ser or Asn-X-Thr) in the envelope protein. Two of these sites were in the gp120 surface subunit of the envelope protein (Asn244 and Asn460), and one site was in the envelope gp41 transmembrane protein (Asn625). Maximal resistance to GNA and HHA in a spreading infection was conferred to cloned variants that lacked all three sites in combination. Variant SIV gp120s exhibited dramatically decreased capacity for binding GNA compared to SIVmac239 gp120 in an enzyme-linked immunosorbent assay (ELISA). Purified gp120s from six independent HIV type 1 (HIV-1) isolates and two SIV isolates from chimpanzees (SIVcpz) consistently bound GNA in ELISA at 3-to 10-fold-higher levels than gp120s from five SIV isolates from rhesus macaques or sooty mangabeys (SIVmac/sm) and four HIV-2 isolates. Thus, our data indicate that characteristic high-mannose carbohydrate contents have been retained in the cross-species transmission lineages for SIVcpz-HIV-1 (high), SIVsm-SIVmac (low), and SIVsm-HIV-2 (low).The envelope proteins of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) are heavily glycosylated. N-linked carbohydrate is attached to the nascent protein at the asparagine of the consensus sequence N-X-S or N-X-T, where X is any amino acid except a proline (31,52,53). The number of potential N-linked carbohydrate attachment sites in the surface subunit of Env (gp120) ranges from 18 to 33, with a median of 25 (34, 65). There are typically 3 or 4 potential N-linked sites in the ectodomain of the Env transmembrane protein (gp41) (34).N-linked glycosylation of a protein consists of the en bloc transfer of the carbohydrate core oligosaccharide (two N-acetylglucosamines, nine mannoses, and three glucoses) from dolichol to the asparagine of the N-linked attachment site (8, 60). Initially the attached carbohydrate is processed into the high-mannose type (8). In the Golgi complex, high-mannose carbohydrate may be further processed into complex or hybrid oligosaccharides (58). Incomplete processing of N-linked carbohydrate results in the production of high-mannose carbohydrate chains, which terminate in mannose (58). Fully processed complex carbohydrate chains terminate in galactose, N-acetylglucosamine, sialic acid, or glucose (33, 57). Hybrid carbohydrate chains have two branches from the core, one tha...

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Simian Immunodeficiency Virus Is Susceptible to Inhibition by Carbohydrate-Binding Agents in a Manner Similar to That of HIV: Implications for Further Preclinical Drug Development

Abstract: ABSTRACT

Cited by 12 publications

References 36 publications

Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells

Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells

Inhibition of Hepatitis C Virus 3a genotype entry through Glanthus Nivalis Agglutinin

Fundamental Difference in the Content of High-Mannose Carbohydrate in the HIV-1 and HIV-2 Lineages

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