Actinohivin, a Broadly Neutralizing Prokaryotic Lectin, Inhibits HIV-1 Infection by Specifically Targeting High-Mannose-Type Glycans on the gp120 Envelope

Abstract

The lectin actinohivin (AH) is a monomeric carbohydrate-binding agent (CBA) with three carbohydratebinding sites. AH strongly interacts with gp120 derived from different X4 and R5 human immunodeficiency virus (HIV) strains, simian immunodeficiency virus (SIV) gp130, and HIV type 1 (HIV-1) gp41 with affinity constants (K D ) in the lower nM range. The gp120 and gp41 binding of AH is selectively reversed by (␣1,2-mannose) 3 oligosaccharide but not by ␣1,3/␣1,6-mannose-or GlcNAc-based oligosaccharides. AH binding to gp120 prevents binding of ␣1,2-mannose-specific monoclonal antibody 2G12, and AH covers a broader epitope on gp120 than 2G12. Prolonged exposure of HIV-1-infected CEM T-cell cultures with escalating AH concentrations selects for mutant virus strains containing N-glycosylation site deletions (predominantly affecting high-mannose-type glycans) in gp120. In contrast to 2G12, AH has a high genetic barrier, since several concomitant N-glycosylation site deletions in gp120 are required to afford significant phenotypic drug resistance. AH is endowed with broadly neutralizing activity against laboratory-adapted HIV strains and a variety of X4 and/or R5 HIV-1 clinical clade isolates and blocks viral entry within a narrow concentration window of variation (ϳ5-fold). In contrast, the neutralizing activity of 2G12 varied up to 1,000-fold, depending on the virus strain. Since AH efficiently prevents syncytium formation in cocultures of persistently HIV-1-infected HuT-78 cells and uninfected CD4؉ T lymphocytes, inhibits dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated capture of HIV-1 and subsequent virus transmission to CD4 ؉ T lymphocytes, does not upregulate cellular activation markers, lacks mitogenic activity, and does not induce cytokines/chemokines in peripheral blood mononuclear cell cultures, it should be considered a potential candidate drug for microbicidal use.

Structural insights into the specific anti-HIV property of actinohivin: structure of its complex with the α(1–2)mannobiose moiety of gp120

“…This unique structure may bring about its highly specific HMTG binding. Furthermore, AH does not exhibit any mitogenic activity (Hoorelbeke et al, 2010;Matoba et al, 2010) in contrast to the other lectins, e.g. CN-V. As shown in Fig.…”

Combinations of Griffithsin with Other Carbohydrate-Binding Agents Demonstrate Superior Activity Against HIV Type 1, HIV Type 2, and Selected Carbohydrate-Binding Agent-Resistant HIV Type 1 Strains

“…9 For actinohivin, a broadly neutralizing prokaryotic lectin, a tight interaction with the envelope protein of SIV was demonstrated by surface plasmon resonance technology, but it lacked anti-SIV activity in several viral replication assays. 40 These data revealed that binding of CBAs to gp120 glycans may occur, but these are not always necessarily in neutralizing viral replication. …”

Broad Antiviral Activity of Carbohydrate-Binding Agents Against Dengue Virus Infection

“…PRM-S also inhibited dose-dependently DENV-2 replication in MDDC but had only a weak antiviral activity in Raji/DC-SIGN + cells [61]. Actinohivin (AH), a small prokaryotic peptidic lectin containing 114 amino acids, exhibits also anti-HIV-1 activity by recognizing high-mannose-type glycans on the viral envelope [92]. Although DENV has high mannose-type glycans on the E-protein, there was no antiviral activity of AH against DENV infection.…”