Actinohivin, a broadly neutralizing prokaryotic lectin, inhibits HIV-1 infection by specifically targeting high-mannose-type glycans on the gp120 envelope.
The lectin actinohivin (AH) is a monomeric carbohydrate-binding agent (CBA) with three carbohydrate-binding 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 (KD) in the lower nM range. The gp120 and gp41 binding of AH is selectively reversed by (alpha1,2-mannose)3 oligosaccharide but not by alpha1,3/alpha1,6-mannose- or GlcNAc-based oligosaccharides. AH binding to gp120 prevents binding of alpha1,2-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 (approximately 5-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.
Hoorelbeke
Bart
B
Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven B-3000, Belgium.
Huskens
Dana
D
Férir
Geoffrey
G
François
Katrien O
KO
Takahashi
Atsushi
A
Van Laethem
Kristel
K
Schols
Dominique
D
Tanaka
Haruo
H
Balzarini
Jan
J
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D000080908:Broadly Neutralizing Antibodies; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000821:virology; D008358:Mannose / Q000737:chemistry / Q000378:metabolism*; D009500:Neutralization Tests; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism
C529157:2G12 monoclonal antibody; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D037102:Lectins; D011134:Polysaccharides; C424136:actinohivin protein, actinomycete; D008358:Mannose