title: The G-quadruplex-forming aptamer AS1411 potently inhibits HIV-1 attachment to the host cell.
abstract: AS1411 is a G-rich aptamer that forms a stable G-quadruplex structure and displays antineoplastic properties both in vitro and in vivo. This oligonucleotide has undergone phase 2 clinical trials. The major molecular target of AS1411 is nucleolin (NCL), a multifunctional nucleolar protein also present in the cell membrane where it selectively mediates the binding and uptake of AS1411. Cell-surface NCL has been recognised as a low-affinity co-receptor for human immunodeficiency virus type 1 (HIV-1) anchorage on target cells. Here we assessed the anti-HIV-1 properties and underlying mechanism of action of AS1411. The antiviral activity of AS1411 was determined towards different HIV-1 strains, host cells and at various times post-infection. Acutely, persistently and latently infected cells were tested, including HIV-1-infected peripheral blood mononuclear cells from a healthy donor. Mechanistic studies to exclude modes of action other than virus binding via NCL were performed. AS1411 efficiently inhibited HIV-1 attachment/entry into the host cell. The aptamer displayed antiviral activity in the absence of cytotoxicity at the tested doses, therefore displaying a wide therapeutic window and favourable selectivity indexes. These findings, besides validating cell-surface-expressed NCL as an antiviral target, open the way for the possible use of AS1411 as a new potent and promisingly safe anti-HIV-1 agent.
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Butovskaya
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lago
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Garzino-Demo
authors.affiliation: KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: sara.richter@unipd.it.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000633:toxicity; D052157:Aptamers, Nucleotide; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000633:toxicity; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: C513936:AGRO 100; D019380:Anti-HIV Agents; D052157:Aptamers, Nucleotide; D009838:Oligodeoxyribonucleotides
keywords: Antiretroviral drug; Aptamer; Attachment; HIV