title: UCLA1, a synthetic derivative of a gp120 RNA aptamer, inhibits entry of human immunodeficiency virus type 1 subtype C.
abstract: Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by the virion surface envelope (Env) glycoproteins, making it a desirable target for antiretroviral entry inhibitors. We previously isolated a family of gp120 binding RNA aptamers and showed that they neutralized the infectivity of HIV-1. In this study, we assessed the activity of a shortened synthetic derivative of the B40 aptamer, called UCLA1, against a large panel of HIV-1 subtype C viruses. UCLA1 tightly bound to a consensus HIV-1 subtype C gp120 and neutralized isolates of the same subtype with 50% inhibitory concentrations (IC(50)s) in the nanomolar range. The aptamer had little toxicity in tests with cell lines and primary cells. Furthermore, it exhibited high therapeutic indices, suggesting that it may be effective at very low doses. Mapping of UCLA1 binding sites on gp120 revealed eight amino acid residues that modulated neutralization resistance. This included residues within the coreceptor binding site, at the base of the V3 loop, and in the bridging sheet within the conserved V1/V2 stem-loop of gp120. The aptamer was also shown to have synergistic effects with T20, a gp41 fusion inhibitor, and IgG1b12 (b12), an anti-CD4 binding site monoclonal antibody. These results suggest that UCLA1 may be suitable for development as a potent HIV-1 entry inhibitor.
authors.affiliation: Emerging Health Technologies Platform, Biosciences Unit, CSIR, Pretoria, South Africa.
authors.forename: Hazel T
authors.initials: HT
authors.lastname: Mufhandu
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Maphuti C
authors.initials: MC
authors.lastname: Madiga
authors.forename: Nancy
authors.initials: N
authors.lastname: Tumba
authors.forename: Kabamba B
authors.initials: KB
authors.lastname: Alexandre
authors.forename: Thandeka
authors.initials: T
authors.lastname: Khoza
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: Makobetsa
authors.initials: M
authors.lastname: Khati
mesh_terms: D052157:Aptamers, Nucleotide / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008958:Models, Molecular; D009500:Neutralization Tests; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D052157:Aptamers, Nucleotide; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors