UCLA1, a Synthetic Derivative of a gp120 RNA Aptamer, Inhibits Entry of Human Immunodeficiency Virus Type 1 Subtype C

Abstract

dEntry 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.

Aptamers against pathogenic microorganisms

“…It was also shown that B40 aptamer at maximum concentration of 2 µM had no cytotoxic effect on cardiomyocytes and PBMC (Lopes de Campos et al, 2009). In order to enhance biological stability of the aptamer B40, a series of minimized B40 analogs containing different chemical modifications were generated (Cohen et al, 2008; Moore et al, 2011a; Mufhandu et al, 2012). The authors suggest that the combination of such modified aptamers with nuclease-inhibiting Zn 2+ ions that are able to enhance antiviral effect of chemically modified aptamers could be applied as a basis for the antiviral drug for topical application.…”

Aptamers: Problems, Solutions and Prospects

“…Nevertheless, aptamers can effectively bind viral capsid proteins. Such binding inhibits the interaction between viruses and cellular receptors and prevents viral entry into the cell [98, 99]. It makes the potential application of aptamers for antiviral prophylaxis or therapy much easier: aptamers can be injected intravenously or applied on the skin as a solution or ointment.…”

Isolation and characterization of 2′-F-RNA aptamers against whole HIV-1 subtype C envelope pseudovirus

“…Thus, we previously isolated aptamers against recombinant monomeric gp120 that showed efficacy against HIV-1 in cell based assays [7][8][9][10] and had no cytotoxic side effects [11]. However, it has been observed that recombinant gp120 and native trimeric gp120 have different antigenic properties [12].…”