Journal Article

Formation of a Unique Cluster of G-Quadruplex Structures in the HIV-1 nef Coding Region: Implications for Antiviral Activity

Perrone, Rosalba, Richter, Sara N., Poe, Jerrod A., Frasson, Ilaria, Palumbo, Manlio, Palù, Giorgio, Smithgall, Thomas E., Nadai, Matteo

2013

Overview

G-quadruplexes are tetraplex structures of nucleic acids that can form in G-rich sequences. Their presence and functional role have been established in telomeres, oncogene promoters and coding regions of the human chromosome. In particular, they have been proposed to be directly involved in gene regulation at the level of transcription. Because the HIV-1 Nef protein is a fundamental factor for efficient viral replication, infectivity and pathogenesis in vitro and in vivo, we investigated G-quadruplex formation in the HIV-1 nef gene to assess the potential for viral inhibition through G-quadruplex stabilization. A comprehensive computational analysis of the nef coding region of available strains showed the presence of three conserved sequences that were uniquely clustered. Biophysical testing proved that G-quadruplex conformations were efficiently stabilized or induced by G-quadruplex ligands in all three sequences. Upon incubation with a G-quadruplex ligand, Nef expression was reduced in a reporter gene assay and Nef-dependent enhancement of HIV-1 infectivity was significantly repressed in an antiviral assay. These data constitute the first evidence of the possibility to regulate HIV-1 gene expression and infectivity through G-quadruplex targeting and therefore open a new avenue for viral treatment.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / AIDS / Antiviral activity / Antiviral drugs / Computer applications / Deoxyribonucleic acid / DNA / GC Rich Sequence - physiology / Gene expression / Gene Expression Regulation, Viral - physiology / Gene regulation / Genomes / HEK293 Cells / HIV / HIV Infections - genetics / HIV Infections - metabolism / HIV Infections - therapy / HIV-1 - chemistry / HIV-1 - physiology / Human immunodeficiency virus / Humans / In vivo methods and tests / Incubation / Infectivity / Kinases / Ligands / Medicine / nef Gene Products, Human Immunodeficiency Virus - chemistry / nef Gene Products, Human Immunodeficiency Virus - genetics / nef Gene Products, Human Immunodeficiency Virus - metabolism / Nef protein / Nucleic acids / Pathogenesis / Proteins / Reporter gene / Telomerase / Telomeres / Transcription / Viral infections / Virus Replication - physiology / Viruses