Inhibition of HIV replication through siRNA carried by CXCR4-targeted chimeric nanobody

Catarina Cunha-Santos, Pedro Ricardo Lucas Perdigao, Francisco Martin, Joana Gomes Oliveira, Miguel Cardoso, Ana Manuel, Nuno Taveira, Joao Goncalves

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Small interfering RNA (siRNA) application in therapy still faces a major challenge with the lack of an efficient and specific delivery system. Current vehicles are often responsible for poor efficacy, safety concerns, and burden costs of siRNA-based therapeutics. Here, we describe a novel strategy for targeted delivery of siRNA molecules to inhibit human immunodeficiency virus (HIV) infection. Specific membrane translocation of siRNA inhibitor was addressed by an engineered nanobody targeting the HIV co-receptor CXCR4 (NbCXCR4) in fusion with a single-chain variable fragment (4M5.3) that carried the FITC-conjugated siRNA. 4M5.3–NbCXCR4 conjugate (4M5.3X4) efficiently targeted CXCR4+ T lymphocytes, specifically translocating siRNA by receptor-mediated endocytosis. Targeted delivery of siRNA directed to the mRNA of HIV transactivator tat silenced Tat-driven viral transcription and inhibited the replication of distinct virus clades. In summary, we have shown that the engineered nanobody chimera developed in this study constitutes an efficient and specific delivery method of siRNAs through CXCR4 receptor.

Original languageEnglish
Pages (from-to)2859-2870
Number of pages12
JournalCellular and Molecular Life Sciences
Volume77
Issue number14
DOIs
Publication statusPublished - 1 Jul 2020

Keywords

  • CXCR4
  • Delivery
  • HIV
  • Nanobody
  • Small interfering RNA

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