HIV and Ribozymes

Abstract

Ribozymes are structured RNA molecules that act as catalysts in different biological reactions. From simple genome cleaving activities in satellite RNAs to more complex functions in cellular protein synthesis and gene regulation, ribozymes play important roles in all forms of life. Several naturally existing ribozymes have been modified for use as therapeutics in different conditions, with HIV-1 infection being one of the most studied. This chapter summarizes data from different preclinical and clinical studies conducted to evaluate the potential of ribozymes to be used in HIV-1 therapies. The different ribozyme motifs that have been modified, as well as their target sites and expression strategies, are described. RNA conjugations used to enhance the antiviral effect of ribozymes are also presented and the results from clinical trials conducted to date are summarized. Studies on anti-HIV-1 ribozymes have provided valuable information on the optimal expression strategies and clinical protocols for RNA gene therapy and remain competitive candidates for future therapy.

Effective Inhibition of HIV-1 Production by Short Hairpin RNAs and Small Interfering RNAs Targeting a Highly Conserved Site in HIV-1 Gag RNA Is Optimized by Evaluating Alternative Length Formats

“…They are similar in structure to pre-miRNAs, except that the intended antisense strand is perfectly complementary to its target RNA and the corresponding sense strand in the shRNA stem (27). shRNAs are typically expressed from RNA polymerase III type 3 promoters, which allow for a defined transcript with 2 to 4 uridines at the 3= end from the polymerase termination signal (28,29). These transcripts are exported from the nucleus by the pre-miRNA transporter exportin 5 and processed by Dicer to yield 21-to 23-nt siRNAs.…”

Proteins, peptides, polysaccharides, and nucleotides with inhibitory activity on human immunodeficiency virus and its enzymes

“…It appears that anti-HIV-1 ribozymes are good therapeutic candidates. The outcome of clinical trials is available (Scarborough and Gatignol 2015).…”

Gene therapy approaches to functional cure and protection of hematopoietic potential in HIV infection

“…Because CCR5 is critical in HIV infection and transmission, as observed with CCR5-Δ32 homozygous cells resistant to HIV infection [38], the manipulation of CCR5 expression on HIV target cells has been intensively investigated and is considered effective . CCR5 can be targeted by zinc finger nucleases [62,63], ribozymes [64], CRISPR/Cas9 methods [65], transcription activator-like effector nucleases [65], and shRNAs [42,66,67]. Among these, several gene therapy methods, including one using lentiviral vector LVsh5/C46, expressing shRNA against CCR5, and HIV-1 entry inhibitor C46 [68] have been tested in clinical trials [51].…”