Targeting frameshifting in the human immunodeficiency virus

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• HIV-1 translation involves a programmed -1 ribosomal frameshift at a slippery sequence.
• A specific secondary structure, the frameshift stimulatory signal, controls frameshift efficiency.
• This frameshift is essential for synthesizing viral enzymes and HIV-1 replication.

Purpose of the Study:

• To explore drug targets for novel antiviral therapies against HIV-1.
• To evaluate different strategies for interfering with the HIV-1 -1 ribosomal frameshift.

Main Methods:

• Selection and modification of compounds binding to the frameshift stimulatory signal.
• Use of antisense oligonucleotides targeting the frameshift stimulatory signal.
• Employing bicistronic reporters to select compounds modulating frameshift efficiency.

Main Results:

• Compounds specifically targeting the HIV-1 frameshift stimulatory signal are the most promising therapeutic approach.
• Antisense oligonucleotides targeting this signal present questionable efficacy.
• Bicistronic reporters primarily select compounds targeting ribosomes, which is less effective.

Conclusions:

• Drug development should focus on compounds that directly target the HIV-1 frameshift stimulatory signal.
• Modulating ribosomal activity is a less promising strategy for HIV-1 antiviral drugs.
• Targeting the programmed -1 ribosomal frameshift offers a viable strategy for new HIV-1 therapeutics.