Single-nucleotide changes in the HIV Rev-response element mediate resistance to compounds that inhibit Rev function

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Two compounds were previously identified that inhibit HIV replication by interfering with Rev protein function.
• The Rev protein and its binding site, the Rev response element (RRE), are critical for HIV-1 RNA processing and viral production.

Purpose of the Study:

• To investigate the mechanisms of drug resistance in HIV variants selected by two Rev inhibitors.
• To understand how mutations in the HIV genome confer resistance to Rev-inhibiting compounds.

Main Methods:

• Generation and characterization of drug-resistant HIV variants from two different proviral clones (NL4-3 and R7/3) under compound selection pressure.
• Analysis of mutations within the Rev response element (RRE) and other viral regions in resistant isolates.
• Assessment of viral response to Rev inhibitors in the presence of identified mutations.

Main Results:

• In HIV(NL4-3), single point mutations in the RRE stem-loop IIC led to resistance by increasing RRE responsiveness to Rev.
• In HIV(R7/3), resistance involved two nucleotide changes in the envelope region, outside the RRE, with both mutations necessary for the phenotype.
• Wild-type HIV(R7/3) showed inhibition despite having an RRE similar to the resistant NL4-3 variant.

Conclusions:

• Drug-resistant HIV variants can emerge through distinct genetic mechanisms.
• Mutations outside the canonical Rev-binding site can significantly impact the Rev/RRE pathway efficiency.
• Understanding these resistance mechanisms is crucial for developing durable antiretroviral therapies.