First characterization of insertions in the HIV-1 integrase-coding region from people with HIV

Area of Science:

• Virology
• Molecular Biology
• Drug Resistance Studies

Background:

• Integrase (IN) is a key enzyme in HIV-1 replication.
• Insertional mutations within the IN-coding sequence can potentially affect viral fitness and drug susceptibility.
• Understanding these mutations is vital for developing effective antiretroviral therapies.

Purpose of the Study:

• To investigate the impact of insertional mutations in the HIV-1 integrase (IN) coding sequence on viral replication and resistance to integrase strand transfer inhibitors (INSTIs).
• To analyze the consequences of specific amino acid insertions at positions 168, 253, 255, and 260 in the IN sequence.

Main Methods:

• Analysis of viral genomes using quantitative PCR.
• Virological and biochemical assays to assess viral replication and integration.
• 3D modeling to understand structural impacts of mutations.
• Testing resistance against potent INSTIs like raltegravir and dolutegravir.

Main Results:

• First documentation of amino acid insertions in the HIV-1 IN-coding sequence at specific positions (168, 253, 255, 260).
• Insertional mutations were found to reduce reverse transcription efficiency and impact viral integration.
• Mutant viruses exhibited delayed replication kinetics.
• No observed resistance to the INSTIs raltegravir and dolutegravir.

Conclusions:

• Observed mutations in people living with HIV-1 do not confer resistance to anti-integrase compounds.
• These insertional mutations are detrimental to HIV-1 replication, potentially impacting viral fitness.