Drug resistant integrase mutants cause aberrant HIV integrations

Area of Science:

• Molecular Biology
• Virology
• Oncology

Background:

• HIV-1 integrase is a key target for antiretroviral therapy, with drugs like raltegravir and elvitegravir inhibiting viral DNA integration.
• Previous studies demonstrated that sub-optimal raltegravir concentrations induce aberrant HIV integrations with host DNA rearrangements.
• Aberrant integration into host oncogenes can potentially lead to uncontrolled cell proliferation.

Purpose of the Study:

• To investigate whether elvitegravir, another integrase inhibitor, also causes aberrant HIV integrations.
• To determine if drug-resistant HIV integrase mutants can induce aberrant integrations independently of drug pressure.
• To explore the potential oncogenic consequences of aberrant HIV integrations.

Main Methods:

• Experimental assessment of HIV integration patterns induced by elvitegravir.
• Analysis of integration events caused by clinically relevant drug-resistant integrase mutants (N155H, G140S/Q148H).
• Evaluation of drug susceptibility (IC50) for wild-type and mutant integrase enzymes.

Main Results:

• Elvitegravir, similar to raltegravir, induces aberrant HIV integrations characterized by host DNA deletions, duplications, insertions, and inversions.
• Drug-resistant integrase mutants (N155H, G140S/Q148H) promote aberrant integrations even without drug presence.
• These mutants exhibit reduced susceptibility to integrase inhibitors, requiring higher drug concentrations for effective inhibition.

Conclusions:

• Both suboptimal drug concentrations and drug-resistant integrase mutations can lead to dangerous aberrant HIV integrations.
• Aberrant integrations, particularly those involving oncogenes like BACH2 and MKL2, can stimulate infected cell proliferation.
• The observed DNA rearrangements associated with aberrant integrations may contribute to oncogenesis, increasing tumor development risk.