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Elucidating the Mechanism by Which HIV-1 Nucleocapsid Mutations Confer Resistance to Integrase Strand Transfer
Yuta Hikichi1, Ryan C Burdick2, Sean C Patro3
1Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD.
Biorxiv : the Preprint Server for Biology
|October 1, 2025
Summary
Mutations in HIV-1 nucleocapsid (NC) accelerate viral DNA integration, reducing susceptibility to integrase strand transfer inhibitors (INSTIs). This highlights the need for genetic testing beyond the integrase gene in individuals with HIV experiencing treatment failure.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Integrase strand transfer inhibitors (INSTIs) are crucial for HIV treatment.
- Some individuals with HIV (PWH) experience virologic failure (VF) despite INSTI therapy, even without resistance mutations in the integrase (IN) gene.
- Previous research identified nucleocapsid (NC) mutations conferring INSTI resistance.
Purpose of the Study:
- To investigate the mechanism by which NC mutations affect INSTI efficacy.
- To determine how NC mutations influence the kinetics of viral DNA integration.
- To explore the combined effect of NC and IN mutations on HIV-1 susceptibility to INSTIs.
Main Methods:
- Selection of HIV-1 for INSTI resistance in primary peripheral blood mononuclear cells.
- Analysis of viral genetic mutations, including in the viral envelope glycoprotein, NC, and IN.
- Assessment of the kinetics of viral DNA integration.
- Evaluation of HIV-1 susceptibility to dolutegravir (DTG) in the presence of selected mutations.
Main Results:
- Selected NC mutations were found to accelerate the kinetics of viral DNA integration.
- This accelerated integration shortens the time window for INSTIs to inhibit the process, leading to reduced sensitivity to DTG.
- In concert, selected NC and IN mutations significantly reduce HIV-1 susceptibility to INSTIs.
- HIV-1 acquired mutations in the viral envelope glycoprotein, NC, and IN during selection for INSTI resistance.
Conclusions:
- NC mutations contribute to INSTI resistance by accelerating viral DNA integration.
- The combined action of NC and IN mutations enhances viral escape from INSTIs.
- Genotypic analysis beyond the IN gene is important for PWH experiencing VF on INSTI-based regimens.
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