Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data

Area of Science:

• Virology
• Genetics
• Drug Discovery

Background:

• Sequence variation in HIV-1 integrase genes is crucial for understanding treatment response to antiretroviral therapy (ART).
• HIV-1 subtype C is prevalent in South India, necessitating studies on its genetic characteristics and drug resistance patterns.

Purpose of the Study:

• To analyze sequence variations in the HIV-1 integrase gene among infected individuals.
• To investigate the impact of these variations on resistance to integrase inhibitors.
• To elucidate the molecular basis of drug resistance for improved inhibitor design.

Main Methods:

• Plasma samples from 161 HIV-1 infected individuals were collected for integrase gene amplification.
• 102 complete HIV-1 subtype C integrase gene sequences were analyzed using sequence analysis and multiple sequence alignment (MSA).
• Molecular modeling and docking techniques (Schrodinger suite) were employed to assess the functional impact of mutations.

Main Results:

• Sequence analysis identified accessory mutations leading to reduced susceptibility to known integrase inhibitors in 14% of analyzed sequences.
• Molecular modeling and docking revealed reduced binding affinity of mutant integrase variants to known inhibitors.
• Combined mutations in subtype C clinical strains further decreased predicted binding values.

Conclusions:

• The study reports the molecular basis for the consequences of mutations in HIV-1 subtype C integrase genes from South India.
• Identified mutations and their impact on drug resistance are valuable for designing and developing improved HIV-1 integrase inhibitors.
• Understanding sequence variations is key to overcoming ART resistance and optimizing treatment strategies.