HIV-1 Evolutionary Dynamics under Nonsuppressive Antiretroviral Therapy

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• Long-term virologic failure on protease inhibitor (PI)-based antiretroviral therapy (ART) without major protease mutations offers a unique model for studying within-host evolution.
• Existing research on HIV-1 intrahost population dynamics primarily focuses on untreated infections, predominantly in subtype B.

Purpose of the Study:

• To analyze whole-genome sequences from longitudinal plasma samples of HIV-1-positive individuals experiencing virologic failure on second-line ART.
• To investigate viral population dynamics, including diversification, recombination, and haplotype competition, in long-term viremic, treatment-experienced individuals.

Main Methods:

• Utilized next-generation sequencing and in silico haplotype reconstruction.
• Analyzed longitudinal plasma samples from eight HIV-1-positive individuals in the ANRS 12249 Treatment as Prevention (TasP) trial.
• Employed drug resistance mutations in reverse transcriptase (RT) as markers for viral haplotypes and assessed linkage disequilibrium.

Main Results:

• Observed significant fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia under nonsuppressive ART.
• Provided evidence for selective sweeps during partial adherence and viral haplotype competition during low drug exposure.
• Demonstrated viral recombination through RT mutation distribution and linkage disequilibrium decay.

Conclusions:

• HIV-1 population structure undergoes dramatic changes during stable viremia under nonsuppressive ART.
• The study provides compelling evidence of within-host viral diversification, recombination, and haplotype competition in treatment-experienced individuals.
• Findings are relevant for understanding HIV dynamics and applicable to other RNA viruses.