Modelling HIV-1 2-LTR dynamics following raltegravir intensification

Area of Science:

• Virology
• Mathematical Modeling
• Immunology

Background:

• Antiviral therapy intensification with HIV integrase inhibitors like raltegravir aims to suppress viral replication.
• 2-LTR HIV-1 DNA circles are a byproduct of viral replication and can serve as a marker for ongoing viral activity.
• Understanding the sources of viral persistence, including reservoir activation and de novo infection, is crucial for HIV eradication strategies.

Purpose of the Study:

• To develop and validate a mathematical model of HIV-1 reservoir dynamics and viral replication.
• To investigate the origins of 2-LTR HIV-1 DNA circles following raltegravir treatment intensification.
• To differentiate between de novo infection and quiescent cell activation as drivers of viral persistence.

Main Methods:

• Development of a mathematical model incorporating de novo infection and infected cell sources.
• Analysis of 2-LTR HIV-1 DNA circle dynamics in response to raltegravir intensification.
• Validation of the model using patient data from the INTEGRAL study.

Main Results:

• The model demonstrates that monotonic increases in 2-LTR DNA correlate with limited de novo infection, primarily driven by raltegravir-unaffected sources like quiescent cell activation.
• Transient increases in 2-LTR DNA suggest significant, efficient de novo infection (R0 > 1) prior to treatment.
• The model showed a statistically significant fit to patient data, with parameter estimates including 2-LTR half-life.

Conclusions:

• HIV-1 2-LTR DNA dynamics post-raltegravir intensification can distinguish between limited de novo infection and efficient viral replication.
• Quiescent infected cell activation is a significant contributor to viral persistence, even under effective antiviral pressure.
• A substantial proportion of patients (7/13) in the INTEGRAL study exhibited viral dynamics consistent with efficient pre-treatment replication.