Modelling HIV-1 2-LTR dynamics following raltegravir intensification

Abstract

A model of reservoir activation and viral replication is introduced accounting for the production of 2-LTR HIV-1 DNA circles following antiviral intensification with the HIV integrase inhibitor raltegravir, considering contributions of de novo infection events and exogenous sources of infected cells, including quiescent infected cell activation. The model shows that a monotonic increase in measured 2-LTR concentration post intensification is consistent with limited de novo infection primarily maintained by sources of infected cells unaffected by raltegravir, such as quiescent cell activation, while a transient increase in measured 2-LTR concentration is consistent with significant levels of efficient (R0 > 1) de novo infection. The model is validated against patient data from the INTEGRAL study and is shown to have a statistically significant fit relative to the null hypothesis of random measurement variation about a mean. We obtain estimates and confidence intervals for the model parameters, including 2-LTR half-life. Seven of the 13 patients with detectable 2-LTR concentrations from the INTEGRAL study have measured 2-LTR dynamics consistent with significant levels of efficient replication of the virus prior to treatment intensification.

Keywords: HIV; cryptic viremia; mathematical biology.

Figure 1.

Virus life cycle. In the site of 2-LTR formation, free virus enters target cells, then undergoes reverse transcription and integration. The infected cell then produces virus and lyses, completing the cycle with a turnover rate of ayR before raltegravir intensification and ay(1 − η_II)R after raltegravir intensification. Active infected cells may also come from exogenous sources not affected by raltegravir at a rate y_e; these sources include but are not limited to activation of quiescent reservoir cells and efficient replication in sites unaffected by raltegravir. Integration failure and 2-LTR formation occur at an intrinsic rate which is proportional to the successful infection rate ayϕk_IIR before raltegravir intensification or ayϕk_II(1 − η_II)R after intensification. The rate of 2-LTR formation in cells affected by raltegravir is proportional to the inhibitory effect of raltegravir, ak_IIη_IIR. 2-LTR-containing cells decay at a rate δ.

Figure 2.

2-LTR responses predicted by the model for varying effective reproduction rates. Either with efficient viral replication (R = 0.9982), intermediate viral replication (R = 0.95) or with little ongoing viral replication (R = 0.7). y_e is scaled to provide identical levels of pre-intensification turnover. The median measured data and the measured data points are shown for comparison.

Figure 3.

Maximum-likelihood prediction and 95% credible prediction intervals compared with measured data for 13 patients.