Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Abstract

Combination Antiretroviral Therapy (cART) can suppress plasma HIV below the limit of detection in normal assays. Recently reported results suggest that viral replication may continue in some patients, despite undetectable levels in the blood. It has been suggested that the appearance of the circularized episomal HIV DNA artifact 2-LTR following treatment intensification with the integrase inhibitor raltegravir is a marker of ongoing viral replication. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. In this study we model the hypothesis that this ongoing replication occurs in lymphoid follicle sanctuary sites and investigate the patterns of 2-LTR formation expected after raltegravir application. Experimental data is used to estimate the reaction and diffusion parameters in the model, and Monte-Carlo simulations are used to explore model behavior subject to variation in these rates. The results suggest that conditions for the formation of an observed transient peak in 2-LTR formation following raltegravir intensification include a sanctuary site diameter larger than 0.2 mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20 mL. Significant levels of uncontrolled replication can occur in the sanctuary sites without measurable changes in the plasma viral load. By contrast, subcritical replication (where the basic reproductive ratio of the virus is less than 1 in all sites) always results in monotonic increases of measured 2-LTR following raltegravir intensification, occurring at levels below the limit of detection.

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…Moreover, HIV persistence is widely believed to result solely from the long lifespan or proliferative ability of latently infected cells (3,50). If this assumption is violated, e.g., by the presence of long-lived drug-protected compartments (43,51,52), then any curative strategy predicated solely on latency reversal would be futile.…”

Increased inflammation in sanctuary sites may explain viral blips in HIV infection

“…We use the multicompartmental model proposed in [44, 32] configured with one main compartment representing the blood, the high endothelial venules and the lymphatic vessels; and N secondary disconnected spherical compartments representing all the lymph nodes’ follicular sites in the human body. In the model we do not explicitly coded each of the N secondary compartments, rather we assume that all of them have the same dynamics.…”

“…$D_{i,j}^{(·)}=0$). As presented in [32] each compartment u i goes to w 0 ( f ( w 0 , μ i ) = 0 for any i ) only if the parameters meet the criteria: $${\hat{R}}_{0_i}=\underset{R_0}{\underbrace{\frac{\beta \lambda \gamma }{da\omega }}}(1-{\eta }_{\mathrm{italicRTI}}{\theta }_i)(1-{\eta }_{PI}{\phi }_i)<1$$…”

“…Previously, we have shown that 2-LTR formation in the blood after (RAL) intensification might be produced due to replication in lymph nodes with suboptimal drug penetration [32]. For low drug concentrations, there is a critical size to the LN before cryptic viremia can exist inside the site.…”

Order preservation of expected information content using Unscented Transform approximation of multivariate prior distributions in HIV 2-LTR experiment design

“…In modeling the dynamics of HIV-1, the formation of 2-LTR circles has been of interest to many researchers [2]-[5], [7], [10]-[12], [14], [16], [18]-[27]. 2-LTR circles are formed when viral DNA fails to integrate into its target host cell.…”