Viral and latent reservoir persistence in HIV-1-infected patients on therapy

Abstract

Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the "critical efficacy" irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.

Figure 1. A Schematic Illustration of the Decay Dynamics of HIV-1 after the Initiation of Highly Active ART

Figure 2. Effect of the Bystander Proliferation of the Latent Reservoir on the Latent Reservoir and on Plasma Viral Load

When there is no ongoing viral replication (ɛ = 1) and the minimum activation rate of the latent reservoir is zero (a _min = 0). The open circles indicate the decay kinetics of the latent reservoir suggested by Strain et al. [30], where they found t_1/2 ≈ 18 wk up to week 35 and t_1/2 ≈ 58 wk for the subsequent 3 y. The solid curve with r = −0.00171 d⁻¹ and ω = 0.00939 d⁻¹ represents the best-fit curve to the data. (A) Latent reservoir. (B) Plasma viral load.

Figure 3. Effect of Persistent Low-Level Activation of the Latent Reservoir on the Latent Reservoir and on Plasma Viral Load

When there is no ongoing viral replication (ɛ = 1) and the rate of bystander proliferation of the latent reservoir is equal to the minimum activation rate (r = a_min), i.e., at the bifurcation condition. (A) Latent reservoir. (B) Plasma viral load.

Figure 4. Effect of Ongoing Viral Replication (ɛ < 1) on the Latent Reservoir, Plasma Viral Load, and the Contribution of Ongoing Viral Replication to the Level of the Latent Reservoir Measured by the Ratio of the Rate of Production of Latently Infected Cells by Ongoing Viral Replication to the Net Removal Rate of Latently Infected Cells

The results were obtained for ɛ values above (ɛ = 0.7 > ɛ_c), at (ɛ = 0.1402 = ɛ_c), and slightly below (ɛ = 0.133 < ɛ_c) the critical drug efficacy (ɛ_c) when a_min = 0, r = −0.00171 d⁻¹, and ω = 0.00939 d⁻¹. (A) Latent reservoir. (B) Plasma viral load. (C) Contribution of ongoing viral replication.

Figure 5. Dependency of the Critical Drug Efficacy on the Concentration of T cells

T_sat represents the concentration that T cells approach as the duration of ART increases. The solid line shows how the critical efficacy depends on T_sat. The dotted line indicates a typical drug efficacy estimated for standard combination ART (ɛ ≈ 0.7), and the dashdot line indicates the critical efficacy when T_sat = T ₀ = 595 cells/μl, i.e., ɛ_c = 0.1402.

Figure 6. Simulated Decay Dynamics of HIV-1 after the Initiation of ART

The initial conditions and parameters used in the simulation are given in Materials and Methods. The results are shown for three different drug efficacies (ɛ = 0.3, 0.5, and 0.7). (A) Viral decay profile. (B) Contribution of long-lived infected cells to plasma virus (φ₁(t) = p_MM*(t) / (NδT*(t) + p_MM*(t))).