Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART

Abstract

Background: In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4+ T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.

Methods: Here we use a mathematical model of T cell dynamics in the setting of HIV-1 infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART.

Results: By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model.

Conclusion: The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-1 infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.

Figure 1

General schematic of model reflecting uninfected cells (U), productively infected cells (P) and latently infected cells (L). λ represents target T cell production. β reflects virus infectivity. α_R is the rate of reversion for productively infected cells to latency. α_Q is the activation rate of latently infected cells. Uninfected, productively infected and latently infected cells each have intrinsic death rates represented by δ_U, δ_P and δ_L, respectively.

Figure 2

Dependence of the latent reservoir decay rate, Λ, on the degree of residual viral replication, r, plotted as Λ vs. 1 - r, for parameter values: λ = 2 × 10⁹ cells/day, α_R = α_Q/100, δ_U = 0.02 day^-1, δ_L = 0.0001 day^-1, and $\overline{L}/\overline{U}$ = 1 × 10^-4. We consider 3 different pairs of δ_P and α_Q values. The predicted value of r*, color coded for each case, is marked at the top of the plot. The marker * indicates the similar r = β_crit/β_untreated value for every pair of δ_P and α_Q.

Figure 3

Decay of (A) productively infected cells (total number of cells) for different degrees of viral infectivity under optimal suppression (β_HAART <β_crit) of replication by HAART (r = 0 and 0.95 β_crit/β_untreated) for different values of δ_U (= 0.02 day^-1 and 0.10 day^-1). Decay of productively infected cells for different degrees of viral infectivity under sub-optimal suppression (β_HAART > β_crit) by HAART for (B) δ_U = 0.02 day^-1 where β_crit/β_untreated ≈ 0.769 and (C) δ_U = 0.20 day^-1 where β_crit/β_untreated ≈ 0.970 (D) Clinically observed decay of viral load after initiation of HAART for 2 HIV⁺ patients with no history of drug resistance: pt. 135 (blue) and pt. 140 (red). Pt. 135's viral load has remained undetectable for an additional 5 years with only 1 blip and pt. 140's viral load has remained undetectable for 1 additional year (data not shown). Open faced markers represent undetectable viral load measurements at the limit of detection for the assay used. (E) Decay of latently infected cells (total number of cells) for different degrees of viral infectivity, where β_crit/β_untreated ≈ 0.769. All simulations were performed with model parameter values listed in Table 1 unless otherwise specified.

Figure 4

Decay of the latent reservoir as a function of time for (A) different degrees of HAART suppression of viral infectivity, r = 0 (black), 0.769 (β_crit/β_untreated) (blue), 0.80 (green), 0.90 (red); and (B) different activation rates, α_Q = 0.0005 day^-1 (black), 0.001 day^-1 (blue), 0.0025 day^-1 (green) and 0.005 day^-1 (red). Parameter values, unless otherwise specified, are: λ = 2 × 10⁹ cells/day, β = 0, α_Q = 0.0005 day^-1, α_R = α_Q/100, δ_U = 0.02 day^-1, δ_P = 0.50 day^-1, δ_L = 0.0001 day^-1 and $\overline{L}/\overline{U}$ = 1 × 10^-4.