Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy

Abstract

Drug treatment of HIV type 1 (HIV-1) infection leads to a rapid initial decay of plasma virus followed by a slower second phase of decay. To investigate the role of HIV-1 retained on follicular dendritic cells (FDCs) in this process, we have developed and analyzed a mathematical model for HIV-1 dynamics in lymphoid tissue (LT) that includes FDCs. Analysis of clinical data using this model indicates that decay of HIV-1 during therapy may be influenced by release of FDC-associated virus. The biphasic character of viral decay can be explained by reversible multivalent binding of HIV-1 to receptors on FDCs, indicating that the second phase of decay is not necessarily caused by long-lived or latently infected cells. Furthermore, viral clearance and death of short-lived productively infected cells may be faster than previously estimated. The model, with reasonable parameter values, is consistent with kinetic measurements of viral RNA in plasma, viral RNA on FDCs, productively infected cells in LT, and CD4(+) T cells in LT during therapy.

Figure 1

HIV-1 and cell dynamics during antiretroviral therapy.

Figure 2

Decay of free and FDC-associated virus in triple therapy patients 20485 and 20497. (A and B) HIV-1 RNA per ml of plasma (points) (14) and the best-fit theoretical curve, found by calculating V + V̂ as a function of treatment time t. (C and D) HIV-1 RNA per g of LT (points) (5) and the best-fit theoretical curve, found by calculating Σ_i=1ⁿ(B_i + B̂_i) as a function of treatment time t. Calculations are based on Eqs. 4-7 and parameter values in Tables 1 and 2.

Figure 3

Persistence of potentially infectious virus during therapy. The theoretical decay curves of Fig. 2 are replotted to show the total body numbers of potentially infectious (solid lines) and therapy-modified (dotted lines) viral particles that are (A and B) free in extracellular fluid and (C and D) associated with FDCs in LT.

Figure 4

Decay of infected cells and recovery of target cells in triple therapy patients 20485 and 20497. (A and B) Infected mononuclear cells per g of LT (points) (5) and the best-fit theoretical decay curve, found by calculating T* + C* as a function of treatment time t. (C and D) CD4⁺ T cells per μg of LT (points) (12) and the best-fit theoretical recovery curve, found by calculating T + T* + C* as a function of treatment time t. Solid lines correspond to calculations with λ = 0 (all target cell expansion because of proliferation), which are based on Eqs. 1–3 and parameter values in Tables 1 and 2. Dotted lines correspond to calculations with p = 0 (all target cell expansion caused by de novo generation), which are based on Eqs. 1–3 and parameter values in Tables 1 and 2 with the following exceptions. For patient 20485, p = 0, λ = 7.2 × 10⁸ d⁻¹, and δ = 3.2 d⁻¹. For patient 20497, p = 0, λ = 4.5 × 10⁸ d⁻¹, and δ = 1.5 d⁻¹.