Dissociation of HIV-1 from follicular dendritic cells during HAART: Mathematical analysis

Abstract

The pool of HIV type 1 (HIV-1) on follicular dendritic cells (FDC) is an important reservoir that has the potential to perpetuate infection (1-3). Although antiretroviral therapies that block viral replication have no direct effect on viral clearance, these therapies are associated with loss of HIV-1 from FDC (4-7). Cavert et al. (4) observed that the amount of HIV-1 on FDC, estimated as Ϸ10 11 virions, decreased by up to 5-fold during the first 2 d of potent antiretroviral therapy and by up to more than four orders of magnitude after 6 mo. This clearance of FDC-associated HIV-1 during antiretroviral therapy suggested that HIV-1 might be eradicated from the FDC reservoir, and an estimate of 30 mo to eradication was proposed (4).To evaluate further the prospect of eradicating or substantially reducing FDC-associated HIV-1 through highly active antiretroviral therapy (HAART), we develop and analyze two related mathematical models for the reversible binding of HIV-1 to FDC via ligand-receptor interactions. One model is a deterministic mass-action model that allows us to follow the time course of dissociation for a population of virions initially on FDC when therapy reduces the pool of virus available for binding to FDC. This model is useful for examining early events during treatment. The other model is a stochastic model that allows us to determine the distribution of dissociation times for individual virions. This model is useful for examining late events during treatment and assessing the treatment time required to eliminate HIV-1 on FDC. These models also allow us to determine how physical quantities, such as the surface density of receptors or the valence of a virion, influence the dissociation process.The mathematical models developed here are based on our current understanding of the physical chemistry of antigen trapping by FDC (8). HIV-1 is held on the surface of FDC through interactions with complement receptors (9) and possibly Fc receptors that bind antibodies attached to HIV-1. FDC express complement receptors CR1, CR2, and CR3 (10). These receptors bind proteolytic fragments of complement component C3 (11): CR1 binds C3b; CR2 binds iC3b, C3dg, and C3d; and CR3 binds iC3b. Ligands of CR2 have been detected on plasma virus (12, 13). One mechanism that contributes to C3 deposition on HIV-1 is direct binding of C1q to sites on the HIV-1 transmembrane glycoprotein gp41 (14), which leads to activation of complement via the classical pathway (15). In our models, we focus on interactions of CR2 on FDC with terminal C3 fragments (C3dg and C3d) on HIV-1. By focusing on this subset of interactions involved in binding of HIV-1 to FDC, we obtain a minimal estimate of the treatment time required to eliminate FDC-associated HIV-1. ModelsModels are based on the reaction scheme illustrated in Fig. 1. We treat CR2 as a monovalent cell-surface receptor, which is consistent with the observed stoichiometry of CR2 binding to C3dg (16), and we treat a complement coated virion as a multivalent ligand that expresses a set of...

Persistence of Infectious HIV on Follicular Dendritic Cells

“…At low densities (as in our mice), many FDC Fc and complement receptors should be available, and trapped HIV immune complexes could be anchored to FDCs in more stable, highly multivalent states of attachment. This postulate is consistent with mathematical modeling of HIV-1 dissociation from FDCs (37), as well as a model of the kinetics of viral decline in patients on HAART (38). Importantly, it has been reported that even under HAART, some HIV replication continues (10, 28 -30, 39), and we reason that this FIGURE 5.…”

“…These data are in apparent contradiction to the longer decay periods observed in our murine study, although Hlavacek et al (37), using a stochastic model of decay, calculated that with a beginning virus load of 10 11 copies of RNA, virions could still be expected for as long as 10 yr. We hypothesize that differences between the Cavert study and ours may be related to analysis of the FDC network under very different conditions of FDC-virus density. At high virus densities (as would occur in untreated subjects), limited numbers of FDC Fc and complement receptors may be available for binding viral immune complexes, resulting in many less stable, univalent interactions.…”

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

“…1) (20). The model omits other processes that might influence the decay of FDC-associated virus, such as turnover of FDCs, internalization of HIV-1, shedding of HIV-1 on iccosomes (22), stripping of HIV-1 by cells that interact with FDCs, structural breakdown of virions, and recovery of the FDC network during therapy (13).…”

“…We consider measurements of plasma viral load (14), FDC-associated HIV-1 RNA (5), infected mononuclear cells in LT (5), and CD4 ϩ T cells in LT (12) during treatment for eight patients. The model combines earlier models for HIV-1 dynamics (19) with a recent model for the reversible binding of HIV-1 to FDCs (20). Fig.…”

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence

“…Infected macrophages and virus trapped on the follicular dendritic network (FDC) of lymphoid tissues are secondary sources (1)(2)(3). These virus sources might be eradicated with a few years of treatment (3,4), although the long-term clearance kinetics of FDC-associated virus is unknown (5,6). Stable, latently infected cells, harboring replication competent virus have been found to persist after many years of suppression of viremia to Ͻ50 copies per ml (7)(8)(9).…”