Influence of follicular dendritic cells on HIV dynamics

Hlavacek, William S.; Stilianakis, Nikolaos I.; Perelson, Alan S.

doi:10.1098/rstb.2000.0642

Cited by 26 publications

(12 citation statements)

References 47 publications

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“…These in situ measurements directly quantify cells producing virus in the tissues, because virions have been detected and quantified in the viral RNA + (vRNA + ) CD4 + T cells (39) that are the principal host cells for virus production in LTs in HIV-1 and simian immunodeficiency virus infections (19,20,22,38,40,41). Thus, enumerating vRNA + cells is also a measure of productively infected cells.…”

Section: Resultsmentioning

confidence: 99%

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher

Staskus²,

Wietgrefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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588

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Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.drug levels | pharmacokinetics | FDC network C ombination antiviral therapy (ART) to suppress HIV-1 replication and reduce plasma viremia to below the limits of detection in peripheral blood (PB) has reduced mortality and dramatically improved quality of life for patients. However, immune reconstitution, measured by changes in the size of populations of CD4 T cells, is often incomplete, even after years of therapy (1-3). During apparently effective therapy, CD4 T-cell populations in PB mononuclear cells (PBMCs), lymph node (LN), and gut-associated lymphoid tissue (GALT) remain abnormally low and innate and adaptive immunity is not fully restored (4). Levels of T-cell activation and innate system activation are often higher than that observed in well-matched uninfected adults (5, 6). These persistent abnormalities may contribute to abnormal vaccine responses (7, 8), a higher than normal incidence of non-AIDS-related cancers (9, 10) and increased risk for clinical conditions associated with chronic inflammation (e.g., cardiac disease, clotting disorders, pulmonary hypertension, emphysema, and stroke) (11-18). Thus, improvements over current approaches to treatment of HIV infection that more fully restore normal immune function might significantly improve health and life expectancy.To that end, we explore here the hypothesis that antiretroviral drug (ARV) concentrations might be insufficient to fully suppress replication in the lymphoid tissue compartments, which are the principal sites where virus is produced, stored as complexes on the follicular dendritic cell network (FDCn) (19-21), and persists in latently infected cells during ART (19,20,22). This hypothesis builds first on the link between the size of the reservoir and the degree of inflammation, arguing that persistent virus production during ART could sustain immune activation (IA) and downstream pathological consequences (23, 24), and second on drug distribution studies in animal models of AIDS in which ...

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Section: Resultsmentioning

confidence: 99%

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher

Staskus²,

Wietgrefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

588

608

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“…Other models have differentiated between latent and active infected cells by introducing a new variable (w) for the latently infected cells [32][33][34][35][36][37]. In [38], an HIV mathematical model has been presented by considering three types of infected cells: latently infected cells (w), short-lived productively infected cells (y), and long-lived productively infected cells (u) as follows:…”

Section: Introductionmentioning

confidence: 99%

Effect of cellular reservoirs and delays on the global dynamics of HIV

2018

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We investigate general HIV infection models with three types of infected cells: latently infected cells, long-lived productively infected cells, and short-lived productively infected cells. We incorporate three discrete or distributed time delays into the models. Moreover, we consider the effect of humoral immunity on the dynamical behavior of the HIV. The HIV-target incidence rate, production/proliferation, and removal rates of the cells and HIV are represented by general nonlinear functions. We show that the solutions of the proposed model are nonnegative and ultimately bounded. We derive two threshold parameters which fully determine the existence and stability of the three steady states of the model. Using Lyapunov functionals, we establish the global stability of the steady states of the model. The theoretical results are confirmed by numerical simulations.MSC: 34D20; 34D23; 37N25; 92B05

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“…FDC reversibly bind virions on their surface and can slowly release them back into the circulation (12). In the asymptotic phase of HIV infection, the pool of virus stored on FDC is estimated to be ϳ10 11 HIV RNA copies (i.e., 5 ϫ 10 10 virions), greatly exceeding the viral load in infected cells or in plasma (15). During HAART, the viral load is reduced significantly, and most trapped virions dissociate from FDC.…”

mentioning

confidence: 99%

“…Palmer et al (8) suggest that candidates for "compartment 3" and "compartment 4" are sanctuary sites with suboptimal drug penetration, long-lived productively infected cells, and latently infected CD4 ϩ cells. Another candidate is follicular dendritic cells (FDC), which can bind virus and later can release that virus into the circulation (11,12). Among these candidates, latently infected CD4 ϩ cells have attracted the most attention (13).…”

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confidence: 99%

Contribution of Follicular Dendritic Cells to Persistent HIV Viremia

Perelson

2013

J Virol

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HIV-1 infections cannot be completely eradicated by drug therapy, as the virus persists in reservoirs. Low-level plasma viremia has been detected in patients treated for over 7 years, but the cellular compartments that support this low-level viremia have not been identified. The decay of HIV-1 during treatment appears to occur in four phases, with the 3rd and 4th phases occurring when the virus is below the limit of detection of conventional assays. Here, we focus on the 3rd phase of decay, which has been estimated to have a half-life of 39 months. We show that follicular dendritic cells (FDC), which have been identified as an HIV reservoir, can be the main source of the low-level viremia detected during the 3rd phase of decay and contribute to viremia at even longer times. Our calculations show that the kinetics of leakage of virus from FDC is consistent with three types of available clinical data. Highly active antiretroviral therapy (HAART) is effective in suppressing progression of HIV infection. In the first few months of suppressive therapy, the plasma HIV-1 RNA load experiences a biphasic decay (1-5). The first phase has a short halflife (1 to 2 days) and is attributed to the loss of infected activated CD4 ϩ T cells. The second phase has a half-life of 1 to 4 weeks and has been attributed to the loss of long-lived infected cells such as resting CD4 ϩ T cells or macrophages (4, 6). The presence of other decay phases has been suggested (5, 7), and a recent study by Palmer et al. (8), using a very sensitive assay with a lower limit of quantification of 0.63 HIV RNA copies/ml (9), identified a third and fourth decay phase in patients on suppressive therapy for 7 years (Fig. 1). Phase 3 had a half-life, 3 , of 39 weeks (supported by a recent study [10]), and phase 4 showed a nearly constant plasma viral load for the period studied out to 7 years. Overall, the median plasma viral load, V(t), for patients on suppressive therapy can be represented by the following equation:where t is the time on therapy, V 1 (t) through V 4 (t) designate the contributions to the plasma viral load of the virus generated by the compartments 1 through 4, V 1 (0) through V 4 (0) designate the contributions of the virus generated by compartments 1 through 4 to the baseline viral load, i ϭ

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Influence of follicular dendritic cells on HIV dynamics

Cited by 26 publications

References 47 publications

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Effect of cellular reservoirs and delays on the global dynamics of HIV

Contribution of Follicular Dendritic Cells to Persistent HIV Viremia

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