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Release of virus from lymphoid tissue affects human immunodeficiency virus type 1 and hepatitis C virus kinetics in the blood

Muller, V., Maree, A.F.M. and De Boer, R.J. 2001. Release of virus from lymphoid tissue affects human immunodeficiency virus type 1 and hepatitis C virus kinetics in the blood. Journal of Virology 75 (6) , pp. 2597-2603. 10.1128/JVI.75.6.2597-2603.2001

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Kinetic parameters of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infections have been estimated from plasma virus levels following perturbation of the chronically infected (quasi-) steady state. We extend previous models by also considering the large pool of virus localized in the lymphoid tissue (LT) compartment. The results indicate that the fastest time scale of HIV-1 plasma load decay during therapy probably reflects the clearance rate of LT virus and not, as previously supposed, the clearance rate of virus in plasma. This resolves the discrepancy between the clearance rate estimates during therapy and those based on plasma apheresis experiments. In the extended models plasma apheresis measurements are indeed expected to reflect the plasma decay rate. We can reconcile all current HIV-1 estimates with this model when, on average, the clearance rate of virus in plasma is approximately 20 day−1, that of LT virus is approximately 3 day−1, and the death rate of virus-producing cells is approximately 0.5 day−1. The fast clearance in the LT compartment increases current estimates for total daily virus production. Because HCV is produced in the liver, we let virus be produced into the blood compartment of our model. The results suggest that extending current HCV models with an LT compartment is not likely to affect current estimates for kinetic parameters and virus production. Estimates for treatment efficacy might be affected, however. Our understanding of the dynamics of human immunodeficiency virus type 1 (HIV-1) infection relies largely on the analysis of changes in the viral load in plasma after initiation of treatment with potent antiretroviral drugs. Quantitative mathematical models have been fitted to clinical data to provide estimates for the virion clearance rate, the average life span of productively infected cells, the viral generation time, and the total daily production of virus (14, 15, 20, 21). These studies have identified two time scales during the first 1 to 2 weeks of potent antiviral therapy. The slower of the two was supposed to reflect the turnover of virus-producing cells, with an average death rate (δ) of about 0.5 day−1. For the faster decay of virus particles a “clearance” rate (c) of about 3 day−1 was found. The estimation of c from the total virus decline was later suggested to be unreliable (7), but an independent measurement of the decline of plasma infectivity (21) supported the estimate of ≃3 day−1. A recent plasma apheresis study yielded significantly faster estimates for the HIV-1 virus clearance (22). Large quantities of plasma were removed from infected patients to create an additional clearance term for the virus. During the 1 to 2 h of apheresis, the virus level in plasma dropped significantly and rapidly returned to baseline levels after the apheresis was stopped. A mathematical model was fitted to the data to obtain estimates for the natural clarance rate c. The estimates for four patients ranged from 9 to 36 day−1, with an average of approximately 23 day−1. Although the early estimates of approximately 3 day−1 were established as lower bounds, we show below that the large discrepancy in the estimates for c can be due to the compartmentalization of the virus pool. The estimates for the turnover rate, δ, of virus-producing cells have also been published as lower bounds (21) and have also been questioned (5). In HIV-1-infected patients, no correlation between δ and the magnitude of the cytotoxic response was found (17). This resulted in a debate on the importance of the cytotoxic immune response (4) and in more sophisticated immune control models (13). It has long been known that the major site of HIV-1 infection is the lymphoid tissue (LT) (3, 19). The trafficking of lymphocytes between the plasma and the LT compartment has been shown to be of potential importance in HIV-1 infection (12, 23). Here we extend this approach to the distribution of virus. A series of studies have confirmed that most of the virus, i.e., on the order of 1010 virions in a typical patient, resides in the LT compartment (1, 6, 18, 24). Most of the virus is bound to the surfaces of follicular dendritic cells (FDCs). Surprisingly, virus in the LT was found to decline at about the same rate as free virus in plasma during therapy (1): during the first two days of therapy, virus in LT declined at a rate of about 0.4 day−1. Later the decay slows down, which may be due to multivalent binding (9). The early parallel declines of virus in LT and plasma suggest that on this time scale of a few days there is a (quasi-) steady state between the two virus compartments that is maintained by an exchange of viral particles. The decay of virus in LT introduces a third time scale, which is intermediate to those for c and δ and which hence influences the established estimates. Mathematical analysis of plasma apheresis (22) and antiviral treatment data (14) has also been carried out for hepatitis C virus (HCV). To explain the rapid drop of the viral load in plasma in about 1 day, which is followed by a slower second-phase decay, Neumann et al. suggested that alpha interferon (IFN-α) blocks the production of new HCV virus particles (14). The first-phase decay was dominated by ac of approximately 6 days−1, and the slow second-phase decay, with 0.01 day−1 < δ < 0.4 day−1 was conjectured to reflect the death rate of virus-producing cells. The HCV estimates from the plasma apheresis study are in much better agreement with the treatment estimates: in two patients virion clearance rates were estimated to be 5.5 and 9.9 day−1. Below we suggest that the reason for this difference between HIV-1 and HCV is the different localization of virus production. Whereas HIV-1 is mostly produced in the LT, HCV is produced in the liver, which connects to the blood plasma compartment. By implementing this difference in the models we are able to show that the impact of an LT virus reservoir on turnover parameter estimates is likely to be much smaller for HCV than for HIV-1. Total virus production estimates are also more reliable.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Publisher: American Society for Microbiology
ISSN: 0022-538X
Date of Acceptance: 20 December 2000
Last Modified: 18 Feb 2019 14:46

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