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Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model.

Ikeda H, Nakaoka S, de Boer RJ, Morita S, Misawa N, Koyanagi Y, Aihara K, Sato K, Iwami S - Retrovirology (2016)

Bottom Line: Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo.Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1.This reveals that Vpu markedly increases the rate of viral replication in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, Fukuoka, 812-8581, Japan.

ABSTRACT

Background: Tetherin is an intrinsic anti-viral factor impairing the release of nascent HIV-1 particles from infected cells. Vpu, an HIV-1 accessory protein, antagonizes the anti-viral action of tetherin. Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo.

Results: To quantitatively assess the role of Vpu in viral replication in vivo, we analyzed time courses of experimental data with viral load and target cell levels in the peripheral blood of humanized mice infected with wild-type and vpu-deficient HIV-1. Our recently developed mathematical model describes the acute phase of this infection reasonably, and allowed us to estimate several parameters characterizing HIV-1 infection in mice. Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1. This reveals that Vpu markedly increases the rate of viral replication in vivo.

Conclusions: Combining experiments with mathematical modeling, we provide an estimate for the contribution of Vpu to viral replication in humanized mice.

No MeSH data available.


Related in: MedlinePlus

Variability of virus dynamics and basic reproduction number in HIV-1 and HIV-1Δvpu infected humanized mice. The predicted variability of the dynamics of target cells (left) and viral loads (right) of WT HIV-1 (a) and HIV-1Δvpu (c) are shown based on Bayesian estimation for the whole datasets using MCMC sampling. The gray regions correspond to 95 % posterior predictive intervals. The solid lines give the best-fit solution for Eqs. (1, 2), and the bullets with error bars show the average with standard deviations. Note that the initial viral loads are set at the detection limit for all samples. The distributions of calculated  from all accepted MCMC parameter estimates for WT HIV-1 and HIV-1Δvpu are shown in b and d, respectively. For each plot, the last 7000 MCMC samples among the total 10,000 samples are used
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Fig1: Variability of virus dynamics and basic reproduction number in HIV-1 and HIV-1Δvpu infected humanized mice. The predicted variability of the dynamics of target cells (left) and viral loads (right) of WT HIV-1 (a) and HIV-1Δvpu (c) are shown based on Bayesian estimation for the whole datasets using MCMC sampling. The gray regions correspond to 95 % posterior predictive intervals. The solid lines give the best-fit solution for Eqs. (1, 2), and the bullets with error bars show the average with standard deviations. Note that the initial viral loads are set at the detection limit for all samples. The distributions of calculated from all accepted MCMC parameter estimates for WT HIV-1 and HIV-1Δvpu are shown in b and d, respectively. For each plot, the last 7000 MCMC samples among the total 10,000 samples are used

Mentions: Hereafter, we used the whole datasets from 9 WT (i.e., vpu-proficient) HIV-1-infected mice and 10 HIV-1Δvpu-infected mice. To assess the variability of kinetic parameters (see Additional file 1), we performed Bayesian estimation for the whole dataset using Markov Chain Monte Carlo (MCMC) sampling. To reduce the number of parameters, we allowed only the parameter r to vary between the two groups, and let all other parameters be shared between WT HIV-1 and HIV-1Δvpu-infected mice. In addition, we allowed for broad variations in terms of the measurement error of viral load among the mouse samples into the parameter estimation via MCMC computation (i.e., the variance of the error distribution to be minimized is not constant as is typically assumed in the nonlinear least square method, c.f., [22]). The dynamics of target cells (i.e., memory CD4+ T cells) and viral load of WT HIV-1 and HIV-1Δvpu produced with the best fit parameter values are shown in Fig. 1a, c, respectively. These results revealed that the Bayesian inference works well because the model describes the acute phase of WT HIV-1 and HIV-1Δvpu infections in humanized mice reasonably well (c.f. [12, 13]). The gray regions correspond to 95 % posterior predictive intervals, the solid lines give the best-fit solution (mean) for Eqs. (1, 2), and the black and orange dots with bars show the average data with the standard deviations. We summarized the kinetic parameters estimated by the Bayesian inference in Table 1. The marginal posterior distributions for each estimated parameter are shown in Additional file 2, together with scatter plots of paired parameters. Although the ranges of these posterior distributions were relatively narrows, they were not identifiable because r, , and correlate with one another. We also fitted our model to the individual data from each of the 9 and 10 humanized mice infected with WT HIV-1 and HIV-1Δvpu, respectively [using the FindMinimum package of Mathematica 9.0 to minimize the sum of squared residuals (see Additional files 2, 3, 5)]. Not surprisingly, this revealed that the two methods gave very consistent estimates for the parameters underlying WT HIV-1 and HIV-1 Δvpu infection in humanized mice.Fig. 1


Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model.

Ikeda H, Nakaoka S, de Boer RJ, Morita S, Misawa N, Koyanagi Y, Aihara K, Sato K, Iwami S - Retrovirology (2016)

Variability of virus dynamics and basic reproduction number in HIV-1 and HIV-1Δvpu infected humanized mice. The predicted variability of the dynamics of target cells (left) and viral loads (right) of WT HIV-1 (a) and HIV-1Δvpu (c) are shown based on Bayesian estimation for the whole datasets using MCMC sampling. The gray regions correspond to 95 % posterior predictive intervals. The solid lines give the best-fit solution for Eqs. (1, 2), and the bullets with error bars show the average with standard deviations. Note that the initial viral loads are set at the detection limit for all samples. The distributions of calculated  from all accepted MCMC parameter estimates for WT HIV-1 and HIV-1Δvpu are shown in b and d, respectively. For each plot, the last 7000 MCMC samples among the total 10,000 samples are used
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getmorefigures.php?uid=PMC4834825&req=5

Fig1: Variability of virus dynamics and basic reproduction number in HIV-1 and HIV-1Δvpu infected humanized mice. The predicted variability of the dynamics of target cells (left) and viral loads (right) of WT HIV-1 (a) and HIV-1Δvpu (c) are shown based on Bayesian estimation for the whole datasets using MCMC sampling. The gray regions correspond to 95 % posterior predictive intervals. The solid lines give the best-fit solution for Eqs. (1, 2), and the bullets with error bars show the average with standard deviations. Note that the initial viral loads are set at the detection limit for all samples. The distributions of calculated from all accepted MCMC parameter estimates for WT HIV-1 and HIV-1Δvpu are shown in b and d, respectively. For each plot, the last 7000 MCMC samples among the total 10,000 samples are used
Mentions: Hereafter, we used the whole datasets from 9 WT (i.e., vpu-proficient) HIV-1-infected mice and 10 HIV-1Δvpu-infected mice. To assess the variability of kinetic parameters (see Additional file 1), we performed Bayesian estimation for the whole dataset using Markov Chain Monte Carlo (MCMC) sampling. To reduce the number of parameters, we allowed only the parameter r to vary between the two groups, and let all other parameters be shared between WT HIV-1 and HIV-1Δvpu-infected mice. In addition, we allowed for broad variations in terms of the measurement error of viral load among the mouse samples into the parameter estimation via MCMC computation (i.e., the variance of the error distribution to be minimized is not constant as is typically assumed in the nonlinear least square method, c.f., [22]). The dynamics of target cells (i.e., memory CD4+ T cells) and viral load of WT HIV-1 and HIV-1Δvpu produced with the best fit parameter values are shown in Fig. 1a, c, respectively. These results revealed that the Bayesian inference works well because the model describes the acute phase of WT HIV-1 and HIV-1Δvpu infections in humanized mice reasonably well (c.f. [12, 13]). The gray regions correspond to 95 % posterior predictive intervals, the solid lines give the best-fit solution (mean) for Eqs. (1, 2), and the black and orange dots with bars show the average data with the standard deviations. We summarized the kinetic parameters estimated by the Bayesian inference in Table 1. The marginal posterior distributions for each estimated parameter are shown in Additional file 2, together with scatter plots of paired parameters. Although the ranges of these posterior distributions were relatively narrows, they were not identifiable because r, , and correlate with one another. We also fitted our model to the individual data from each of the 9 and 10 humanized mice infected with WT HIV-1 and HIV-1Δvpu, respectively [using the FindMinimum package of Mathematica 9.0 to minimize the sum of squared residuals (see Additional files 2, 3, 5)]. Not surprisingly, this revealed that the two methods gave very consistent estimates for the parameters underlying WT HIV-1 and HIV-1 Δvpu infection in humanized mice.Fig. 1

Bottom Line: Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo.Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1.This reveals that Vpu markedly increases the rate of viral replication in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, Fukuoka, 812-8581, Japan.

ABSTRACT

Background: Tetherin is an intrinsic anti-viral factor impairing the release of nascent HIV-1 particles from infected cells. Vpu, an HIV-1 accessory protein, antagonizes the anti-viral action of tetherin. Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo.

Results: To quantitatively assess the role of Vpu in viral replication in vivo, we analyzed time courses of experimental data with viral load and target cell levels in the peripheral blood of humanized mice infected with wild-type and vpu-deficient HIV-1. Our recently developed mathematical model describes the acute phase of this infection reasonably, and allowed us to estimate several parameters characterizing HIV-1 infection in mice. Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1. This reveals that Vpu markedly increases the rate of viral replication in vivo.

Conclusions: Combining experiments with mathematical modeling, we provide an estimate for the contribution of Vpu to viral replication in humanized mice.

No MeSH data available.


Related in: MedlinePlus