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Quantitative analysis of the processes and signaling events involved in early HIV-1 infection of T cells.

Santos G, Valenzuela-Fernández A, Torres NV - PLoS ONE (2014)

Bottom Line: The model also shows the positive effect of gelsolin on actin capping by means of the nucleation effect.These findings allow us to propose novel approaches in the search for new therapeutic strategies.Also it is shown that HIV-1 should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells to be infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Biología de Sistemas y Modelización Matemática, Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de Biología, Universidad de La Laguna, San Cristóbal de La Laguna, Tenerife, España; Instituto de Tecnología Biomédica, Universidad de La Laguna, San Cristóbal de La Laguna, Tenerife, Spain.

ABSTRACT
Lymphocyte invasion by HIV-1 is a complex, highly regulated process involving many different types of molecules that is prompted by the virus's association with viral receptors located at the cell-surface membrane that culminates in the formation of a fusion pore through which the virus enters the cell. A great deal of work has been done to identify the key actors in the process and determine the regulatory interactions; however, there have been no reports to date of attempts being made to fully understand the system dynamics through a systemic, quantitative modeling approach. In this paper, we introduce a dynamic mathematical model that integrates the available information on the molecular events involved in lymphocyte invasion. Our model shows that moesin activation is induced by virus signaling, while filamin-A is mobilized by the receptor capping. Actin disaggregation from the cap is facilitated by cofilin. Cofilin is inactivated by HIV-1 signaling in activated lymphocytes, while in resting lymphocytes another signal is required to activate cofilin in the later stages in order to accelerate the decay of the aggregated actin as a restriction factor for the viral entry. Furthermore, stopping the activation signaling of moesin is sufficient to liberate the actin filaments from the cap. The model also shows the positive effect of gelsolin on actin capping by means of the nucleation effect. These findings allow us to propose novel approaches in the search for new therapeutic strategies. In particular, gelsolin inhibition is seen as a promising target for preventing HIV-1 entry into lymphocytes, due to its role in facilitating the capping needed for the invasion. Also it is shown that HIV-1 should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells to be infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.

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Comparison of the model predictions for two alternative roles of gelsolin in the cap formation.Red bars represent the experimental measurements of actin capping in a control situation or after over-expressing gelsolin. Blue bars represent the model prediction with the standard deviation of all solutions selected (see Material and Methods). A. A set of scenarios is evaluated in the model assuming different actin capping influences of gelsolin. In “a” K7 was increased by 50%, assuming that gelsolin has a negative effect on actin capping. In “b”, K6 was increased to mimic a gelsolin activation on the actin capping by increasing the actin remodeling dynamics. B. Model verification of scenario “b” shown in panel A. The measured and the predicted maximum peak of the capping of receptors on the gelsolin over-expressed cell lines are shown. C. In “a” K6, the parameter that models gelsolin stimulation of actin capping, takes the value of 0.75 times the value in Control; in “b” this figure is 0.5 times.
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pone-0103845-g005: Comparison of the model predictions for two alternative roles of gelsolin in the cap formation.Red bars represent the experimental measurements of actin capping in a control situation or after over-expressing gelsolin. Blue bars represent the model prediction with the standard deviation of all solutions selected (see Material and Methods). A. A set of scenarios is evaluated in the model assuming different actin capping influences of gelsolin. In “a” K7 was increased by 50%, assuming that gelsolin has a negative effect on actin capping. In “b”, K6 was increased to mimic a gelsolin activation on the actin capping by increasing the actin remodeling dynamics. B. Model verification of scenario “b” shown in panel A. The measured and the predicted maximum peak of the capping of receptors on the gelsolin over-expressed cell lines are shown. C. In “a” K6, the parameter that models gelsolin stimulation of actin capping, takes the value of 0.75 times the value in Control; in “b” this figure is 0.5 times.

Mentions: In Figure 5, the red bars show the actin capping measurements [14], while the blue bars correspond to the model predictions. Figure 5A shows the results obtained in K7, K6, K4 and K10 following the changes described above.


Quantitative analysis of the processes and signaling events involved in early HIV-1 infection of T cells.

Santos G, Valenzuela-Fernández A, Torres NV - PLoS ONE (2014)

Comparison of the model predictions for two alternative roles of gelsolin in the cap formation.Red bars represent the experimental measurements of actin capping in a control situation or after over-expressing gelsolin. Blue bars represent the model prediction with the standard deviation of all solutions selected (see Material and Methods). A. A set of scenarios is evaluated in the model assuming different actin capping influences of gelsolin. In “a” K7 was increased by 50%, assuming that gelsolin has a negative effect on actin capping. In “b”, K6 was increased to mimic a gelsolin activation on the actin capping by increasing the actin remodeling dynamics. B. Model verification of scenario “b” shown in panel A. The measured and the predicted maximum peak of the capping of receptors on the gelsolin over-expressed cell lines are shown. C. In “a” K6, the parameter that models gelsolin stimulation of actin capping, takes the value of 0.75 times the value in Control; in “b” this figure is 0.5 times.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126662&req=5

pone-0103845-g005: Comparison of the model predictions for two alternative roles of gelsolin in the cap formation.Red bars represent the experimental measurements of actin capping in a control situation or after over-expressing gelsolin. Blue bars represent the model prediction with the standard deviation of all solutions selected (see Material and Methods). A. A set of scenarios is evaluated in the model assuming different actin capping influences of gelsolin. In “a” K7 was increased by 50%, assuming that gelsolin has a negative effect on actin capping. In “b”, K6 was increased to mimic a gelsolin activation on the actin capping by increasing the actin remodeling dynamics. B. Model verification of scenario “b” shown in panel A. The measured and the predicted maximum peak of the capping of receptors on the gelsolin over-expressed cell lines are shown. C. In “a” K6, the parameter that models gelsolin stimulation of actin capping, takes the value of 0.75 times the value in Control; in “b” this figure is 0.5 times.
Mentions: In Figure 5, the red bars show the actin capping measurements [14], while the blue bars correspond to the model predictions. Figure 5A shows the results obtained in K7, K6, K4 and K10 following the changes described above.

Bottom Line: The model also shows the positive effect of gelsolin on actin capping by means of the nucleation effect.These findings allow us to propose novel approaches in the search for new therapeutic strategies.Also it is shown that HIV-1 should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells to be infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Biología de Sistemas y Modelización Matemática, Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de Biología, Universidad de La Laguna, San Cristóbal de La Laguna, Tenerife, España; Instituto de Tecnología Biomédica, Universidad de La Laguna, San Cristóbal de La Laguna, Tenerife, Spain.

ABSTRACT
Lymphocyte invasion by HIV-1 is a complex, highly regulated process involving many different types of molecules that is prompted by the virus's association with viral receptors located at the cell-surface membrane that culminates in the formation of a fusion pore through which the virus enters the cell. A great deal of work has been done to identify the key actors in the process and determine the regulatory interactions; however, there have been no reports to date of attempts being made to fully understand the system dynamics through a systemic, quantitative modeling approach. In this paper, we introduce a dynamic mathematical model that integrates the available information on the molecular events involved in lymphocyte invasion. Our model shows that moesin activation is induced by virus signaling, while filamin-A is mobilized by the receptor capping. Actin disaggregation from the cap is facilitated by cofilin. Cofilin is inactivated by HIV-1 signaling in activated lymphocytes, while in resting lymphocytes another signal is required to activate cofilin in the later stages in order to accelerate the decay of the aggregated actin as a restriction factor for the viral entry. Furthermore, stopping the activation signaling of moesin is sufficient to liberate the actin filaments from the cap. The model also shows the positive effect of gelsolin on actin capping by means of the nucleation effect. These findings allow us to propose novel approaches in the search for new therapeutic strategies. In particular, gelsolin inhibition is seen as a promising target for preventing HIV-1 entry into lymphocytes, due to its role in facilitating the capping needed for the invasion. Also it is shown that HIV-1 should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells to be infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.

Show MeSH
Related in: MedlinePlus