Limits...
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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Model prediction and experimental verification of the LIMK1 signaling pathway knockdown and the actin polymerization inhibitor Lat-A on the virus infectivity.A. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the LIMK signaling pathway by a 50%. B. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the LIMK signaling pathway by a 50%. C. The black lines (control condition where cofilin is active before infection) show the model's predicted dynamics of the actin capping. Pink lines show the solutions obtained when the initial state of cofilin, just before infection, was inactive. Dark blue lines represent the predicted dynamics of the actin capping after the activation of virus signaling on the cofilin. Light blue lines represent an increase of the intensity of the activation signaling of cofilin by the virus D. Experimental measurements of infectivity of the virus in increased initial concentrations of the actin-severing factor Lat-A (Yoder et al. 2008, [7]). E. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the WAVE2 signaling pathway by a 50%. F. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the WAVE2 signaling pathway by a 50%.
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pone-0103845-g007: Model prediction and experimental verification of the LIMK1 signaling pathway knockdown and the actin polymerization inhibitor Lat-A on the virus infectivity.A. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the LIMK signaling pathway by a 50%. B. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the LIMK signaling pathway by a 50%. C. The black lines (control condition where cofilin is active before infection) show the model's predicted dynamics of the actin capping. Pink lines show the solutions obtained when the initial state of cofilin, just before infection, was inactive. Dark blue lines represent the predicted dynamics of the actin capping after the activation of virus signaling on the cofilin. Light blue lines represent an increase of the intensity of the activation signaling of cofilin by the virus D. Experimental measurements of infectivity of the virus in increased initial concentrations of the actin-severing factor Lat-A (Yoder et al. 2008, [7]). E. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the WAVE2 signaling pathway by a 50%. F. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the WAVE2 signaling pathway by a 50%.

Mentions: Another work showed that knockdown of this LIMK1 signaling pathway decreased actin cap [23]. Again our model was able to reproduce this effect. Figure 7A and 7B displays the dynamics of the active cofilin and actin, respectively, before (black line) and after (red line) a 50% decrease in the strength of the LIMK1 signaling pathway. The model predicts a very slight decrease in the inactivation of cofilin, which, however, is enough to cause a decrease the actin cap to a third of the previous value. This prediction correlates very well with the results of Xu et al. 2012 [23] since it reproduces not only the observed fall in the peak of actin cap but also the observation of the almost negligible change in the ratio of activation of cofilin.


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)

Model prediction and experimental verification of the LIMK1 signaling pathway knockdown and the actin polymerization inhibitor Lat-A on the virus infectivity.A. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the LIMK signaling pathway by a 50%. B. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the LIMK signaling pathway by a 50%. C. The black lines (control condition where cofilin is active before infection) show the model's predicted dynamics of the actin capping. Pink lines show the solutions obtained when the initial state of cofilin, just before infection, was inactive. Dark blue lines represent the predicted dynamics of the actin capping after the activation of virus signaling on the cofilin. Light blue lines represent an increase of the intensity of the activation signaling of cofilin by the virus D. Experimental measurements of infectivity of the virus in increased initial concentrations of the actin-severing factor Lat-A (Yoder et al. 2008, [7]). E. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the WAVE2 signaling pathway by a 50%. F. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the WAVE2 signaling pathway by a 50%.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103845-g007: Model prediction and experimental verification of the LIMK1 signaling pathway knockdown and the actin polymerization inhibitor Lat-A on the virus infectivity.A. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the LIMK signaling pathway by a 50%. B. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the LIMK signaling pathway by a 50%. C. The black lines (control condition where cofilin is active before infection) show the model's predicted dynamics of the actin capping. Pink lines show the solutions obtained when the initial state of cofilin, just before infection, was inactive. Dark blue lines represent the predicted dynamics of the actin capping after the activation of virus signaling on the cofilin. Light blue lines represent an increase of the intensity of the activation signaling of cofilin by the virus D. Experimental measurements of infectivity of the virus in increased initial concentrations of the actin-severing factor Lat-A (Yoder et al. 2008, [7]). E. Black line displays the original solution showed in Figure 1 while the red line represents the model prediction of the COFILINa variable after inhibition of the WAVE2 signaling pathway by a 50%. F. Black line displays the original solution showed in Figure 1; red line represents the model prediction of the ACTIN variable after inhibition of the WAVE2 signaling pathway by a 50%.
Mentions: Another work showed that knockdown of this LIMK1 signaling pathway decreased actin cap [23]. Again our model was able to reproduce this effect. Figure 7A and 7B displays the dynamics of the active cofilin and actin, respectively, before (black line) and after (red line) a 50% decrease in the strength of the LIMK1 signaling pathway. The model predicts a very slight decrease in the inactivation of cofilin, which, however, is enough to cause a decrease the actin cap to a third of the previous value. This prediction correlates very well with the results of Xu et al. 2012 [23] since it reproduces not only the observed fall in the peak of actin cap but also the observation of the almost negligible change in the ratio of activation of cofilin.

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