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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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Model verification of the cofilin activity decay.Red dots and line represent the dynamics of the active cofilin during the invasion of HIV-1 as determined by Yoder et al. 2008 [7]. These observations are compared with the predicted dynamics (blue line) of the same model variable (Cofa).
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pone-0103845-g008: Model verification of the cofilin activity decay.Red dots and line represent the dynamics of the active cofilin during the invasion of HIV-1 as determined by Yoder et al. 2008 [7]. These observations are compared with the predicted dynamics (blue line) of the same model variable (Cofa).

Mentions: Finally, we compared the model predictions regarding the dynamics of the inactive cofilin with the experimental observations provided by Yoder et al. 2008 [7]. In Figure 8 it can be seen that there is a decay of this protein as the invasion progresses. Here, the model prediction is close to the experimental data only in the very first moments, after which it deviates significantly. Soon after the first 10 hours the predicted cofilin is above the experimental measurements. But it turns out that, in the light of the model hypothesis, these discrepancies help us gain a better comprehension of the role of the cellular factors that are operating in the invasion process. In our simplified model, it was assumed that cofilin is the only actin-severing factor which is regulated by HIV. However, it has been proposed that another actin-severing factor such as gelsolin might play a significant role in this process [14]. It is thus suggested that the observed discrepancies could be attributed to the role that these, somewhat neglected, actin-severing HIV-1 regulated factors play during invasion.


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 verification of the cofilin activity decay.Red dots and line represent the dynamics of the active cofilin during the invasion of HIV-1 as determined by Yoder et al. 2008 [7]. These observations are compared with the predicted dynamics (blue line) of the same model variable (Cofa).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103845-g008: Model verification of the cofilin activity decay.Red dots and line represent the dynamics of the active cofilin during the invasion of HIV-1 as determined by Yoder et al. 2008 [7]. These observations are compared with the predicted dynamics (blue line) of the same model variable (Cofa).
Mentions: Finally, we compared the model predictions regarding the dynamics of the inactive cofilin with the experimental observations provided by Yoder et al. 2008 [7]. In Figure 8 it can be seen that there is a decay of this protein as the invasion progresses. Here, the model prediction is close to the experimental data only in the very first moments, after which it deviates significantly. Soon after the first 10 hours the predicted cofilin is above the experimental measurements. But it turns out that, in the light of the model hypothesis, these discrepancies help us gain a better comprehension of the role of the cellular factors that are operating in the invasion process. In our simplified model, it was assumed that cofilin is the only actin-severing factor which is regulated by HIV. However, it has been proposed that another actin-severing factor such as gelsolin might play a significant role in this process [14]. It is thus suggested that the observed discrepancies could be attributed to the role that these, somewhat neglected, actin-severing HIV-1 regulated factors play during invasion.

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