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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 moesin role on the HIV-1 viral entry process.Panel A shows the total amount of functional moesin on the peak of activated moesin (at 90 minutes after infection) as determined by Barrero-Villar et al. 2009 [10]. Panel B shows the result of the MOESINratio value obtained from the model by modifying the parameter rate K6 (related with the total amount of moesin). The red color refers to N-Moe (a dominant negative N-terminal fragment of the protein which impedes the physiological function of the intact moesin); the black refers to the control conditions and the green to the FL-Moe (an intact form of the protein which increases the total amount of moesin inside the lymphocyte).
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pone-0103845-g004: Model verification of the moesin role on the HIV-1 viral entry process.Panel A shows the total amount of functional moesin on the peak of activated moesin (at 90 minutes after infection) as determined by Barrero-Villar et al. 2009 [10]. Panel B shows the result of the MOESINratio value obtained from the model by modifying the parameter rate K6 (related with the total amount of moesin). The red color refers to N-Moe (a dominant negative N-terminal fragment of the protein which impedes the physiological function of the intact moesin); the black refers to the control conditions and the green to the FL-Moe (an intact form of the protein which increases the total amount of moesin inside the lymphocyte).

Mentions: Our model was able to reproduce the observation made by Barrero-Villar et al. 2009 [10] regarding the role of moesin during the invasion. This work evaluates the effect of changing the total amount of functional moesin (or overexpressing a dominant negative mutant of moesin) on the peak of activated moesin. As stated above [see the Mathematical Model section], these experiments can be simulated in our model by proportionally modifying the corresponding rate parameter K6, which gives the total amount of functional moesin (see Supporting Information). The agreement of the model predictions regarding the moesin ratio value (Figure 4B) with the experimental maximum of the peak of activated moesin [Figure 4A] supports the reliability of our model as an integrated representation of the role of moesin in the process. We are thus provided with a suitable framework to assess the relative importance of the components of the system under different conditions.


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 moesin role on the HIV-1 viral entry process.Panel A shows the total amount of functional moesin on the peak of activated moesin (at 90 minutes after infection) as determined by Barrero-Villar et al. 2009 [10]. Panel B shows the result of the MOESINratio value obtained from the model by modifying the parameter rate K6 (related with the total amount of moesin). The red color refers to N-Moe (a dominant negative N-terminal fragment of the protein which impedes the physiological function of the intact moesin); the black refers to the control conditions and the green to the FL-Moe (an intact form of the protein which increases the total amount of moesin inside the lymphocyte).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103845-g004: Model verification of the moesin role on the HIV-1 viral entry process.Panel A shows the total amount of functional moesin on the peak of activated moesin (at 90 minutes after infection) as determined by Barrero-Villar et al. 2009 [10]. Panel B shows the result of the MOESINratio value obtained from the model by modifying the parameter rate K6 (related with the total amount of moesin). The red color refers to N-Moe (a dominant negative N-terminal fragment of the protein which impedes the physiological function of the intact moesin); the black refers to the control conditions and the green to the FL-Moe (an intact form of the protein which increases the total amount of moesin inside the lymphocyte).
Mentions: Our model was able to reproduce the observation made by Barrero-Villar et al. 2009 [10] regarding the role of moesin during the invasion. This work evaluates the effect of changing the total amount of functional moesin (or overexpressing a dominant negative mutant of moesin) on the peak of activated moesin. As stated above [see the Mathematical Model section], these experiments can be simulated in our model by proportionally modifying the corresponding rate parameter K6, which gives the total amount of functional moesin (see Supporting Information). The agreement of the model predictions regarding the moesin ratio value (Figure 4B) with the experimental maximum of the peak of activated moesin [Figure 4A] supports the reliability of our model as an integrated representation of the role of moesin in the process. We are thus provided with a suitable framework to assess the relative importance of the components of the system under different conditions.

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