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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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Representation of the molecular events simulated in the mathematical model.Molecules included in the model as variables are the following: HIV, REC (CD4 and CXCR4 or CCR5 receptors for HIV-1 infection on lymphocyte cell-surface), FILAMIN, MOESIN (phosphorylated and active; dephosphorylated and non-active), COFILIN (a, active; i, inactive), and ACTIN. Molecules recruited at the HIV-1-triggered capping regions are indicated by the c subscript, while non-capped molecules outside this region are indicated by the nc subscript. As it is assumed that gelsolin remains constant during the whole process, it is not incorporated as a variable in the model. Numbered arrows (from 1 to 13) are the processes included in the model, and dashed arrows are the interactions from the molecules to the processes (black are positive, red are negative). Gelsolin acts by remodeling the amount and size of actin filaments, so the total amount of actin and its reorganization is reduced by higher expression of gelsolin (negative influence of GELSOLIN on processes 4 and 10, see Material and Methods for details); furthermore, appropriate levels of gelsolin facilitate, through the orchestrated severing and remodeling of actin filaments, the capping of actin filaments at viral entry regions (positive effect of GELSOLIN on process 6). Continuous arrows serve as an additional explanation of molecular events taking place during the invasion. Thus, red arrows represent depolymerization of actin filaments, blue arrows represent components which assist the depolymerization of actin filaments (e.g., active cofilin and inactivation of moesin in fusion pore formation), the green arrow indicates actin monomer incorporation to the growing actin filaments, and the purple arrow represents the actin severing and remodeling by gelsolin, thereby controlling the size of actin filaments and the amount of filaments reorganized to the viral entry regions on the plasma membrane of target cells.
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pone-0103845-g001: Representation of the molecular events simulated in the mathematical model.Molecules included in the model as variables are the following: HIV, REC (CD4 and CXCR4 or CCR5 receptors for HIV-1 infection on lymphocyte cell-surface), FILAMIN, MOESIN (phosphorylated and active; dephosphorylated and non-active), COFILIN (a, active; i, inactive), and ACTIN. Molecules recruited at the HIV-1-triggered capping regions are indicated by the c subscript, while non-capped molecules outside this region are indicated by the nc subscript. As it is assumed that gelsolin remains constant during the whole process, it is not incorporated as a variable in the model. Numbered arrows (from 1 to 13) are the processes included in the model, and dashed arrows are the interactions from the molecules to the processes (black are positive, red are negative). Gelsolin acts by remodeling the amount and size of actin filaments, so the total amount of actin and its reorganization is reduced by higher expression of gelsolin (negative influence of GELSOLIN on processes 4 and 10, see Material and Methods for details); furthermore, appropriate levels of gelsolin facilitate, through the orchestrated severing and remodeling of actin filaments, the capping of actin filaments at viral entry regions (positive effect of GELSOLIN on process 6). Continuous arrows serve as an additional explanation of molecular events taking place during the invasion. Thus, red arrows represent depolymerization of actin filaments, blue arrows represent components which assist the depolymerization of actin filaments (e.g., active cofilin and inactivation of moesin in fusion pore formation), the green arrow indicates actin monomer incorporation to the growing actin filaments, and the purple arrow represents the actin severing and remodeling by gelsolin, thereby controlling the size of actin filaments and the amount of filaments reorganized to the viral entry regions on the plasma membrane of target cells.

Mentions: However, the existing descriptions and interpretations are in many cases “element biased”, since there is currently no integrated picture of the process where all the system components are simultaneously considered in a dynamic and quantitative way. In this work, we have tried to fill this gap by proposing a mathematical model where a great deal of the available information about the elements and the interactions among them is organized and integrated in a dynamic fashion (Figure 1).


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)

Representation of the molecular events simulated in the mathematical model.Molecules included in the model as variables are the following: HIV, REC (CD4 and CXCR4 or CCR5 receptors for HIV-1 infection on lymphocyte cell-surface), FILAMIN, MOESIN (phosphorylated and active; dephosphorylated and non-active), COFILIN (a, active; i, inactive), and ACTIN. Molecules recruited at the HIV-1-triggered capping regions are indicated by the c subscript, while non-capped molecules outside this region are indicated by the nc subscript. As it is assumed that gelsolin remains constant during the whole process, it is not incorporated as a variable in the model. Numbered arrows (from 1 to 13) are the processes included in the model, and dashed arrows are the interactions from the molecules to the processes (black are positive, red are negative). Gelsolin acts by remodeling the amount and size of actin filaments, so the total amount of actin and its reorganization is reduced by higher expression of gelsolin (negative influence of GELSOLIN on processes 4 and 10, see Material and Methods for details); furthermore, appropriate levels of gelsolin facilitate, through the orchestrated severing and remodeling of actin filaments, the capping of actin filaments at viral entry regions (positive effect of GELSOLIN on process 6). Continuous arrows serve as an additional explanation of molecular events taking place during the invasion. Thus, red arrows represent depolymerization of actin filaments, blue arrows represent components which assist the depolymerization of actin filaments (e.g., active cofilin and inactivation of moesin in fusion pore formation), the green arrow indicates actin monomer incorporation to the growing actin filaments, and the purple arrow represents the actin severing and remodeling by gelsolin, thereby controlling the size of actin filaments and the amount of filaments reorganized to the viral entry regions on the plasma membrane of target cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103845-g001: Representation of the molecular events simulated in the mathematical model.Molecules included in the model as variables are the following: HIV, REC (CD4 and CXCR4 or CCR5 receptors for HIV-1 infection on lymphocyte cell-surface), FILAMIN, MOESIN (phosphorylated and active; dephosphorylated and non-active), COFILIN (a, active; i, inactive), and ACTIN. Molecules recruited at the HIV-1-triggered capping regions are indicated by the c subscript, while non-capped molecules outside this region are indicated by the nc subscript. As it is assumed that gelsolin remains constant during the whole process, it is not incorporated as a variable in the model. Numbered arrows (from 1 to 13) are the processes included in the model, and dashed arrows are the interactions from the molecules to the processes (black are positive, red are negative). Gelsolin acts by remodeling the amount and size of actin filaments, so the total amount of actin and its reorganization is reduced by higher expression of gelsolin (negative influence of GELSOLIN on processes 4 and 10, see Material and Methods for details); furthermore, appropriate levels of gelsolin facilitate, through the orchestrated severing and remodeling of actin filaments, the capping of actin filaments at viral entry regions (positive effect of GELSOLIN on process 6). Continuous arrows serve as an additional explanation of molecular events taking place during the invasion. Thus, red arrows represent depolymerization of actin filaments, blue arrows represent components which assist the depolymerization of actin filaments (e.g., active cofilin and inactivation of moesin in fusion pore formation), the green arrow indicates actin monomer incorporation to the growing actin filaments, and the purple arrow represents the actin severing and remodeling by gelsolin, thereby controlling the size of actin filaments and the amount of filaments reorganized to the viral entry regions on the plasma membrane of target cells.
Mentions: However, the existing descriptions and interpretations are in many cases “element biased”, since there is currently no integrated picture of the process where all the system components are simultaneously considered in a dynamic and quantitative way. In this work, we have tried to fill this gap by proposing a mathematical model where a great deal of the available information about the elements and the interactions among them is organized and integrated in a dynamic fashion (Figure 1).

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