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.
Highlights
The invasion and infection of CD4+ T lymphocytes by human immunodeficiency virus type 1 (HIV-1) is a complex process involving many cellular events that have been the subject of many studies [1]
The signaling structure involved in the actin mobilization observed throughout the first stages of lymphocyte invasion by HIV-1 has recently been elucidated in great detail
We have a considerable body of information offering a great deal of insight into the series of coordinated events involved in lymphocyte invasion by HIV-1
Summary
The invasion and infection of CD4+ T lymphocytes by human immunodeficiency virus type 1 (HIV-1) is a complex process involving many cellular events that have been the subject of many studies [1]. As a consequence of this interaction, HIV-1 Env-gp120 changes its conformation, exposing other regions of the viral protein responsible for its binding to a second co-receptor, either CCR5 or CXCR4 These bindings trigger a signaling pathway inside the lymphocyte that culminates with the formation of an actin cap in a pole of the cell (hereinafter ‘cap’), driving CD4 and co-receptor co-localization and direct interaction, in an actin-dependent manner. These HIV-1 Envgp120/CD4-mediated actin and receptor reorganization and capping events have been shown to correlate with the infectivity of the virus [2]. This fact will be a central issue the present study, since we will choose a cap indicator as a measure of HIV-1 infectivity
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