RT info:eu-repo/semantics/article
T1 Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells
A1 Valenzuela Fernández, Agustín
A1 Santos, Guido
A1 Torres, Néstor V.
A2 Medicina Física y Farmacología
AB Lymphocyte invasion by HIV-1 is a complex, highly regulated process involving many different types of molecules that isprompted by the virus’s association with viral receptors located at the cell-surface membrane that culminates in theformation of a fusion pore through which the virus enters the cell. A great deal of work has been done to identify the keyactors in the process and determine the regulatory interactions; however, there have been no reports to date of attemptsbeing made to fully understand the system dynamics through a systemic, quantitative modeling approach. In this paper, weintroduce a dynamic mathematical model that integrates the available information on the molecular events involved inlymphocyte invasion. Our model shows that moesin activation is induced by virus signaling, while filamin-A is mobilized bythe receptor capping. Actin disaggregation from the cap is facilitated by cofilin. Cofilin is inactivated by HIV-1 signaling inactivated lymphocytes, while in resting lymphocytes another signal is required to activate cofilin in the later stages in orderto accelerate the decay of the aggregated actin as a restriction factor for the viral entry. Furthermore, stopping theactivation signaling of moesin is sufficient to liberate the actin filaments from the cap. The model also shows the positiveeffect of gelsolin on actin capping by means of the nucleation effect. These findings allow us to propose novel approachesin the search for new therapeutic strategies. In particular, gelsolin inhibition is seen as a promising target for preventing HIV1 entry into lymphocytes, due to its role in facilitating the capping needed for the invasion. Also it is shown that HIV-1should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells tobe infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.
YR 2014
FD 2014
LK http://riull.ull.es/xmlui/handle/915/35365
UL http://riull.ull.es/xmlui/handle/915/35365
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 19-nov-2024