Gelsolin activity controls efficient early HIV-1 infection

García-Expósito, Laura; Ziglio, Serena; Barroso-González, Jonathan; Armas-Rillo, Laura de; Valera, M. S.; Zipeto, Donato; Machado, José David; Valenzuela-Fernández, Agustı́n

doi:10.1186/1742-4690-10-39

Cited by 40 publications

(86 citation statements)

References 49 publications

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“…Also these model results correlate well with the above commented observations about the different actin dynamics and cortical F-actin amounts between non-cycling resting and cycling cell lines [8], [14], [30], [31]. In this concern, chemokine-induced actin cytoskeleton reorganization has been associated to the establishment of HIV-1 latency in infected resting CD4+ T cells [32].…”

Section: Resultssupporting

confidence: 87%

“…In García-Expósito et al 2013 [14], it is shown that specific knockdown of endogenous gelsolin (represented in our model as an inhibition of gelsolin function) increases the total actin expression by about 30%. Accordingly, we increased parameters K 4 and K 10 by 30%.…”

Section: Resultsmentioning

confidence: 63%

“…Resting CD4+ T cells represent a major reservoir of HIV-1 [39], [40], being responsible for viremia when antiretroviral therapy is stopped [40]. All these data could be explained in terms of actin dynamics and cortical F-actin amount, which is different between non-cycling resting and active primary cells or cycling cell lines, with a less or a highly dynamic actin cytoskeleton, respectively [14], [30], [31]. Therefore, HIV-1-triggered actin signaling seems critical for the infection of primary CD4+ T cells.…”

Section: Resultsmentioning

confidence: 99%

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Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

2014

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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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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

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Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

2014

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“…Using this approach, we observed ryngo-1-23 to inhibit HIV fusion early (around chemokine receptor binding) versus late (post chemokine receptor binding around the final stages of fusion) in the fusion reaction. This observation can be interpreted twofold: Gelsolin mediated F-actin reorganisation induced by dynamin rings is critical for CD4/chemokine receptor dynamics that in turn is essential for chemokine receptor engagement post CD4 binding [72]. Alternatively, ryngo-1-23 could act by sequestering existing dynamin pools within dynamin rings away from HIV fusion reaction.…”

Section: Role Of Dynamin In Hiv Entrymentioning

confidence: 99%

Resolving the Sites of HIV Entry: Dynamin Networks Hold the Key

Aggarwal¹,

Turville²

2017

J Cell Signal

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HIV/AIDS pandemic continues to represent a major health concern worldwide and novel strategies are being devised to develop a cure for HIV infection. Central to this is a deeper understanding of host-virus interactions especially at the point of virus entry. HIV can enter target cells either by direct fusion with the plasma membrane or via endocytosis. Herein, we will review the evidence for and against either pathway especially in the context of quiescent CD4 T cells, arguably the most important cellular latent reservoir for HIV. The use of complementary approaches such as single molecule imaging, molecular techniques and small molecule inhibitors have greatly added to our understanding of HIV fusion sites. Cellular GTPase dynamin has emerged as a key player in the process given its ability to modulate HIV infection during virus entry and at later stages of virus replication cycle. These new insights into HIV fusion process in physiologically relevant target cells may in turn be leveraged to advance not only HIV cure efforts, but also immunotherapy.

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“…For example, García-Expósito and colleagues found that, through its severing of cortical actin and by controlling the amount of actin available for reorganization during HIV-1 Env-mediated viral fusion, entry and infection, gelsolin can constitute a barrier that restricts HIV-1 infection of CD4+ lymphocytes in a pre-fusion step [12]. A study indicated that group B Streptococcus (GBS)-β-haemolysin is solely responsible for gelsolin increase causing, through membrane permeability defects, calcium influx and calpain activation [13].…”

Section: Introductionmentioning

confidence: 99%

Genetic Regulation of Gelsolin in Lung in Mouse Model and its Potential Broad Spectrum of Biological Functions

Liu¹,

Feng²,

Zhu³

et al. 2016

Immunome Res

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Considerable studies have been done on the potential biological function of gelsolin and its connection to human immune system, diseases and other disorders. The objective of our study was to identify genetic factors that regulate gelsolin in mouse lung and analyze its function immune system using well defined recombinant inbred strains. For this purpose we chose the BXD recombinant inbred (RI) strains derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Whole genome gene expression in lung was used for the eQTL mapping. Bioinformatics tools and genotyping data were used for the candidate gene analysis. Gene network and correlation processes were used to assess the association between gelsolin and biological traits. Data indicated that an eQTL on chromosome 9 covering a genomic area between 21Mb and 30Mb is a major play in regulation of the gelsolin expression level. Analysis of genetic elements within this region revealed that Ncapd3 is the most favorite candidate gene. Its expression level is highly associated to that of gelsolin. The expression level of gelsolin between mouse strains with two genotype of SNP (rs13480109) in a regulatory region of the Ncapd3 showed a significant difference. Additional association analysis suggest that gelsolin may has a broad spectrum of biological function. The expression level of gelsolin has very high correlation with genes in a variety of biological function. These highly associated genes are mainly for protein binding. The expression of gelsolin is also correlated to multiple known immune phenotypes. These data contribute significantly to our current knowledge on the biological function of gelsolin.

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Gelsolin activity controls efficient early HIV-1 infection

Cited by 40 publications

References 49 publications

Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

Resolving the Sites of HIV Entry: Dynamin Networks Hold the Key

Genetic Regulation of Gelsolin in Lung in Mouse Model and its Potential Broad Spectrum of Biological Functions

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