Early Events of HIV-1 Infection: Can Signaling be the Next Therapeutic Target?

Jones, K.L.; Smyth, Redmond P.; Pereira, Candida da Fonseca; Cameron, Paul; Lewin, Sharon R.; Jaworowski, Anthony; Mak, Johnson

doi:10.1007/s11481-011-9268-5

Cited by 9 publications

(7 citation statements)

References 188 publications

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“…Future studies can also address potential differences between signaling of CXCR4 and CCR5, another HIV-1 coreceptor, since differential engagement of these chemokine receptors can have unique effects on target gene expression [86] and host factor requirements for infection of primary cells [87] . In all, our study uncovered several members of signal transduction pathways that HIV-1 may modulate in order to successfully infect T cells, of which targeting has become an attractive avenue for anti-HIV-1 therapeutics [88] .…”

Section: Discussionmentioning

confidence: 97%

Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

Wojcechowskyj

Lee²,

Seeholzer³

et al. 2011

PLoS ONE

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CXCL12 (SDF-1) is a chemokine that binds to and signals through the seven transmembrane receptor CXCR4. The CXCL12/CXCR4 signaling axis has been implicated in both cancer metastases and human immunodeficiency virus type 1 (HIV-1) infection and a more complete understanding of CXCL12/CXCR4 signaling pathways may support efforts to develop therapeutics for these diseases. Mass spectrometry-based phosphoproteomics has emerged as an important tool in studying signaling networks in an unbiased fashion. We employed stable isotope labeling with amino acids in cell culture (SILAC) quantitative phosphoproteomics to examine the CXCL12/CXCR4 signaling axis in the human lymphoblastic CEM cell line. We quantified 4,074 unique SILAC pairs from 1,673 proteins and 89 phosphopeptides were deemed CXCL12-responsive in biological replicates. Several well established CXCL12-responsive phosphosites such as AKT (pS473) and ERK2 (pY204) were confirmed in our study. We also validated two novel CXCL12-responsive phosphosites, stathmin (pS16) and AKT1S1 (pT246) by Western blot. Pathway analysis and comparisons with other phosphoproteomic datasets revealed that genes from CXCL12-responsive phosphosites are enriched for cellular pathways such as T cell activation, epidermal growth factor and mammalian target of rapamycin (mTOR) signaling, pathways which have previously been linked to CXCL12/CXCR4 signaling. Several of the novel CXCL12-responsive phosphoproteins from our study have also been implicated with cellular migration and HIV-1 infection, thus providing an attractive list of potential targets for the development of cancer metastasis and HIV-1 therapeutics and for furthering our understanding of chemokine signaling regulation by reversible phosphorylation.

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Section: Discussionmentioning

confidence: 97%

Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

Wojcechowskyj

Lee²,

Seeholzer³

et al. 2011

PLoS ONE

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“…Virus-mediated cell signalling may represent a potential therapeutic target to treat early HIV-1 infection (reviewed in [37]) and in fact, HIV-1 Env-fusogenic activity appears to be both Ca 2+ [38] and phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) dependent [10,22,24,36]. By activating type Iα phosphatidylinositol-4-phosphate 5-kinase (PI4P5-K Iα) at virus-cell contact regions, HIV-1 is known to trigger the production of this PIP 2 -fusogenic lipid to promote fusion pore formation and viral infection [22], and the depletion of syntenin-1 allows a higher pool of free PIP 2 to accumulate at the plasma membrane after HIV-1 attachment [10].…”

Section: Discussionmentioning

confidence: 99%

Gelsolin activity controls efficient early HIV-1 infection

et al. 2013

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BackgroundHIV-1 entry into target lymphocytes requires the activity of actin adaptors that stabilize and reorganize cortical F-actin, like moesin and filamin-A. These alterations are necessary for the redistribution of CD4-CXCR4/CCR5 to one pole of the cell, a process that increases the probability of HIV-1 Envelope (Env)-CD4/co-receptor interactions and that generates the tension at the plasma membrane necessary to potentiate fusion pore formation, thereby favouring early HIV-1 infection. However, it remains unclear whether the dynamic processing of F-actin and the amount of cortical actin available during the initial virus-cell contact are required to such events.ResultsHere we show that gelsolin restructures cortical F-actin during HIV-1 Env-gp120-mediated signalling, without affecting cell-surface expression of receptors or viral co-receptor signalling. Remarkably, efficient HIV-1 Env-mediated membrane fusion and infection of permissive lymphocytes were impaired when gelsolin was either overexpressed or silenced, which led to a loss or gain of cortical actin, respectively. Indeed, HIV-1 Env-gp120-induced F-actin reorganization and viral receptor capping were impaired under these experimental conditions. Moreover, gelsolin knockdown promoted HIV-1 Env-gp120-mediated aberrant pseudopodia formation. These perturbed-actin events are responsible for the inhibition of early HIV-1 infection.ConclusionsFor the first time we provide evidence 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. These findings provide important insights into the complex molecular and actin-associated dynamics events that underlie early viral infection. Thus, we propose that gelsolin is a new factor that can limit HIV-1 infection acting at a pre-fusion step, and accordingly, cell-signals that regulate gelsolin expression and/or its actin-severing activity may be crucial to combat HIV-1 infection.

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“…Given differences in the requirements for CCR5 and CXCR4 under homeostatic conditions, effective inhibition may require different approaches to ensure the functionality of CXCR4 in particular. An alternative method to target both co-receptors may lie in drugs targeting common downstream signaling effectors induced by HIV-co-receptor interactions [ 41 ]. Although such drugs may not serve as antiretrovirals on their own, as they do not sufficiently block the viral life cycle, they could potentially act to ameliorate co-receptor mediated neuroinflammation and pathology.…”

Section: Co-receptors As Targets In Antiretroviral Therapymentioning

confidence: 99%

Co-receptor signaling in the pathogenesis of neuroHIV

et al. 2021

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The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

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Early Events of HIV-1 Infection: Can Signaling be the Next Therapeutic Target?

Cited by 9 publications

References 188 publications

Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

Gelsolin activity controls efficient early HIV-1 infection

Co-receptor signaling in the pathogenesis of neuroHIV

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