Dual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection

García-Vidal, Edurne; Badía, Roger; Pujantell, Maria; Castellví, Marc; Felip, E.; Clotet, Bonaventura; Riveira-Muñoz, Eva; Ballana, Ester; Esté, José A.

doi:10.1016/j.antiviral.2019.05.003

Cited by 10 publications

(9 citation statements)

References 51 publications

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“…Still, our in vitro verification processes revealed that simplistic assumptions of negative correlations may be inadequate, as indicated by the failure of two negatively correlated compounds (Vorinostat and Valproic acid) to protect Vero cultures against acute HSV-1 infection ( Figure 2 ). Both Vorinostat and Valproic acid are well-recognized histone deacetylase inhibitors (HDACs) that have been associated with stimulation of replication of a wide range of viruses such as Human Immunodeficiency Virus (HIV), 25 – 27 Human Herpes Virus 8 (HHV-8), 28 and Cytomegalovirus (CMV). 29 Besides, valproic acid also interferes with cellular lipid metabolism and affects the composition of cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

Zheng

D’Aiuto

Demers

et al. 2021

Antivir Chem Chemother

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Background Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. Results We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. Conclusions These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

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Section: Discussionmentioning

confidence: 99%

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

Zheng

D’Aiuto

Demers

et al. 2021

Antivir Chem Chemother

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show abstract

“…Although an in-depth discussion of this topic is beyond the scope of the present articles, some key information is summarized in Table 3. Vif APOBEC family members [125] Vpr Several (see Table 1) [126,127] Vpx SAMHD1 [128] Several inhibitors are being studied in the perspective of potentiating antigen presentation to CD8 + cytotoxic T lymphocytes by reverting Nef-induced downregulation of MHC class I, as discussed [123]. Vif inhibition of the cytidine deaminase activity of APOBEC family members has been selected as a target of pharmacological screening by mutagenizing these restriction factors [125].…”

Section: Pharmacological Targeting Of Hiv Proteinsmentioning

confidence: 99%

“…Concerning BST-2/Tetherin, a high-throughput screening has identified candidate inhibitors capable of interfering with Vpu-mediated inhibition [ 124 ]. In the case of HIV-2-restricted Vpx, midostaurin was identified as possessing both pro- and anti-viral effects in macrophages by, on the one hand, blocking the cell cycle in the G 2 /M phase, thereby preventing SAMHD1 phosphorylation and activation; on the other hand, in the absence of SAMHD1, midostaurin showed enhancing effects on proviral transcription and viral replication [ 128 ].…”

Section: Pharmacological Targeting Of Hiv Proteinsmentioning

confidence: 99%

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

Pagani¹,

Demela²,

Ghezzi³

et al. 2022

IJMS

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In addition to CD4+ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication, although with substantial differences. In contrast to activated CD4+ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by the virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing or curtailing virus replication in macrophages and T cells, particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factors determining the restriction or reactivation of virus replication in these cells.

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“…A recent study using 418 structurally diverse, cellpermeable, and medicinally active kinase inhibitors in a latent cell line model showed that control of kinase activity can affect a wide range of cellular pathways or signaling cascades and block HIV-1 latency reversal [107]. One such multikinase inhibitor, midostaurin, plays a dual role by activating latency reversal and blocking viral replication or reversal in the presence or absence of SAM domain and HD domain-containing protein 1 (SAMDH1), respectively [108,109]. Kinome profiling recognizes the contribution of PIM-1 kinase in latent HIV infection and reactivation in T cell lines, as well as in primary CD4 T cells [110].…”

Section: Protein Kinases In Hiv Latencymentioning

confidence: 99%

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

Khanal

Schank

Gazzar

et al. 2021

Cells

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Eradication of latent human immunodeficiency virus (HIV) infection is a global health challenge. Reactivation of HIV latency and killing of virus-infected cells, the so-called “kick and kill” or “shock and kill” approaches, are a popular strategy for HIV cure. While antiretroviral therapy (ART) halts HIV replication by targeting multiple steps in the HIV life cycle, including viral entry, integration, replication, and production, it cannot get rid of the occult provirus incorporated into the host-cell genome. These latent proviruses are replication-competent and can rebound in cases of ART interruption or cessation. In general, a very small population of cells harbor provirus, serve as reservoirs in ART-controlled HIV subjects, and are capable of expressing little to no HIV RNA or proteins. Beyond the canonical resting memory CD4+ T cells, HIV reservoirs also exist within tissue macrophages, myeloid cells, brain microglial cells, gut epithelial cells, and hematopoietic stem cells (HSCs). Despite a lack of active viral production, latently HIV-infected subjects continue to exhibit aberrant cellular signaling and metabolic dysfunction, leading to minor to major cellular and systemic complications or comorbidities. These include genomic DNA damage; telomere attrition; mitochondrial dysfunction; premature aging; and lymphocytic, cardiac, renal, hepatic, or pulmonary dysfunctions. Therefore, the arcane machineries involved in HIV latency and its reversal warrant further studies to identify the cryptic mechanisms of HIV reservoir formation and clearance. In this review, we discuss several molecules and signaling pathways, some of which have dual roles in maintaining or reversing HIV latency and reservoirs, and describe some evolving strategies and possible approaches to eliminate viral reservoirs and, ultimately, cure/eradicate HIV infection.

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Dual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection

Cited by 10 publications

References 51 publications

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

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