A broad drug arsenal to attack a strenuous latent HIV reservoir

Stoszko, Mateusz; Ne, Enrico; Abner, Erik; Mahmoudi, Tokameh

doi:10.1016/j.coviro.2019.06.001

Cited by 27 publications

(37 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5a). Since the ICD strategy does not depend on other components of the host immune system such as CD8+ T cells or NK cells, this system can be used to measure proapoptotic compounds that have previously been studied to selectively eliminate HIV-1- So far more than 160 compounds have been identified with latency reversing activity, and our work has identified DDX3 inhibitors as another category of compounds to reverse viral latency 68 . In addition to latency reversal, DDX3 inhibitors target multiple steps of the HIV-1 replication cycle: transcription, nucleocytoplasmic export of the vRNA, translation and generation of infectious viral particles.…”

Section: Discussionmentioning

confidence: 99%

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Rao

Lungu

Steijaert

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work we demonstrate the effect of DEAD-box polypeptide 3, X-Linked (DDX3) inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death; pharmacological targeting of DDX3 reversed HIV-1 latency and selectively induced apoptosis in viral RNA-expressing CD4+ T cells from PLWHIV but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV in an in vitro culture model over five days resulted in an approximately 30% reduction of the inducible latent HIV-1 reservoir as determined by quantitation of CA HIV-1 RNA, by TILDA, as well as by FISH-Flow technology. RNA sequencing analysis revealed that while overall gene expression was minimally dysregulated, treatment of independent donor CD4+ T cells with DDX3 inhibitors led to significant downregulation of BIRC5 and HSPB1A, genes critical to cell survival during HIV-1 infection, providing mechanism for the observed selective cell death. Our data support the translation of DDX3 inhibitor class compounds into HIV-1 curative strategies and provide proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards elimination of the inducible reservoir.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Rao

Lungu

Steijaert

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Distinct classes of LRAs have been shown to target different subpopulations of proviruses (Abner et al, 2018;Battivelli et al, 2018;Chen et al, 2017;Stoszko et al, 2019). Thus far none of the clinically tested LRAs has been able to induce strong viral expression or to significantly deplete the latent reservoir in patients, pointing to potential limitations of single treatments (Spivak and Planelles 2017;Rasmussen and Søgaard 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Thus far none of the clinically tested LRAs has been able to induce strong viral expression or to significantly deplete the latent reservoir in patients, pointing to potential limitations of single treatments (Spivak and Planelles 2017;Rasmussen and Søgaard 2018). The heterogeneous nature of latent HIV integrations, the complex molecular mechanisms that contribute to maintaining HIV latency, together with individual genetic variability, dictate that a cocktail of stimulatory compounds targeting distinct cellular and HIV gene regulatory pathways would be most effective to activate the latent reservoir in HIV-1 infected patients (Stoszko et al, 2019). Indeed, preclinical studies demonstrate that combination treatments can result in synergism and lead to stronger HIV-1 latency reversal (Bouchat et al, 2016;Stoszko et al, 2015;Marian et al, 2018;Hashemi et al, 2018;Darcis et al, 2015;Abner and Jordan, 2019;Laird et al, 2015;Rasmussen and Lewin, 2016;Stoszko et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The heterogeneous nature of latent HIV integrations, the complex molecular mechanisms that contribute to maintaining HIV latency, together with individual genetic variability, dictate that a cocktail of stimulatory compounds targeting distinct cellular and HIV gene regulatory pathways would be most effective to activate the latent reservoir in HIV-1 infected patients (Stoszko et al, 2019). Indeed, preclinical studies demonstrate that combination treatments can result in synergism and lead to stronger HIV-1 latency reversal (Bouchat et al, 2016;Stoszko et al, 2015;Marian et al, 2018;Hashemi et al, 2018;Darcis et al, 2015;Abner and Jordan, 2019;Laird et al, 2015;Rasmussen and Lewin, 2016;Stoszko et al, 2019). Here we found that GTX, a molecule that targets the HIV-1 transcription elongation step, strongly synergized with LRAs that de-repress chromatin structure, namely BAF and HDAC inhibitors, which respectively target complexes that position the latent LTR chromatin in a repressive configuration (Rafati et al, 2011), or deacetylate histones compacting LTR chromatin.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of regulation of HIV-1 gene expression have identified distinct molecular mechanisms and cellular pathways at play, which can be targeted pharmacologically to activate expression of latent HIV (De Crignis and Mahmoudi, 2016;Ne et al, 2018;Stoszko et al, 2019).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb and reverses HIV-1 latency

Stoszko

Al‐Hatmi

Škríba

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

A leading pharmacological strategy towards HIV cure requires "shock" or activation of HIV gene expression in latently infected cells with Latency Reversal Agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs we used fungal secondary metabolites (extrolites) as a source of bio-active molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the P-TEFb inhibitory 7SK snRNP complex to be significantly reduced upon GTX treatment of independent donor CD4+T cells. GTX disrupted 7SK snRNP, releasing active P-TEFb, which then phosphorylated RNA Pol II CTD, inducing HIV transcription. Our data highlight the power of combining a medium throughput bioassay, mycology and orthogonal mass spectrometry to identify novel potentially therapeutic compounds.

show abstract

Ten decadal advances in fungal biology leading towards human well-being

et al. 2022

Self Cite

View full text Add to dashboard Cite

Fungi are an understudied resource possessing huge potential for developing products that can greatly improve human well-being. In the current paper, we highlight some important discoveries and developments in applied mycology and interdisciplinary Life Science research. These examples concern recently introduced drugs for the treatment of infections and neurological diseases; application of –OMICS techniques and genetic tools in medical mycology and the regulation of mycotoxin production; as well as some highlights of mushroom cultivaton in Asia. Examples for new diagnostic tools in medical mycology and the exploitation of new candidates for therapeutic drugs, are also given. In addition, two entries illustrating the latest developments in the use of fungi for biodegradation and fungal biomaterial production are provided. Some other areas where there have been and/or will be significant developments are also included. It is our hope that this paper will help realise the importance of fungi as a potential industrial resource and see the next two decades bring forward many new fungal and fungus-derived products.

show abstract

A broad drug arsenal to attack a strenuous latent HIV reservoir

Cited by 27 publications

References 82 publications

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb and reverses HIV-1 latency

Ten decadal advances in fungal biology leading towards human well-being

Contact Info

Product

Resources

About