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- Publisher Website: 10.1371/journal.ppat.1007498
- Scopus: eid_2-s2.0-85060021507
- PMID: 30645648
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Article: Reiterative Enrichment and Authentication of CRISPRi Targets (REACT) identifies the proteasome as a key contributor to HIV-1 latency
Title | Reiterative Enrichment and Authentication of CRISPRi Targets (REACT) identifies the proteasome as a key contributor to HIV-1 latency |
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Authors | |
Issue Date | 2019 |
Citation | PLoS Pathogens, 2019, v. 15, n. 1, article no. e1007498 How to Cite? |
Abstract | The establishment of HIV-1 latency gives rise to persistent chronic infection that requires life-long treatment. To reverse latency for viral eradiation, the HIV-1 Tat protein and its associated ELL2-containing Super Elongation Complexes (ELL2-SECs) are essential to activate HIV-1 transcription. Despite efforts to identify effective latency-reversing agents (LRA), avenues for exposing latent HIV-1 remain inadequate, prompting the need to identify novel LRA targets. Here, by conducting a CRISPR interference-based screen to reiteratively enrich loss-of-function genotypes that increase HIV-1 transcription in latently infected CD4 + T cells, we have discovered a key role of the proteasome in maintaining viral latency. Downregulating or inhibiting the proteasome promotes Tat-transactivation in cell line models. Furthermore, the FDA-approved proteasome inhibitors bortezomib and carfilzomib strongly synergize with existing LRAs to reactivate HIV-1 in CD4 + T cells from antiretroviral therapy-suppressed individuals without inducing cell activation or proliferation. Mechanistically, downregulating/inhibiting the proteasome elevates the levels of ELL2 and ELL2-SECs to enable Tat-transactivation, indicating the proteasome-ELL2 axis as a key regulator of HIV-1 latency and promising target for therapeutic intervention. |
Persistent Identifier | http://hdl.handle.net/10722/324071 |
ISSN | 2023 Impact Factor: 5.5 2023 SCImago Journal Rankings: 2.223 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Li, Zichong | - |
dc.contributor.author | Wu, Jun | - |
dc.contributor.author | Chavez, Leonard | - |
dc.contributor.author | Hoh, Rebecca | - |
dc.contributor.author | Deeks, Steven G. | - |
dc.contributor.author | Pillai, Satish K. | - |
dc.contributor.author | Zhou, Qiang | - |
dc.date.accessioned | 2023-01-13T03:01:18Z | - |
dc.date.available | 2023-01-13T03:01:18Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | PLoS Pathogens, 2019, v. 15, n. 1, article no. e1007498 | - |
dc.identifier.issn | 1553-7366 | - |
dc.identifier.uri | http://hdl.handle.net/10722/324071 | - |
dc.description.abstract | The establishment of HIV-1 latency gives rise to persistent chronic infection that requires life-long treatment. To reverse latency for viral eradiation, the HIV-1 Tat protein and its associated ELL2-containing Super Elongation Complexes (ELL2-SECs) are essential to activate HIV-1 transcription. Despite efforts to identify effective latency-reversing agents (LRA), avenues for exposing latent HIV-1 remain inadequate, prompting the need to identify novel LRA targets. Here, by conducting a CRISPR interference-based screen to reiteratively enrich loss-of-function genotypes that increase HIV-1 transcription in latently infected CD4 + T cells, we have discovered a key role of the proteasome in maintaining viral latency. Downregulating or inhibiting the proteasome promotes Tat-transactivation in cell line models. Furthermore, the FDA-approved proteasome inhibitors bortezomib and carfilzomib strongly synergize with existing LRAs to reactivate HIV-1 in CD4 + T cells from antiretroviral therapy-suppressed individuals without inducing cell activation or proliferation. Mechanistically, downregulating/inhibiting the proteasome elevates the levels of ELL2 and ELL2-SECs to enable Tat-transactivation, indicating the proteasome-ELL2 axis as a key regulator of HIV-1 latency and promising target for therapeutic intervention. | - |
dc.language | eng | - |
dc.relation.ispartof | PLoS Pathogens | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | Reiterative Enrichment and Authentication of CRISPRi Targets (REACT) identifies the proteasome as a key contributor to HIV-1 latency | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1371/journal.ppat.1007498 | - |
dc.identifier.pmid | 30645648 | - |
dc.identifier.pmcid | PMC6333332 | - |
dc.identifier.scopus | eid_2-s2.0-85060021507 | - |
dc.identifier.volume | 15 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | article no. e1007498 | - |
dc.identifier.epage | article no. e1007498 | - |
dc.identifier.eissn | 1553-7374 | - |
dc.identifier.isi | WOS:000457400000017 | - |