Viruses, 2022-10, Vol.14 (10), p.2288
2022
Details
- Autor(en) / Beteiligte
- Titel
- Host Cell Redox Alterations Promote Latent HIV-1 Reactivation through Atypical Transcription Factor Cooperativity
- Ist Teil von
- Viruses, 2022-10, Vol.14 (10), p.2288
- Ort / Verlag
- Basel: MDPI AG
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Immune cell state alterations rewire HIV-1 gene expression, thereby influencing viral latency and reactivation, but the mechanisms are still unfolding. Here, using a screen approach on CD4+ T cell models of HIV-1 latency, we revealed Small Molecule Reactivators (SMOREs) with unique chemistries altering the CD4+ T cell state and consequently promoting latent HIV-1 transcription and reactivation through an unprecedented mechanism of action. SMOREs triggered rapid oxidative stress and activated a redox-responsive program composed of cell-signaling kinases (MEK-ERK axis) and atypical transcription factor (AP-1 and HIF-1α) cooperativity. SMOREs induced an unusual AP-1 phosphorylation signature to promote AP-1/HIF-1α binding to the latent HIV-1 proviral genome for its activation. Consistently, latent HIV-1 reactivation was compromised with pharmacologic inhibition of oxidative stress sensing or of cell-signaling kinases, and transcription factor’s loss of expression, thus functionally linking the host redox-responsive program to viral transcriptional rewiring. Notably, SMOREs induced the redox program in primary CD4+ T cells and reactivated latent HIV-1 in aviremic patient samples alone and in combination with known latency-reversing agents, thus providing physiological relevance. Our findings suggest that manipulation of redox-sensitive pathways could be exploited to alter the course of HIV-1 latency, thus rendering host cells responsive to help achieve a sterilizing cure.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1999-4915eISSN: 1999-4915DOI: 10.3390/v14102288Titel-ID: cdi_doaj_primary_oai_doaj_org_article_c7a4d40bbedc40dd9dbcbd1dc2a1f3a3
- Format
- –
- Schlagworte
- Activator protein 1, Apoptosis, CD4 antigen, CD4 lymphocytes, Cell culture, cell signaling, Cooperativity, Cytokines, Development and progression, Diseases, Drug therapy, Epigenetics, Extracellular signal-regulated kinase, Flow cytometry, Gene expression, Genomes, Health aspects, HIV, HIV infection, HIV-1, Human immunodeficiency virus, Hypoxia-inducible factor 1a, Immunological research, Inactivation, Kinases, Latency, latency reversing agents, Lymphocytes, Lymphocytes T, Oxidation-reduction reaction, Oxidative stress, Phosphorylation, Physiological aspects, Proteins, reactivation, Relapse, Transcription factors, Virus latency, Viruses