1. Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3
- Author
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Christine Rouzioux, Ben Berkhout, Monsef Benkirane, Alessandro Marcello, Anna Kula, Lavina Gharu, Stéphane De Wit, Véronique Avettand-Fenoel, Alexander O. Pasternak, Ambra Sarracino, Maryana Bardina, Carine Van Lint, Medical Microbiology and Infection Prevention, and AII - Infectious diseases
- Subjects
CD4-Positive T-Lymphocytes ,Gene Expression Regulation, Viral ,0301 basic medicine ,reservoir ,THP-1 Cells ,latency-reverting agents, LRA ,Gene Expression ,HIV Infections ,RNA-binding protein ,Biology ,Virologie générale ,Jurkat cells ,Microbiology ,Virus ,Host-Microbe Biology ,Jurkat Cells ,03 medical and health sciences ,Nuclear Matrix-Associated Proteins ,Transcription (biology) ,Virology ,Gene expression ,Humans ,RNA Processing, Post-Transcriptional ,posttranscriptional control mechanisms ,latency ,Regulation of gene expression ,Host Microbial Interactions ,human immunodeficiency virus ,RNA-Binding Proteins ,Biologie moléculaire ,RNA ,Provirus ,human immunodeficiency virus, HIV-1 ,QR1-502 ,Virus Latency ,3. Good health ,Cell biology ,posttranscription ,shock and kill ,030104 developmental biology ,MATR3 ,LRA ,latency-reverting agents ,HIV-1 ,RNA, Viral ,Virus Activation ,RNA binding proteins ,Research Article - Abstract
Posttranscriptional regulation of HIV-1 replication is finely controlled by viral and host factors. Among the former, Rev controls the export of partially spliced and unspliced viral RNAs from the nucleus and their translation in the cytoplasm or incorporation into new virions as genomic viral RNA. To investigate the functional role of the Rev cofactor MATR3 in the context of HIV infection, we modulated its expression in Jurkat cells and primary peripheral blood lymphocytes (PBLs). We confirmed that MATR3 is a positive regulator of HIV-1 acting at a posttranscriptional level. By applying the same approach to J-lat cells, a well-established model for the study of HIV-1 latency, we observed that MATR3 depletion did not affect transcriptional reactivation of the integrated provirus, but caused a reduction of Gag production. Following these observations, we hypothesized that MATR3 could be involved in the establishment of HIV-1 posttranscriptional latency. Indeed, mechanisms acting at the posttranscriptional level have been greatly overlooked in favor of transcriptional pathways. MATR3 was almost undetectable in resting PBLs, but could be promptly upregulated upon cellular stimulation with PHA. However, HIV latency-reversing agents were poor inducers of MATR3 levels, providing a rationale for their inability to fully reactivate the virus. These data have been confirmed ex vivo in cells derived from patients under suppressive ART. Finally, in the context of MATR3-depleted J-lat cells, impaired reactivation by SAHA could be fully rescued by MATR3 reconstitution, demonstrating a direct role of MATR3 in the posttranscriptional regulation of HIV-1 latency.IMPORTANCE The life cycle of HIV-1 requires integration of a DNA copy into the genome of the host cell. Transcription of the viral genes generates RNAs that are exported to the cytoplasm with the contribution of viral and cellular factors to get translated or incorporated in the newly synthesized virions. It has been observed that highly effective antiretroviral therapy, which is able to reduce circulating virus to undetectable levels, cannot fully eradicate the virus from cellular reservoirs that harbor a transcriptionally latent provirus. Thus, persistence of latently infected cells is the major barrier to a cure for HIV-1 infection. In order to purge these reservoirs of latently infected cells, it has been proposed to activate transcription to stimulate the virus to complete its life cycle. This strategy is believed to unmask these reservoirs, making them vulnerable to the immune system. However, limited successes of this approach may indicate additional posttranscriptional restrictions that need to be overcome for full virus reactivation. In this work we identify the cellular protein MATR3 as an essential cofactor of viral RNA processing. Reactivation of HIV-1 transcription per se is not sufficient to allow completion of a full life cycle of the virus if MATR3 is depleted. Furthermore, MATR3 is poorly expressed in quiescent CD4+ T lymphocytes that are the major reservoir of latent HIV-1. Cells derived from aviremic HIV-1 patients under antiretroviral therapy didn't express MATR3, and most importantly, latency-reversing agents proposed for the rescue of latent provirus were ineffective for MATR3 upregulation. To conclude, our work identifies a cellular factor required for full HIV-1 reactivation and points to the revision of the current strategies for purging viral reservoirs that focus only on transcription., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2018