Scaffold attachment factor B suppresses HIV-1 infection of CD4+ T cells by preventing binding of RNA polymerase II to HIV-1's long terminal repeat

et al. 2019

mBio

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Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.

Section: Resultsmentioning

confidence: 99%

Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation

et al. 2019

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“…5B and C). To confirm that the observed correlation of RBMX expression and HIV-1 reactivation is not an artifact in a single cell line, we tested this in the HIV-1 latently infected Jurkat T-cell (C11 clone) which harbors an HIV-1 proviral DNA encoding green fluorescent protein (GFP) (13,(36)(37)(38). Similar to results obtained in ACH2 cells, the knockdown of endogenous RBMX in C11 cells with shRNAs promoted both basal (medium) and TNF-␣stimulated HIV-1 reactivation ( Fig.…”

Section: Fig 4 Rbmx Binds With and Maintains H3k9me3 Modification Formentioning

confidence: 99%

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 ⁺ T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA

Jiang

et al. 2020

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Reversible repression of HIV-1 5′ long terminal repeat (5′-LTR)-mediated transcription represents the main mechanism for HIV-1 to maintain latency. Identification of host factors that modulate LTR activity and viral latency may help develop new antiretroviral therapies. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are known to regulate gene expression and possess multiple physiological functions. hnRNP family members have recently been identified as the sensors for viral nucleic acids to induce antiviral responses, highlighting the crucial roles of hnRNPs in regulating viral infection. A member of the hnRNP family, X-linked RNA-binding motif protein (RBMX), has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5′-LTR-driven transcription of viral genome in CD4+ T cells. Mechanistically, RBMX binds to HIV-1 proviral DNA at the LTR downstream region and maintains the repressive trimethylation of histone H3 lysine 9 (H3K9me3), leading to a blockage of the recruitment of the positive transcription factor phosphorylated RNA polymerase II (RNA pol II) and consequential impediment of transcription elongation. This RBMX-mediated modulation of HIV-1 transcription maintains viral latency by inhibiting viral reactivation from an integrated proviral DNA. Our findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies. IMPORTANCE HIV-1 latency featuring silence of transcription from HIV-1 proviral DNA represents a major obstacle for HIV-1 eradication. Reversible repression of HIV-1 5′-LTR-mediated transcription represents the main mechanism for HIV-1 to maintain latency. The 5′-LTR-driven HIV gene transcription can be modulated by multiple host factors and mechanisms. The hnRNPs are known to regulate gene expression. A member of the hnRNP family, RBMX, has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5′-LTR-driven transcription of viral genome in CD4+ T cells and maintains viral latency. These findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

“…The initiation and elongation of HIV-LTR-driven transcription can be assessed by quantifying the production of various lengths of viral messenger RNAs with (RT-) PCR using specific primers (68,70). We found that MALAT1 knockout significantly decreased the production of initial viral message RNAs, but did not further decrease the production of elongated viral RNAs, indicating that the depletion of MALAT1 impaired the initiation of HIV-LTR-driven transcription, but not the elongation (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

“…The reversible silencing of LTR-driven transcription is critical for an integrated provirus to maintain viral latency (68,70,77–80). The promotion effect of MALAT1 on HIV-1 LTR-driven gene expression suggests a potential role for MALAT1 in reactivating HIV-1 from latency.…”

Section: Resultsmentioning

confidence: 99%

“…To confirm that the observed correlation of MALAT1 expression and HIV-1 reactivation is not an artifact in a single cell line, we tested this in the HIV-1 latently infected Jurkat T-cell (C11 clone) that harboring an HIV-1 proviral DNA encoding GFP (68,70,77,81). Similar to results obtained in ACH2 cells, upon stimulation with PMA/Ionomycin (Figure 6C), the endogenous expression of MALAT1 was elevated (Figure 6C); accompanying the elevated MALAT1 expression, HIV-1 was reactivated from C11 clone, as demonstrated by HIV-1 gag mRNA production (Figure 6D), and GFP expression (Figure 6E), and the reduction of EZH2 recruitment to HIV-1 5′-LTR regions was observed (Figure 6F).…”

Section: Resultsmentioning

confidence: 99%

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Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter

et al. 2019

Nucleic Acids Research

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126

108

Long noncoding RNAs (lncRNAs) may either repress or activate HIV-1 replication and latency; however, specific mechanisms for their action are not always clear. In HIV-1 infected CD4 + T cells, we performed RNA-Sequencing (RNA-Seq) analysis and discovered an up-regulation of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), an lncRNA previously described in cancer cells that associate with cancer pathogenesis. Moreover, we found that MALAT1 promoted HIV-1 transcription and infection, as its knockdown by CRISPR/Cas9 markedly reduced the HIV-1 long terminal repeat (LTR)-driven gene transcription and viral replication. Mechanistically, through an association with chromatin modulator polycomb repressive complex 2 (PRC2), MALAT1 detached the core component enhancer of zeste homolog 2 (EZH2) from binding with HIV-1 LTR promoter, and thus removed PRC2 complex-mediated methylation of histone H3 on lysine 27 (H3K27me3) and relieved epigenetic silencing of HIV-1 transcription. Moreover, the reactivation of HIV-1 stimulated with latency reversal agents (LRAs) induced MALAT1 expression in latently infected cells. Successful combination antiretroviral therapy (cART) was accompanied by significantly diminished MALAT1 expression in patients, suggesting a positive correlation of MALAT1 expression with HIV-1 replication. Our data have identified MALAT1 as a promoter of HIV-1 transcription, and suggested that MALAT1 may be targeted for the development of new therapeutics.