HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Crespo, Raquel; Rao, Shringar; Mahmoudi, Tokameh

doi:10.3389/fcimb.2022.855092

Cited by 13 publications

(21 citation statements)

References 247 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to silencing HIV-1 transcription initiation, our findings demonstrate that PCID2 enforces blocks at post-transcriptional steps of latency (Figure 3-6). Co– and post-transcriptional regulation of HIV-1 gene expression are crucial steps during the establishment and maintenance of viral latency and include blocks at 5’capping, alternative splicing, nucleocytoplasmic export, vRNA surveillance, translation and assembly 4 . We distinctively show that knockdown of PCID2 in latently infected cell lines mis-regulates the abundance of intron-containing and CS vRNA species, resulting in a marked decrease in levels of US vRNA and accumulation of spliced vRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…During HIV-1 infection, only CS vRNAs, because of their 2kb size, are exported via NXF1-NXT1. Larger, intron-containing vRNA species need viral protein Rev and other co-factors for their efficient export to the cytoplasm 4,51 . In yeast, absence or loss of function of Thp1 (PCID2 orthologue) leads to overall inhibition of spliced mRNA export 23 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

Crespo,

Ne,

Reinders

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

HIV-1 latency results from tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. To elucidate the molecular players that govern latency, we previously performed a dCas9-chromatin immunoprecipitation coupled with mass spectrometry (Catchet-MS) and identified the interactome of the latent HIV-1 LTR. Here we characterize the Catchet-MS-identified PCI domain-containing 2 (PCID2) protein, a component of the TREX2 complex, to play a dual role in promoting HIV-1 latency by enforcing both transcriptional repression and post-transcriptional blocks to HIV-1 gene expression. PCID2 bound the latent HIV-1 LTR and repressed transcription initiation during latency. Depletion of PCID2 remodelled the chromatin landscape at the HIV-1 promoter and resulted in transcriptional activation and reversal of latency. Immunoprecipitation coupled to Mass Spectrometry identified PCID2-interacting proteins to include members of the spliceosome, including negative viral RNA (vRNA) alternative splicing regulators, and PCID2 depletion resulted in over-splicing of intron-containing vRNA and misregulated expression of vRNA splice variants. We demonstrate that MCM3AP and DSS1, two other RNA-binding TREX2 complex subunits that comprise the dock of the complex also inhibit transcription initiation and viral RNA alternative splicing during latency and similarly to PCID2 function as prominent latency associated repressors of HIV-1 gene expression. Thus, PCID2 is a novel HIV-1 latency-promoting factor, which in context of the TREX2 sub-complex PCID2-DSS1-MCM3AP blocks transcription and dysregulates vRNA processing.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

Crespo,

Ne,

Reinders

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The LRA classes that influence this process can be classified as derepressors antagonizing the repressive latent HIV-1 promotor locus, or as activators that directly stimulate viral transcription initiation or elongation. The importance of blocks at the posttranscriptional level has also come to light recently and may be targetable by LRAs (9)(10)(11)(12). In contrast to the numbers identified in vitro, only a few LRAs have regulatory approval and can currently be used in clinical settings.…”

Section: Introductionmentioning

confidence: 99%

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

et al. 2023

Self Cite

View full text Add to dashboard Cite

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

show abstract

“…After acute HIV infection, there is a major difference in the distribution of HIV RNA and HIV DNA levels in patients, and the high level of virus replication can lead to continuous immune activation, inflammation and progressive damage to the immune function. HIV RNA is a common indicator of the level of virus replication in patients ( 1 ). Clinical statistics show that the HIV RNA level in plasma of untreated acute infection is usually 0.25–95.5 × 10 5 copies/ml ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of HSPA14 in patients with acute HIV-1 infection and its effect on HIV-1 replication

Kang

Sun

2023

Front. Immunol.

View full text Add to dashboard Cite

IntroductionHeat shock protein (HSPs) are important intracellular factors, which are often involved in the regulation of viral replication including HIV-1 in infected individuals as molecular chaperone proteins. Heat shock proteins 70 (HSP70/HSPA) family play important roles in HIV replication, but this family contain many subtypes, and it is unclear how these subtypes participate in and affect HIV replication.MethodsTo detect the interaction between HSPA14 and HspBP1 by CO-IP. Simulating HIV infection status in vitro to detect the change of intracellular HSPA14 expression after HIV infection in different cells. Constructing HSPA14 overexpression or knockdown cells to detect intracellular HIV replication levels after in vitro infection. Detecting the difference of HSPA expression levels in CD4+ T cells of untreated acute HIV-infected patients with different viral load.ResultsIn this study, we found that HIV infection can lead to changes in the transcriptional level of many HSPA subtypes, among which HSPA14 interacts with HIV transcriptional inhibitor HspBP1. The expression of HSPA14 in Jurkat and primary CD4+T cells infected with HIV were inhibited, overexpression of HSPA14 inhibited HIV replication, while knocking down HSPA14 promoted HIV replication. We also found that the expression level of HSPA14 is higher in peripheral blood CD4+T cells of untreated acute HIV infection patients with low viral load.ConclusionHSPA14 is a potential HIV replication inhibitor and may restrict HIV replication by regulating the transcriptional inhibitor HspBP1. Further studies are needed to determine the specific mechanism by which HSPA14 regulates viral replication

show abstract

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Cited by 13 publications

References 247 publications

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

Expression of HSPA14 in patients with acute HIV-1 infection and its effect on HIV-1 replication

Contact Info

Product

Resources

About