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Article ; Online: Functional Analysis of Spike from SARS-CoV-2 Variants Reveals the Role of Distinct Mutations in Neutralization Potential and Viral Infectivity.

Kuzmina, Alona / Wattad, Seraj / Engel, Stanislav / Rosenberg, Elli / Taube, Ran

2022 Volume 14, Issue 4

Abstract: Enhanced viral transmission and escape from vaccine-elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral ... ...

Abstract	Enhanced viral transmission and escape from vaccine-elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral variants on viral infectivity and neutralization sensitivity has not been completely defined. Here, we use pseudoviruses to assess the contribution of spike mutations within the Receptor Binding Domain (RBD) and the Furin Cleavage Site (FCS), and appear in circulating viral variants, on viral infectivity and neutralization potential against sera that was drawn from fully vaccinated individuals. Our functional analysis demonstrates that single, P681H, P681R or A701V-FCS mutations do not play a role in viral infectivity and neutralization potential. However, when in conjunction with the RBD-N501Y mutation, viral infectivity is enhanced. Similarly, combining the E484K-RBD mutation to the spike that carries FCS mutations reduces neutralization sensitivity with no effects on viral infectivity. Employing a similar approach onto the spike from Delta or Lota SARS-CoV-2 variants further reveals that specific RBD mutations affect neutralization sensitivity or viral infectivity differently. Our results validate the efficacy of the Pfizer third dose vaccine against Delta and Lota SARS-CoV-2 variants, and outline the significance of distinct RBD mutations in promoting viral infectivity and neutralization sensitivity to post-vaccination sera.
MeSH term(s)	Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; Humans ; Mutation ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14040803
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Article ; Online: Direct and indirect effects of CYTOR lncRNA regulate HIV gene expression.

Kuzmina, Alona / Sadhu, Lopamudra / Hasanuzzaman, Md / Fujinaga, Koh / Schwartz, Jacob C / Fackler, Oliver T / Taube, Ran

PLoS pathogens

2024 Volume 20, Issue 4, Page(s) e1012172

Abstract: The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a ...

Abstract	The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a stable pool of infected cell reservoir that is resistant to therapy and thus a main barrier towards complete elimination of viral infection. While the mechanisms by which host proteins govern viral gene expression and latency are well-studied, the emerging regulatory functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and viral latency have not yet been thoroughly explored. Here, we report the identification of the Cytoskeleton Regulator (CYTOR) long non-coding RNA (lncRNA) as an activator of HIV gene expression that is upregulated following T cell stimulation. Functional studies show that CYTOR suppresses viral latency by directly binding to the HIV promoter and associating with the cellular positive transcription elongation factor (P-TEFb) to activate viral gene expression. CYTOR also plays a global role in regulating cellular gene expression, including those involved in controlling actin dynamics. Depletion of CYTOR expression reduces cytoplasmic actin polymerization in response to T cell activation. In addition, treating HIV-infected cells with pharmacological inhibitors of actin polymerization reduces HIV gene expression. We conclude that both direct and indirect effects of CYTOR regulate HIV gene expression.
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1012172
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Article ; Online: Genome-wide CRISPR knockout screen identifies ZNF304 as a silencer of HIV transcription that promotes viral latency.

Krasnopolsky, Simona / Kuzmina, Alona / Taube, Ran

PLoS pathogens

2020 Volume 16, Issue 9, Page(s) e1008834

Abstract: Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in ...

Abstract	Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a whole-genome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency. Of several top candidates, the KRAB-containing zinc finger protein, ZNF304, was identified as the top hit. ZNF304 silences HIV gene transcription through associating with TRIM28 and recruiting to the viral promoter heterochromatin-inducing methyltransferases, including the polycomb repression complex (PRC) and SETB1. Depletion of ZNF304 expression reduced levels of H3K9me3, H3K27me3 and H2AK119ub repressive histone marks on the HIV promoter as well as SETB1 and TRIM28, ultimately enhancing HIV gene transcription. Significantly, ZNF304 also promoted HIV latency, as its depletion delayed the entry of HIV infected cells into latency. In primary CD4+ cells, ectopic expression of ZNF304 silenced viral transcription. We conclude that by associating with TRIM28 and recruiting host transcriptional repressive complexes, SETB1 and PRC, to the HIV promoter, ZNF304 silences HIV gene transcription and promotes viral latency.
MeSH term(s)	CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; CRISPR-Cas Systems ; Gene Expression Regulation, Viral ; Gene Knockout Techniques ; Gene Silencing ; Genome-Wide Association Study ; HIV-1/physiology ; Humans ; Jurkat Cells ; Promoter Regions, Genetic ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Tripartite Motif-Containing Protein 28/genetics ; Tripartite Motif-Containing Protein 28/metabolism ; Virus Latency
Chemical Substances	Repressor Proteins ; Transcription Factors ; ZNF304 protein, human ; TRIM28 protein, human (EC 2.3.2.27) ; Tripartite Motif-Containing Protein 28 (EC 2.3.2.27)
Language	English
Publishing date	2020-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1008834
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Article ; Online: CRISPRi-mediated depletion of Spt4 and Spt5 reveals a role for DSIF in the control of HIV latency.

Krasnopolsky, Simona / Novikov, Alex / Kuzmina, Alona / Taube, Ran

Biochimica et biophysica acta. Gene regulatory mechanisms

2020 Volume 1864, Issue 1, Page(s) 194656

Abstract: Pivotal studies on the control of HIV transcription has laid the foundations for our understanding of how metazoan transcription is executed, and what are the factors that control this step. Part of this work established a role for DRB Sensitivity ... ...

Abstract	Pivotal studies on the control of HIV transcription has laid the foundations for our understanding of how metazoan transcription is executed, and what are the factors that control this step. Part of this work established a role for DRB Sensitivity Inducing Factor (DSIF), consisting of Spt4 and Spt5, in promoting pause-release of RNA Polymerase II (Pol II) for optimal elongation. However, while there has been substantial progress in understanding the role of DSIF in mediating HIV gene transcription, its involvement in establishing viral latency has not been explored. Moreover, the effects of depleting Spt4 or Spt5, or simultaneously knocking down both subunits of DSIF have not been examined. In this study, we employed CRISPR interference (CRIPSRi) to knockdown the expression of Spt4, Spt5 or the entire DSIF complex, and monitored effects on HIV transcription and viral latency. Knocking down DSIF, or each of its subunits, inhibited HIV transcription, primarily at the step of Tat transactivation. This was accompanied by a decrease in promoter occupancy of Pol II and Cdk9, and to a lesser extent, AFF4. Interestingly, targeting the expression of one subunit of DSIF, reduced the protein stability of its counterpart partner. Moreover, depletion of Spt4, Spt5 or DSIF complex impaired cell growth, but did not cause cell death. Finally, knockdown of Spt4, Spt5 or DSIF, facilitated entry of HIV into latency. We conclude that each DSIF subunit plays a role in maintaining the stability of its other partner, achieving optimal function of the DSIF to enhance viral gene transcription.
MeSH term(s)	CRISPR-Cas Systems ; Gene Expression Regulation, Viral ; HIV-1/physiology ; Humans ; Jurkat Cells ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; RNA Interference ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Transcriptional Activation ; Transcriptional Elongation Factors/genetics ; Transcriptional Elongation Factors/metabolism ; Virus Latency ; tat Gene Products, Human Immunodeficiency Virus/genetics ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Nuclear Proteins ; Repressor Proteins ; SUPT4H1 protein, human ; SUPT5H protein, human ; Transcriptional Elongation Factors ; tat Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2020-12-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2918786-2
ISSN	1876-4320 ; 1874-9399
ISSN (online)	1876-4320
ISSN	1874-9399
DOI	10.1016/j.bbagrm.2020.194656
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Article ; Online: Differential platelet activation through an interaction with spike proteins of different SARS-CoV-2 variants.

Sevilya, Ziv / Kuzmina, Alona / Cipok, Michal / Hershkovitz, Vera / Keidar-Friedman, Danielle / Taube, Ran / Lev, Eli I

Journal of thrombosis and thrombolysis

2023 Volume 56, Issue 4, Page(s) 538–547

Abstract: COVID-19 disease is associated with an increased risk of thrombotic complications, which contribute to high short-term mortality. Patients with COVID-19 demonstrate enhanced platelet turnover and reactivity, which may have a role in the development of ... ...

Abstract	COVID-19 disease is associated with an increased risk of thrombotic complications, which contribute to high short-term mortality. Patients with COVID-19 demonstrate enhanced platelet turnover and reactivity, which may have a role in the development of thrombotic events and disease severity. Evidence has suggested direct interaction between SARS-CoV-2 and platelets, resulting in platelets activation. Here, we compare the effect of various SARS-CoV-2 spike variants on platelet activation. Engineered lentiviral particles were pseudotyped with spike SARS-CoV-2 variants and incubated with Platelet Rich Plasma obtained from healthy individuals. The pseudotyped SARS-CoV-2 exhibiting the wild-type Wuhan-Hu spike protein stimulated platelets to increase expression of the surface CD62P and activated αIIbβ3 markers by 3.5 ± 1.2 and 3.3 ± 0.7 fold, respectively (P = 0.004 and 0.003). The Delta variant induced much higher levels of platelet activation; CD62P expression was increased by 6.6 ± 2.2 fold and activated αIIbβ3 expression was increased by 5.0 ± 1.5 fold (P = 0.005 and 0.026, respectively). The Omicron BA.1 and the Alpha variants induced the lowest level of activation; CD62P expression was increased by 1.7 ± 0.4 and 1.6 ± 0.9 fold, respectively (P = 0.003 and 0.008), and activated αIIbβ3 expression by 1.8 ± 1.1 and 1.6 ± 0.8, respectively (P = 0.003 and 0.001). The Omicron BA.2 variant induced an increase of platelets activation comparable to the Wuhan-Hu (2.8 ± 1.2 and 2.1 ± 1.3 fold for CD62P and activated αIIbβ3 markers, respectively). The results obtained for various COVID-19 variants are in correlation with the clinical severity and mortality reported for these variants.
Language	English
Publishing date	2023-09-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1230645-9
ISSN	1573-742X ; 0929-5305
ISSN (online)	1573-742X
ISSN	0929-5305
DOI	10.1007/s11239-023-02891-x
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Article: Changes within the P681 residue of spike dictate cell fusion and syncytia formation of Delta and Omicron variants of SARS-CoV-2 with no effects on neutralization or infectivity.

Kuzmina, Alona / Korovin, Dina / Cohen Lass, Ido / Atari, Nofar / Ottolenghi, Aner / Hu, Pan / Mandelboim, Michal / Rosental, Benyamin / Rosenberg, Elli / Diaz-Griffero, Felipe / Taube, Ran

Heliyon

2023 Volume 9, Issue 6, Page(s) e16750

Abstract: The rapid spread and dominance of the Omicron SARS-CoV-2 lineages have posed severe health challenges worldwide. While extensive research on the role of the Receptor Binding Domain (RBD) in promoting viral infectivity and vaccine sensitivity has been ... ...

Abstract	The rapid spread and dominance of the Omicron SARS-CoV-2 lineages have posed severe health challenges worldwide. While extensive research on the role of the Receptor Binding Domain (RBD) in promoting viral infectivity and vaccine sensitivity has been well documented, the functional significance of the
Language	English
Publishing date	2023-06-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e16750
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Article ; Online: Super elongation complex promotes early HIV transcription and its function is modulated by P-TEFb.

Kuzmina, Alona / Krasnopolsky, Simona / Taube, Ran

Transcription

2017 Volume 8, Issue 3, Page(s) 133–149

Abstract: Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The ... ...

Abstract	Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear. Here we revisit the contribution of SEC in early steps of HIV gene transcription. In the absence of Tat, the AF4/FMR2 Family member 4 (AFF4) of SEC efficiently activates HIV transcription, while gene activation by its homolog AFF1 is substantially lower. Differential recruitment to the HIV promoter and association with Human Polymerase-Associated Factor complex (PAFc) play key role in this functional distinction between AFF4 and AFF1. Moreover, while depletion of cyclin T1 expression has subtle effects on HIV gene transcription in the absence of Tat, knockout (KO) of AFF1, AFF4, or both proteins slightly repress this early step of viral transcription. Upon Tat expression, HIV transcription reaches optimal levels despite KO of AFF1 or AFF4 expression. However, double AFF1/AFF4 KO completely diminishes Tat trans-activation. Significantly, our results show that P-TEFb phosphorylates AFF4 and modulates SEC assembly, AFF1/4 dimerization and recruitment to the viral promoter. We conclude that SEC promotes both early steps of HIV transcription in the absence of Tat, as well as elongation of transcription, when Tat is expressed. Significantly, SEC functions are modulated by P-TEFb.
Language	English
Publishing date	2017-05-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2646974-1
ISSN	2154-1272 ; 2154-1264
ISSN (online)	2154-1272
ISSN	2154-1264
DOI	10.1080/21541264.2017.1295831
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Article ; Online: SARS CoV-2 Delta variant exhibits enhanced infectivity and a minor decrease in neutralization sensitivity to convalescent or post-vaccination sera.

Kuzmina, Alona / Wattad, Seraj / Khalaila, Yara / Ottolenghi, Aner / Rosental, Benyamin / Engel, Stanislav / Rosenberg, Elli / Taube, Ran

iScience

2021 Volume 24, Issue 12, Page(s) 103467

Abstract: Since their identification, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Kappa and Delta have rapidly spread to become globally dominant. However, their infectivity and sensitivity to administered vaccines have not been documented. We ... ...

Abstract	Since their identification, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Kappa and Delta have rapidly spread to become globally dominant. However, their infectivity and sensitivity to administered vaccines have not been documented. We monitored the neutralization potential of convalescent or BNT162b2 post-vaccination sera against Kappa and Delta SARS-CoV-2 pseudoviruses. We show that both variants were successfully neutralized by convalescent and post-vaccination sera, exhibiting a mild decrease in their neutralization sensitivity. Of the two variants, Delta presented enhanced infectivity levels compared with Kappa or wild-type SARS-CoV-2. Nevertheless, both variants were not as infectious or resistant to post-vaccination sera as the Beta variant of concern. Interestingly, the Delta plus variant (AY.1/B.1.617.2.1) exhibited high resistance to post-vaccination sera, similar to that of the Beta SARS-CoV-2. However, its infectivity levels were close to those of wild-type SARS-CoV-2. These results account for the worldwide prevalence of Delta variant of concern and confirm the efficacy of the BNT162b2 vaccine against circulating other Delta variants.
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.103467
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Article ; Online: P681 mutations within the polybasic motif of spike dictate fusogenicity and syncytia formation of SARS CoV-2 variants

Kuzmina, Alona / Atari, Nofar / Ottolenghi, Aner / Korovin, Dina / lass, Ido Cohen / Rosental, Benyamin / Rosenberg, Elli / Mandelboim, Michal / Taube, Ran

bioRxiv

Abstract: The rapid spread and dominance of the Omicron SARS-CoV-2 over its Delta variant has posed severe global challenges. While extensive research on the role of the Receptor Binding Domain on viral infectivity and vaccine sensitivity has been documented, the ... ...

Abstract	The rapid spread and dominance of the Omicron SARS-CoV-2 over its Delta variant has posed severe global challenges. While extensive research on the role of the Receptor Binding Domain on viral infectivity and vaccine sensitivity has been documented, the role of the spike <sub>681</sub>PRRAR/SV<sub>687</sub> polybasic motif is less clear. Here we monitored infectivity and vaccine sensitivity of Omicron SARS-CoV-2 pseudovirus against sera samples that were drawn four months post administration of the third dose of BNT162b2 mRNA vaccine. Our findings show that relative to Wuhan-Hu and Delta SARS-CoV-2, Omicron displayed enhanced infectivity and a sharp decline in its sensitivity to vaccine-induced neutralizing antibodies. Furthermore, while the spike proteins form Wuhan-Hu (P681), Omicron (H681) and BA.2 (H681) pseudoviruses modestly promoted cell fusion and syncytia formation, Delta spike (P681R) displayed enhanced fusogenic activity and syncytia formation capability. Live-viruses plaque formation assays confirmed these findings and demonstrated that relatively to the Wuhan-Hu and Omicron SARS-CoV-2, Delta formed more plaques that were smaller in size. Introducing a single P681R point mutation within the Wuhan-Hu spike, or H681R within Omicron spike, restored fusion potential to similar levels observed for Delta spike. Conversely, a R681P point mutation within Delta spike efficiency abolished fusion potential. We conclude that over time, the efficiency of the third dose of the Pfizer vaccine against SARS CoV-2 is waned, and cannot neutralize Omicron. We further verify that the P681 position of the viral spike dictates fusogenicity and syncytia formation.
Keywords	covid19
Language	English
Publishing date	2022-04-27
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.04.26.489630
Database	COVID19

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Article ; Online: Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation.

Krasnopolsky, Simona / Marom, Lital / Victor, Rachel A / Kuzmina, Alona / Schwartz, Jacob C / Fujinaga, Koh / Taube, Ran

Retrovirology

2019 Volume 16, Issue 1, Page(s) 16

Abstract: Background: The human immunodeficiency virus (HIV) cell reservoir is currently a main obstacle towards complete eradication of the virus. This infected pool is refractory to anti-viral therapy and harbors integrated proviruses that are transcriptionally ...

Abstract	Background: The human immunodeficiency virus (HIV) cell reservoir is currently a main obstacle towards complete eradication of the virus. This infected pool is refractory to anti-viral therapy and harbors integrated proviruses that are transcriptionally repressed but replication competent. As transcription silencing is key for establishing the HIV reservoir, significant efforts have been made to understand the mechanism that regulate HIV gene transcription, and the role of the elongation machinery in promoting this step. However, while the role of the super elongation complex (SEC) in enhancing transcription activation of HIV is well established, the function of SEC in modulating viral latency is less defined and its cell partners are yet to be identified. Results: In this study we identify fused in sarcoma (FUS) as a partner of AFF4 in cells. FUS inhibits the activation of HIV transcription by AFF4 and ELL2, and silences overall HIV gene transcription. Concordantly, depletion of FUS elevates the occupancy of AFF4 and Cdk9 on the viral promoter and activates HIV gene transcription. Live cell imaging demonstrates that FUS co-localizes with AFF4 within nuclear punctuated condensates, which are disrupted upon treating cells with aliphatic alcohol. In HIV infected cells, knockout of FUS delays the gradual entry of HIV into latency, and similarly promotes viral activation in a T cell latency model that is treated with JQ1. Finally, effects of FUS on HIV gene transcription are also exhibited genome wide, where FUS mainly occupies gene promoters at transcription starting sites, while its knockdown leads to an increase in AFF4 and Cdk9 occupancy on gene promoters of FUS affected genes. Conclusions: Towards eliminating the HIV infected reservoir, understanding the mechanisms by which the virus persists in the face of therapy is important. Our observations show that FUS regulates both HIV and global gene transcription and modulates viral latency, thus can potentially serve as a target for future therapy that sets to reactivate HIV from its latent state.
MeSH term(s)	Cyclin-Dependent Kinase 9 ; Disease Reservoirs/virology ; Gene Silencing ; HEK293 Cells ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Jurkat Cells ; Promoter Regions, Genetic ; Proviruses/genetics ; RNA-Binding Protein FUS/metabolism ; T-Lymphocytes/virology ; Transcription, Genetic ; Transcriptional Elongation Factors/genetics ; Virus Activation ; Virus Latency/genetics
Chemical Substances	AFF4 protein, human ; ELL2 protein, human ; FUS protein, human ; RNA-Binding Protein FUS ; Transcriptional Elongation Factors ; CDK9 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
Language	English
Publishing date	2019-06-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2142602-8
ISSN	1742-4690 ; 1742-4690
ISSN (online)	1742-4690
ISSN	1742-4690
DOI	10.1186/s12977-019-0478-x
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