scholarly journals Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

2020 ◽  
Vol 16 (3) ◽  
pp. e1008430 ◽  
Author(s):  
Weili Kong ◽  
Ayan Biswas ◽  
Dawei Zhou ◽  
Guillaume Fiches ◽  
Koh Fujinaga ◽  
...  
Keyword(s):  
Viral Latency ◽  
Nucleolar Protein ◽  
Hiv 1

scholarly journals The evolution of regulatory elements in the emerging promoter variant strains of HIV-1

2021 ◽  
Author(s):  
Disha Bhange ◽  
Nityanand Prasad ◽  
Swati Singh ◽  
Harshit Kumar Prajapati ◽  
Shesh Prakash Maurya ◽  
...  
Keyword(s):  
Viral Latency ◽  
Regulatory Elements ◽  
The Other ◽  
Clinical Samples ◽  
Latent Reservoir ◽  
Viral Gene ◽  
Viral Promoter ◽  
Reservoir Characteristics ◽  
Hiv 1

AbstractIn a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter-variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but not significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a co-infection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time-points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.Significance StatementA unique conglomeration of TFBS enables the HIV-1 promoter to accomplish two diametrically opposite functions – transcriptional activation and transcriptional silencing. The various phases of viral latency - establishment, maintenance, and reversal - collectively determine the replication fitness of individual viral strains. A profound variation in the TFBS composition of the viral promoter may significantly alter the viral latency properties and the latent reservoir characteristics. Although the duplication of certain TFBS remains a quality unique to HIV-1C, the high-level genetic recombination of HIV-1 may promote the transfer of such molecular properties to the other HIV-1 subtypes. The emergence of several promoter-variant viral strains may make the task of a ‘functional cure’ more challenging in HIV-1C.

scholarly journals The KAT5-Acetyl-Histone4-Brd4 axis silences HIV-1 transcription and promotes viral latency

2018 ◽  
Vol 14 (4) ◽  
pp. e1007012 ◽  
Author(s):  
Zichong Li ◽  
Uri Mbonye ◽  
Zeming Feng ◽  
Xiaohui Wang ◽  
Xiang Gao ◽  
...  
Keyword(s):  
Viral Latency ◽  
Hiv 1

scholarly journals SAMHD1 Impairs HIV-1 Gene Expression and Negatively Modulates Reactivation of Viral Latency in CD4+ T Cells

2018 ◽  
Vol 92 (15) ◽  
Author(s):  
Jenna M. Antonucci ◽  
Sun Hee Kim ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Tai-Wei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Leukemia Virus ◽  
Viral Latency ◽  
Viral Reservoir ◽  
Latently Infected ◽  
Ltr Promoter ◽  
Hiv 1

ABSTRACT Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) replication in nondividing cells by degrading intracellular deoxynucleoside triphosphates (dNTPs). SAMHD1 is highly expressed in resting CD4+ T cells, which are important for the HIV-1 reservoir and viral latency; however, whether SAMHD1 affects HIV-1 latency is unknown. Recombinant SAMHD1 binds HIV-1 DNA or RNA fragments in vitro, but the function of this binding remains unclear. Here we investigate the effect of SAMHD1 on HIV-1 gene expression and reactivation of viral latency. We found that endogenous SAMHD1 impaired HIV-1 long terminal repeat (LTR) activity in monocytic THP-1 cells and HIV-1 reactivation in latently infected primary CD4+ T cells. Overexpression of wild-type (WT) SAMHD1 suppressed HIV-1 LTR-driven gene expression at a transcriptional level. Tat coexpression abrogated SAMHD1-mediated suppression of HIV-1 LTR-driven luciferase expression. SAMHD1 overexpression also suppressed the LTR activity of human T-cell leukemia virus type 1 (HTLV-1), but not that of murine leukemia virus (MLV), suggesting specific suppression of retroviral LTR-driven gene expression. WT SAMHD1 bound to proviral DNA and impaired reactivation of HIV-1 gene expression in latently infected J-Lat cells. In contrast, a nonphosphorylated mutant (T592A) and a dNTP triphosphohydrolase (dNTPase) inactive mutant (H206D R207N [HD/RN]) of SAMHD1 failed to efficiently suppress HIV-1 LTR-driven gene expression and reactivation of latent virus. Purified recombinant WT SAMHD1, but not the T592A and HD/RN mutants, bound to fragments of the HIV-1 LTR in vitro. These findings suggest that SAMHD1-mediated suppression of HIV-1 LTR-driven gene expression potentially regulates viral latency in CD4+ T cells. IMPORTANCE A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir that exists in resting CD4+ T cells, the main targets of HIV-1. The viral reservoir is maintained through a variety of mechanisms, including regulation of the HIV-1 LTR promoter. The host protein SAMHD1 restricts HIV-1 replication in nondividing cells, but its role in HIV-1 latency remains unknown. Here we report a new function of SAMHD1 in regulating HIV-1 latency. We found that SAMHD1 suppressed HIV-1 LTR promoter-driven gene expression and reactivation of viral latency in cell lines and primary CD4+ T cells. Furthermore, SAMHD1 bound to the HIV-1 LTR in vitro and in a latently infected CD4+ T-cell line, suggesting that the binding may negatively modulate reactivation of HIV-1 latency. Our findings indicate a novel role for SAMHD1 in regulating HIV-1 latency, which enhances our understanding of the mechanisms regulating proviral gene expression in CD4+ T cells.

Sequence evolution and escape from specific immune pressure of an HIV-1 Rev epitope with extensive sequence similarity to human nucleolar protein 6

2012 ◽  
Vol 79 (3) ◽  
pp. 174-185 ◽  
Author(s):  
S. D. Allard ◽  
A. L. de Goede ◽  
B. De Keersmaecker ◽  
C. Heirman ◽  
P. Lacor ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Nucleolar Protein ◽  
Sequence Evolution ◽  
Extensive Sequence ◽  
Immune Pressure ◽  
Hiv 1

Nucleolar Protein B23 Stimulates Nuclear Import of the HIV-1 Rev Protein and NLS-Conjugated Albumin†

Biochemistry ◽  
1997 ◽  
Vol 36 (13) ◽  
pp. 3941-3949 ◽  
Author(s):  
Attila Szebeni ◽  
Bam Mehrotra ◽  
Amy Baumann ◽  
Stephen A. Adam ◽  
Paul T. Wingfield ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Nucleolar Protein ◽  
Protein B23 ◽  
Hiv 1 ◽  
Rev Protein

Location of the HIV-1 Rev protein during mitosis: inactivation of the nuclear export signal alters the pathway for postmitotic reentry into nucleoli

1996 ◽  
Vol 109 (9) ◽  
pp. 2239-2251 ◽  
Author(s):  
M. Dundr ◽  
G.H. Leno ◽  
N. Lewis ◽  
D. Rekosh ◽  
M.L. Hammarskjoid ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Nucleolar Protein ◽  
Early Prophase ◽  
Nucleolar Proteins ◽  
Late Telophase ◽  
Export Signal ◽  
Hiv 1 ◽  
Rev Protein

The HIV-1 Rev protein localizes predominantly to the nucleolus of HIV-1-infected or Rev-expressing cells. The subcellular location of Rev during mitotic nucleolar disintegration was examined at various stages of mitosis in synchronized Rev-expressing CMT3 cells. During early prophase Rev was predominantly located in disintegrating nucleoli and began to accumulate at the peripheral regions of chromosomes in late prophase, eventually distributing uniformly on all chromosomes in prometaphase. In anaphase Rev remained associated with the perichromosomal regions, but significant amounts of Rev were also seen in numerous nucleolus-derived foci. The movement of Rev from disintegrating nucleoli to perichromosomal regions and foci was similar to that of nonribosomal nucleolar proteins, including fibrillarin, nucleolin, protein B23 and p52 of the granular component. During telophase Rev remained associated with perichromosomal regions and mitotic foci until the nuclear envelope started to reform. When nuclear envelope formation was complete in late telophase, nonribosomal nucleolar proteins were present in prenucleolar bodies (PNBs) which were eventually incorporated into nucleoli; at the same time, Rev was excluded from nuclei. In contrast, a trans-dominant negative Rev protein containing an inactive nuclear export signal reentered nuclei by the nonribosomal nucleolar protein pathway in late telophase, associating with PNBs and reformed nucleoli. Rev protein reentry into postmitotic nuclei was delayed until early G1 phase, but before the arrival of ribosomal protein S6. Thus, Rev behaves like a nonribosomal nucleolar protein through mitosis until early telophase; however, its nuclear reentry seems to require reestablishment of both a nuclear import system and active nucleoli.

scholarly journals Depicting HIV-1 Transcriptional Mechanisms: A Summary of What We Know

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1385
Author(s):  
Antoine Dutilleul ◽  
Anthony Rodari ◽  
Carine Van Lint
Keyword(s):  
Drug Targets ◽  
Viral Latency ◽  
Health Issues ◽  
Cellular Mechanisms ◽  
New Therapeutic Approaches ◽  
Precise Understanding ◽  
Hiv Eradication ◽  
Host Cell Factors ◽  
Main Barrier ◽  
Hiv 1

Despite the introduction of combinatory antiretroviral therapy (cART), HIV-1 infection cannot be cured and is still one of the major health issues worldwide. Indeed, as soon as cART is interrupted, a rapid rebound of viremia is observed. The establishment of viral latency and the persistence of the virus in cellular reservoirs constitute the main barrier to HIV eradication. For this reason, new therapeutic approaches have emerged to purge or restrain the HIV-1 reservoirs in order to cure infected patients. However, the viral latency is a multifactorial process that depends on various cellular mechanisms. Since these new therapies mainly target viral transcription, their development requires a detailed and precise understanding of the regulatory mechanism underlying HIV-1 transcription. In this review, we discuss the complex molecular transcriptional network regulating HIV-1 gene expression by focusing on the involvement of host cell factors that could be used as potential drug targets to design new therapeutic strategies and, to a larger extent, to reach an HIV-1 functional cure.

scholarly journals HIV-1 Vpr Induces Degradation of Nucleolar Protein CCDC137 as a Consequence of Cell Cycle Arrest

2021 ◽  
Author(s):  
Laura Jean Martins ◽  
Ana Beatriz DePaula-Silva ◽  
Vicente Planelles
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Coiled Coil ◽  
Acid Resistance ◽  
Ubiquitin Proteasome System ◽  
Nucleolar Protein ◽  
Regulatory Subunit ◽  
M Cell ◽  
Cycle Arrest ◽  
Hiv 1

Expression of HIV-1 accessory proteins Vif and Vpr results in G2/M cell cycle arrest by hijacking the host ubiquitin-proteasome system. Vif directs cell cycle arrest by targeting protein phosphatase 2, regulatory subunit B alpha (PP2AB56) for degradation. However, the ubiquitination target(s) of Vpr that is directly responsible for G2/M arrest has remained elusive. Recently, Vpr directed degradation of nucleolar protein coiled-coil domain containing 137 (CCDC137), also known as retinoic acid resistance factor (RaRF), has been implicated as the proximal event leading to G2/M cell cycle arrest. In this study we aimed to further investigate this finding. We confirm that CCDC137 is targeted for degradation in the presence of Vpr with a requirement for the CUL4ADDB1.DCAF1 E3 ligase complex. However, degradation of CCDC137 is a general consequence, rather than a trigger, of G2/M arrest. Thus, whether induced by Vpr expression or pharmacologically via CDK1 inhibition, G2/M blockade results in degradation of CCDC137. Furthermore, siRNA-mediated depletion of CCDC137 failed to induce G2/M arrest.

scholarly journals Viral latency and potential eradication of HIV-1

2012 ◽  
Vol 10 (8) ◽  
pp. 855-857 ◽  
Author(s):  
Kenneth A Matreyek ◽  
Ilker Oztop ◽  
Eric O Freed ◽  
Alan Engelman
Keyword(s):  
Viral Latency ◽  
Hiv 1
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