scholarly journals The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 60
Author(s):  
Subha Dahal ◽  
Ran Cheng ◽  
Peter K. Cheung ◽  
Terek Been ◽  
Ramy Malty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Processing ◽  
Viral Gene Expression ◽  
Dna Amplification ◽  
Early Gene ◽  
Viral Gene ◽  
Structural Protein ◽  
Virus Particles ◽  
Reduced Toxicity ◽  
Hiv 1

Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.

scholarly journals Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia

2021 ◽  
Vol 17 (7) ◽  
pp. e1009689
Author(s):  
Benjamin E. Warner ◽  
Michael B. Yee ◽  
Mingdi Zhang ◽  
Rebecca S. Hornung ◽  
Benedikt B. Kaufer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Varicella Zoster Virus ◽  
Postherpetic Neuralgia ◽  
Viral Gene Expression ◽  
Viral Reactivation ◽  
Early Gene ◽  
Viral Gene ◽  
Structural Protein ◽  
Regulation Of Expression ◽  
Varicella Zoster

Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.

scholarly journals Fourth NF-κB site in HIV-1 subtype-C LTR confers functional advantage to viral gene expression

Retrovirology ◽  
2009 ◽  
Vol 6 (S2) ◽  
Author(s):  
Mahesh Bachu ◽  
Rajesh V Murali ◽  
Anil MHKH Babu ◽  
Venkat SRK Yedavalli ◽  
Kuan-Teh Jeang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Subtype C ◽  
Functional Advantage ◽  
Hiv 1

scholarly journals Impact of Tat Genetic Variation on HIV-1 Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Luna Li ◽  
Satinder Dahiya ◽  
Sandhya Kortagere ◽  
Benjamas Aiamkitsumrit ◽  
David Cunningham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcriptional Activation ◽  
Viral Gene Expression ◽  
Functional Domains ◽  
Viral Gene ◽  
Molecular Architecture ◽  
Viral Transactivator ◽  
Hiv Drugs ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation withintatof different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability withintatmay impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

scholarly journals 8 Implication of the HIV-1 pol gene intragenic enhancer in myeloid-specific viral gene expression

2017 ◽  
Vol 3 ◽  
pp. 8
Author(s):  
R. Verdikt ◽  
L. Colin ◽  
C. Vanhulle ◽  
B. Van Driessche ◽  
A. Kula ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv 1

Differential viral gene expression and its effect on the biological properties of the cell clones of an HIV-1-infected cell line

Virology ◽  
1990 ◽  
Vol 177 (1) ◽  
pp. 380-383 ◽  
Author(s):  
V.S. Kalyanaraman ◽  
V. Rodriguez ◽  
S. Josephs ◽  
R.C. Gallo ◽  
M.G. Sarngadharan
Keyword(s):  
Gene Expression ◽  
Infected Cell ◽  
Cell Line ◽  
Viral Gene Expression ◽  
Biological Properties ◽  
Viral Gene ◽  
Infected Cell Line ◽  
Cell Clones ◽  
Hiv 1

scholarly journals Actin-based motility drives baculovirus transit to the nucleus and cell surface

2010 ◽  
Vol 190 (2) ◽  
pp. 187-195 ◽  
Author(s):  
Taro Ohkawa ◽  
Loy E. Volkman ◽  
Matthew D. Welch
Keyword(s):  
Gene Expression ◽  
Actin Polymerization ◽  
Nuclear Periphery ◽  
Viral Gene Expression ◽  
Early Gene ◽  
Evolutionary Strategy ◽  
Viral Gene ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Nuclear Entry

Most viruses move intracellularly to and from their sites of replication using microtubule-based mechanisms. In this study, we show that nucleocapsids of the baculovirus Autographa californica multiple nucleopolyhedrovirus undergo intracellular motility driven by actin polymerization. Motility requires the viral P78/83 capsid protein and the host Arp2/3 complex. Surprisingly, the virus directs two sequential and coordinated phases of actin-based motility. Immediately after cell entry, motility enables exploration of the cytoplasm and collision with the nuclear periphery, speeding nuclear entry and the initiation of viral gene expression. Nuclear entry itself requires transit through nuclear pore complexes. Later, after the onset of early gene expression, motility is required for accumulation of a subpopulation of nucleocapsids in the tips of actin-rich surface spikes. Temporal coordination of actin-based nuclear and surface translocation likely enables rapid transmission to neighboring cells during infection in insects and represents a distinctive evolutionary strategy for overcoming host defenses.

scholarly journals Epitranscriptomic Addition of m5C to HIV-1 Transcripts Regulates Viral Gene Expression

2019 ◽  
Vol 26 (2) ◽  
pp. 217-227.e6 ◽  
Author(s):  
David G. Courtney ◽  
Kevin Tsai ◽  
Hal P. Bogerd ◽  
Edward M. Kennedy ◽  
Brittany A. Law ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv 1

scholarly journals Highly Divergent Lentiviral Tat Proteins Activate Viral Gene Expression by a Common Mechanism

1999 ◽  
Vol 19 (7) ◽  
pp. 4592-4599 ◽  
Author(s):  
Paul D. Bieniasz ◽  
Therese A. Grdina ◽  
Hal P. Bogerd ◽  
Bryan R. Cullen
Keyword(s):  
Gene Expression ◽  
Protein Complex ◽  
Equine Infectious Anemia Virus ◽  
Viral Gene Expression ◽  
Human Cells ◽  
Common Mechanism ◽  
Viral Gene ◽  
Target Element ◽  
Anemia Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Tat protein (hTat) activates transcription initiated at the viral long terminal repeat (LTR) promoter by a unique mechanism requiring recruitment of the human cyclin T1 (hCycT1) cofactor to the viral TAR RNA target element. While activation of equine infectious anemia virus (EIAV) gene expression by the EIAV Tat (eTat) protein appears similar in that the target element is a promoter proximal RNA, eTat shows little sequence homology to hTat, does not activate the HIV-1 LTR, and is not active in human cells that effectively support hTat function. To address whether eTat and hTat utilize similar or distinct mechanisms of action, we have cloned the equine homolog of hCycT1 (eCycT1) and examined whether it is required to mediate eTat function. Here, we report that expression of eCycT1 in human cells fully rescues eTat function and that eCycT1 and eTat form a protein complex that specifically binds to the EIAV, but not the HIV-1, TAR element. While hCycT1 is also shown to interact with eTat, the lack of eTat function in human cells is explained by the failure of the resultant protein complex to bind to EIAV TAR. Critical sequences in eCycT1 required to support eTat function are located very close to the amino terminus, i.e., distal to the HIV-1 Tat-TAR interaction motif previously identified in the hCycT1 protein. Together, these data provide a molecular explanation for the species tropism displayed by eTat and demonstrate that highly divergent lentiviral Tat proteins activate transcription from their cognate LTR promoters by essentially identical mechanisms.

HIV-1 infection and the developing nervous system: Lineage-specific regulation of viral gene expression and replication in distinct neuronal precursors

1997 ◽  
Vol 3 (4) ◽  
pp. 290-298 ◽  
Author(s):  
Fabrizio Ensoli ◽  
Hong Wang ◽  
Valeria Fiorelli ◽  
Steven L Zeichner ◽  
Maria Rita De Cristofaro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Neuronal Precursors ◽  
Specific Regulation ◽  
Hiv 1 ◽  
Developing Nervous System
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