Faculty Opinions recommendation of BET bromodomain inhibition as a novel strategy for reactivation of HIV-1.

2012 ◽  
Author(s):  
Karen Anderson ◽  
Pinar Iyidogan
Keyword(s):  
Novel Strategy ◽  
Hiv 1

scholarly journals Excessive RNA Splicing and Inhibition of HIV-1 Replication Induced by Modified U1 Small Nuclear RNAs

2010 ◽  
Vol 84 (24) ◽  
pp. 12790-12800 ◽  
Author(s):  
Dibyakanti Mandal ◽  
Zehua Feng ◽  
C. Martin Stoltzfus
Keyword(s):  
Rna Splicing ◽  
Virus Production ◽  
Viral Rna ◽  
Splice Sites ◽  
Rna Transcripts ◽  
Cellular Factors ◽  
Novel Strategy ◽  
Definition Of ◽  
T Cell Lines ◽  
Hiv 1

ABSTRACT HIV-1 RNA undergoes a complex splicing process whereby over 40 different mRNA species are produced by alternative splicing. In addition, approximately half of the RNA transcripts remain unspliced and either are used to encode Gag and Gag-Pol proteins or are packaged into virions as genomic RNA. It has previously been shown that HIV-1 splicing is regulated by cis elements that bind to cellular factors. These factors either enhance or repress definition of exons that are flanked by the HIV-1 3′ splice sites. Here we report that expression of modified U1 snRNPs with increased affinity to HIV-1 downstream 5′ splice sites and to sequences within the first tat coding exon act to selectively increase splicing at the upstream 3′ splice sites in cotransfected 293T cells. This results in a decrease of unspliced viral RNA levels and an approximately 10-fold decrease in virus production. In addition, excessive splicing of viral RNA is concomitant with a striking reduction in the relative amounts of Gag processing intermediates and products. We also show that T cell lines expressing modified U1 snRNAs exhibit reduced HIV-1 replication. Our results suggest that induction of excessive HIV-1 RNA splicing may be a novel strategy to inhibit virus replication in human patients.

scholarly journals PIWIL4 Maintains HIV-1 Latency by Enforcing Epigenetically Suppressive Modifications on the 5′ Long Terminal Repeat

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Zhangping He ◽  
Shuliang Jing ◽  
Tao Yang ◽  
Jingliang Chen ◽  
Feng Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Long Terminal Repeat ◽  
Terminal Repeat ◽  
P Element ◽  
Latent Reservoir ◽  
Jurkat T Cells ◽  
Latently Infected ◽  
Novel Strategy ◽  
Hiv 1

ABSTRACT Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/β/γ, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4+ T lymphocytes and resting CD4+ T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5′ long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs). IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.

scholarly journals Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1581 ◽  
Author(s):  
Megan E. Meuser ◽  
Adel A. Rashad ◽  
Gabriel Ozorowski ◽  
Alexej Dick ◽  
Andrew B. Ward ◽  
...  
Keyword(s):  
Kinetic Parameter ◽  
Small Molecule ◽  
Conformational Equilibrium ◽  
Therapeutic Modality ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
Antiviral Compounds ◽  
Novel Strategy ◽  
Positive Effect ◽  
Hiv 1

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.

scholarly journals BET bromodomain inhibition as a novel strategy for reactivation of HIV-1

2012 ◽  
Vol 92 (6) ◽  
pp. 1147-1154 ◽  
Author(s):  
Camellia Banerjee ◽  
Nancie Archin ◽  
Daniel Michaels ◽  
Anna C. Belkina ◽  
Gerald V. Denis ◽  
...  
Keyword(s):  
Novel Strategy ◽  
Hiv 1

scholarly journals Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

2009 ◽  
Vol 206 (5) ◽  
pp. 1117-1134 ◽  
Author(s):  
Brandon F. Keele ◽  
Hui Li ◽  
Gerald H. Learn ◽  
Peter Hraber ◽  
Elena E. Giorgi ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Productive Infection ◽  
Infection Model ◽  
Mucosal Transmission ◽  
Molecular Features ◽  
Early Diversification ◽  
Mucosal Infection ◽  
Novel Strategy ◽  
Viral Sequences ◽  
Hiv 1

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research.

scholarly journals An Essential Role of INI1/hSNF5 Chromatin Remodeling Protein in HIV-1 Posttranscriptional Events and Gag/Gag-Pol Stability

2016 ◽  
Vol 90 (21) ◽  
pp. 9889-9904 ◽  
Author(s):  
Annalena La Porte ◽  
Jennifer Cano ◽  
Xuhong Wu ◽  
Doyel Mitra ◽  
Ganjam V. Kalpana
Keyword(s):  
Particle Production ◽  
Protein Levels ◽  
Mediated Effects ◽  
Viral Particle Production ◽  
Novel Strategy ◽  
The Stability ◽  
Novel Therapeutic Strategies ◽  
Hiv 1 ◽  
Rna Levels

ABSTRACTINI1/hSNF5/SMARCB1/BAF47 is an HIV-specific integrase (IN)-binding protein that influences HIV-1 transcription and particle production. INI1 binds to SAP18 (Sin3a-associated protein, 18 kDa), and both INI1 and SAP18 are incorporated into HIV-1 virions. To determine the significance of INI1 and the INI1-SAP18 interaction during HIV-1 replication, we isolated a panel ofSAP18-interaction-defective (SID)-INI1 mutants using a yeast reverse two-hybrid screen. The SID-INI1 mutants, which retained the ability to bind to IN, cMYC, and INI1 but were impaired for binding to SAP18, were tested for their effects on HIV-1 particle production. SID-INI1 dramatically reduced the intracellular Gag/Gag-Pol protein levels and, in addition, decreased viral particle production. The SID-INI1-mediated effects were less dramatic intranscomplementation assays using IN deletion mutant viruses with Vpr-reverse transcriptase (RT)-IN. SID-INI1 did not inhibit long-terminal-repeat (LTR)-mediated transcription, but it marginally decreased the steady-stategagRNA levels, suggesting a posttranscriptional effect. Pulse-chase analysis indicated that in SID-INI1-expressing cells, the pr55Gag levels decreased rapidly. RNA interference analysis indicated that small hairpin RNA (shRNA)-mediated knockdown ofINI1reduced the intracellular Gag/Gag-Pol levels and further inhibited HIV-1 particle production. These results suggest that SID-INI1 mutants inhibit multiple stages of posttranscriptional events of HIV-1 replication, including intracellular Gag/Gag-Pol RNA and protein levels, which in turn inhibits assembly and particle production. Interfering INI1 leads to a decrease in particle production and Gag/Gag-Pol protein levels. Understanding the role of INI1 and SAP18 in HIV-1 replication is likely to provide novel insight into the stability of Gag/Gag-Pol, which may lead to the development of novel therapeutic strategies to inhibit HIV-1 late events.IMPORTANCESignificant gaps exist in our current understanding of the mechanisms and host factors that influence HIV-1 posttranscriptional events, includinggagRNA levels, Gag/Gag-Pol protein levels, assembly, and particle production. Our previous studies suggested that the IN-binding host factor INI1 plays a role in HIV-1 assembly. An ectopically expressed minimal IN-binding domain of INI1, S6, potently and selectively inhibited HIV-1 Gag/Gag-Pol trafficking and particle production. However, whether or not endogenous INI1 and its interacting partners, such as SAP18, are required for late events was unknown. Here, we report that endogenous INI1 and its interaction with SAP18 are necessary to maintain intracellular levels of Gag/Gag-Pol and for particle production. Interfering INI1 or the INI1-SAP18 interaction leads to the impairment of these processes, suggesting a novel strategy for inhibiting posttranscriptional events of HIV-1 replication.

scholarly journals Bis-3-Chloropiperidines Targeting TAR RNA as A Novel Strategy to Impair the HIV-1 Nucleocapsid Protein

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1874
Author(s):  
Alice Sosic ◽  
Giulia Olivato ◽  
Caterina Carraro ◽  
Richard Göttlich ◽  
Dan Fabris ◽  
...  
Keyword(s):  
Rna Sequences ◽  
Protein Inhibition ◽  
Rna Targeting ◽  
Activation Response ◽  
Tar Rna ◽  
Novel Strategy ◽  
Bulge Loop ◽  
Targeting Strategy ◽  
Hiv 1

Specific RNA sequences regulate functions essential to life. The Trans-Activation Response element (TAR) is an RNA stem–bulge–loop structure involved in several steps of HIV-1 replication. In this work, we show how RNA targeting can inhibit HIV-1 nucleocapsid (NC), a highly conserved protein known to catalyze nucleic acid melting and strand transfers during reverse transcription. Our RNA targeting strategy consists of the employment of bis-3-chloropiperidines (B-CePs) to impair RNA melting through bifunctional alkylation. Specific interactions between B-CePs and TAR RNA were analytically investigated by gel electrophoresis and mass spectrometry, allowing the elucidation of B-CePs’ recognition of TAR, and highlighting an RNA-directed mechanism of protein inhibition. We propose that B-CePs can freeze TAR tridimensional conformation, impairing NC-induced dynamics and finally inhibiting its functions in vitro.

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