viral genome replication
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mBio ◽  
2022 ◽  
Author(s):  
Sho Miyamoto ◽  
Masahiro Nakano ◽  
Takeshi Morikawa ◽  
Ai Hirabayashi ◽  
Ryoma Tamura ◽  
...  

Influenza A virus ribonucleoprotein complex (RNP) is responsible for viral genome replication, thus playing essential roles in the virus life cycle. RNP formation occurs in the nuclei of infected cells; however, little is known about the nuclear domains involved in this process.


2021 ◽  
Author(s):  
Federico Munafò ◽  
Elisa Donati ◽  
Nicoletta Brindani ◽  
Giuliano Ottonello ◽  
Andrea Armirotti ◽  
...  

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as one of the most promising targets for pharmacological intervention against SARS-CoV-2. To this end, we experimentally tested luteolin and quercetin for their ability to inhibit the RdRp enzyme. These two compounds are ancestors of flavonoid natural compounds known for a variety of basal pharmacological activities. Luteolin and quercetin returned a single-digit IC50 of 4.6 µM and 6.9 µM, respectively. Then, through dynamic docking simulations, we identified possible binding modes of these compounds to a recently published cryo-EM structure of RdRp. Collectively, these data indicate that these two compounds are a valid starting point for further optimization and development of a new class of RdRp inhibitors to treat SARS-CoV-2 and potentially other viral infections.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuofeng Yuan ◽  
Bingpeng Yan ◽  
Jianli Cao ◽  
Zi-Wei Ye ◽  
Ronghui Liang ◽  
...  

AbstractCoronavirus Disease 2019 (COVID-19) is predominantly a respiratory tract infection that significantly rewires the host metabolism. Here, we monitored a cohort of COVID-19 patients’ plasma lipidome over the disease course and identified triacylglycerol (TG) as the dominant lipid class present in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced metabolic dysregulation. In particular, we pinpointed the lipid droplet (LD)-formation enzyme diacylglycerol acyltransferase (DGAT) and the LD stabilizer adipocyte differentiation-related protein (ADRP) to be essential host factors for SARS-CoV-2 replication. Mechanistically, viral nucleo capsid protein drives DGAT1/2 gene expression to facilitate LD formation and associates with ADRP on the LD surface to complete the viral replication cycle. DGAT gene depletion reduces SARS-CoV-2 protein synthesis without compromising viral genome replication/transcription. Importantly, a cheap and orally available DGAT inhibitor, xanthohumol, was found to suppress SARS-CoV-2 replication and the associated pulmonary inflammation in a hamster model. Our findings not only uncovered the mechanistic role of SARS-CoV-2 nucleocapsid protein to exploit LDs-oriented network for heightened metabolic demand, but also the potential to target the LDs-synthetase DGAT and LDs-stabilizer ADRP for COVID-19 treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Lisett Liblekas ◽  
Alla Piirsoo ◽  
Annika Laanemets ◽  
Eva-Maria Tombak ◽  
Airiin Laaneväli ◽  
...  

The life-cycle of human papillomaviruses (HPVs) includes three distinct phases of the viral genome replication. First, the viral genome is amplified in the infected cells, and this amplification is often accompanied by the oligomerization of the viral genomes. Second stage includes the replication of viral genomes in concert with the host cell genome. The viral genome is further amplified during the third stage of the viral-life cycle, which takes place only in the differentiated keratinocytes. We have previously shown that the HPV18 genomes utilize at least two distinct replication mechanisms during the initial amplification. One of these mechanisms is a well-described bidirectional replication via theta type of replication intermediates. The nature of another replication mechanism utilized by HPV18 involves most likely recombination-dependent replication. In this paper, we show that the usage of different replication mechanisms is a property shared also by other HPV types, namely HPV11 and HPV5. We further show that the emergence of the recombination dependent replication coincides with the oligomerization of the viral genomes and is dependent on the replicative DNA polymerases. We also show that the oligomeric genomes of HPV18 replicate almost exclusively using recombination dependent mechanism, whereas monomeric HPV31 genomes replicate bi-directionally during the maintenance phase of the viral life-cycle.


2021 ◽  
Author(s):  
Selma Dahmane ◽  
Adeline Kerviel ◽  
Dustin R. Morado ◽  
Kasturika Shankar ◽  
Björn Ahlman ◽  
...  

SummaryEnteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic membranes for viral genome replication. New virions are thought to be assembled near the genome replication sites and are released in vesicles through secretory autophagy. Here, we use cryo-electron tomography to show that poliovirus assembles directly on replication membranes. Assembly progression beyond a membrane-bound half-capsid intermediate requires the host lipid kinase VPS34, whereas inhibition of ULK1, the initiator of canonical autophagy, leads to accumulation of virions in vast intracellular arrays followed by an increased release at later time points. We further identify multiple layers of selectivity in virus-induced autophagy, with a strong selection for RNA-loaded virions over empty capsids and the segregation of virions from a second class of autophagic membranes containing protein filaments bundles. These findings provide an integrated structural framework for multiple stages of the poliovirus life cycle.


Insects ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 890
Author(s):  
Huimin Guo ◽  
Benzheng Zhang ◽  
Xin Zheng ◽  
Juan Sun ◽  
Huiduo Guo ◽  
...  

The pathogenicity of different concentrations of Bombyx mori nuclear polyhedrosis virus- Zhenjiang strain (BmNPV ZJ) and Yunnan strain (BmNPV YN) was assessed in Baiyu larvae. The structures of the two viral strains were observed by negative-staining electron microscopy, and their proliferation was examined by quantitative polymerase chain reaction (qPCR). The genomic sequences of these two viruses were obtained to investigate the differences in their pathogenicity. The lethal concentration 50 (LC50) of BmNPV ZJ against Baiyu larvae was higher than that of BmNPV YN, indicating a relatively more robust pathogenicity in BmNPV YN. Electron microscopic images showed that the edges of BmNPV YN were clearer than those of BmNPV ZJ. The qPCR analysis demonstrated significantly higher relative expressions of immediately early 1 gene (ie-1), p143, vp39, and polyhedrin genes (polh) in BmNPV ZJ than in BmNPV YN at 12–96 h. The complete genomes of BmNPV ZJ and BmNPV YN were, respectively, 135,895 bp and 143,180 bp long, with 141 and 145 coding sequences and 40.93% and 39.71% GC content. Considering the BmNPV ZJ genome as a reference, 893 SNP loci and 132 InDel mutations were observed in the BmNPV YN genome, resulting in 106 differential gene sequences. Among these differential genes, 76 (including 22 hub genes and 35 non-hub genes) possessed amino acid mutations. Thirty genes may have been related to viral genome replication and transcription and five genes may have been associated with the viral oral infection. These results can help in understanding the mechanisms of pathogenicity of different strains of BmNPV in silkworms.


Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1819
Author(s):  
Jinwei Zhang

The cellular metabolism of host tRNAs and life cycle of HIV-1 cross paths at several key virus–host interfaces. Emerging data suggest a multi-faceted interplay between host tRNAs and HIV-1 that plays essential roles, both structural and regulatory, in viral genome replication, genome packaging, and virion biogenesis. HIV-1 not only hijacks host tRNAs and transforms them into obligatory reverse transcription primers but further commandeers tRNAs to regulate the localization of its major structural protein, Gag, via a specific interface. This review highlights recent advances in understanding tRNA–HIV-1 interactions, primarily from a structural perspective, which start to elucidate their underlying molecular mechanisms, intrinsic specificities, and biological significances. Such understanding may provide new avenues toward developing HIV/AIDS treatments and therapeutics including small molecules and RNA biologics that target these host–virus interfaces.


Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1155
Author(s):  
Xiaoqin Zheng ◽  
Zeyu Sun ◽  
Liang Yu ◽  
Danrong Shi ◽  
Miaojin Zhu ◽  
...  

SARS-CoV-2 infection has caused a global pandemic that has severely damaged both public health and the economy. The nucleocapsid protein of SARS-CoV-2 is multifunctional and plays an important role in ribonucleocapsid formation and viral genome replication. In order to elucidate its functions, interaction partners of the SARS-CoV-2 N protein in human cells were identified via affinity purification and mass spectrometry. We identified 160 cellular proteins as interaction partners of the SARS-CoV-2 N protein in HEK293T and/or Calu-3 cells. Functional analysis revealed strong enrichment for ribosome biogenesis and RNA-associated processes, including ribonucleoprotein complex biogenesis, ribosomal large and small subunits biogenesis, RNA binding, catalysis, translation and transcription. Proteins related to virus defence responses, including MOV10, EIF2AK2, TRIM25, G3BP1, ZC3HAV1 and ZCCHC3 were also identified in the N protein interactome. This study comprehensively profiled the viral–host interactome of the SARS-CoV-2 N protein in human cells, and the findings provide the basis for further studies on the pathogenesis and antiviral strategies for this emerging infection.


Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1674
Author(s):  
Sunanda Baidya ◽  
Yoko Nishimoto ◽  
Seiichi Sato ◽  
Yasuhiro Shimada ◽  
Nozomi Sakurai ◽  
...  

The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. It has previously been reported that a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP), shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. Here, we show that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5′-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA, or lipopolysaccharide. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5′-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation.


Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1602
Author(s):  
Marina Plotnikova ◽  
Alexey Lozhkov ◽  
Ekaterina Romanovskaya-Romanko ◽  
Irina Baranovskaya ◽  
Mariia Sergeeva ◽  
...  

Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: ‘preventive’ (pretreatment); ‘preventive/therapeutic’ (pre/post); and ‘therapeutic’ (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the ‘preventive’ and ‘preventive/therapeutic’ regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.


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