molecular virology
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2022 ◽  
Vol 103 (1) ◽  
Author(s):  
William N. D. Gao ◽  
Chen Gao ◽  
Janet E. Deane ◽  
David C. J. Carpentier ◽  
Geoffrey L. Smith ◽  
...  

The morphogenesis of vaccinia virus (VACV, family Poxviridae), the smallpox vaccine, is a complex process involving multiple distinct cellular membranes and resulting in multiple different forms of infectious virion. Efficient release of enveloped virions, which promote systemic spread of infection within hosts, requires the VACV protein E2 but the molecular basis of E2 function remains unclear and E2 lacks sequence homology to any well-characterised family of proteins. We solved the crystal structure of VACV E2 to 2.3 Å resolution, revealing that it comprises two domains with novel folds: an N-terminal annular (ring) domain and a C-terminal globular (head) domain. The C-terminal head domain displays weak structural homology with cellular (pseudo)kinases but lacks conserved surface residues or kinase features, suggesting that it is not enzymatically active, and possesses a large surface basic patch that might interact with phosphoinositide lipid headgroups. Recent deep learning methods have revolutionised our ability to predict the three-dimensional structures of proteins from primary sequence alone. VACV E2 is an exemplar ‘difficult’ viral protein target for structure prediction, being comprised of multiple novel domains and lacking sequence homologues outside Poxviridae. AlphaFold2 nonetheless succeeds in predicting the structures of the head and ring domains with high and moderate accuracy, respectively, allowing accurate inference of multiple structural properties. The advent of highly accurate virus structure prediction marks a step-change in structural virology and beckons a new era of structurally-informed molecular virology.


2022 ◽  
Author(s):  
Guiqing Hu ◽  
Mark A Silveria ◽  
Michael S Chapman ◽  
Scott M Stagg

Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV's molecular virology is needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near universal entry receptor, AAVR, and structures by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N-termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors. IMPORTANCE: With 150 clinical trials for 30 diseases underway, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction, has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains.


mBio ◽  
2021 ◽  
Vol 12 (5) ◽  
Author(s):  
David R. Franz ◽  
James W. Le Duc

The human and economic toll of the coronavirus disease 2019 (COVID-19) pandemic and the unknowns regarding the origins of the virus, with a backdrop of enormous advances in technologies and human understanding of molecular virology, have raised global concerns about the safety of the legitimate infectious disease research enterprise. We acknowledge the safety and security risks resulting from the broad availability of tools and knowledge, tools and knowledge that can be exploited equally for good or harm.


2021 ◽  
Author(s):  
William ND Gao ◽  
Chen Gao ◽  
Janet E Deane ◽  
David C.J. Carpentier ◽  
Geoffrey L. Smith ◽  
...  

The morphogenesis of vaccinia virus (VACV, family Poxviridae), the smallpox vaccine, is a complex process involving multiple distinct cellular membranes and resulting in multiple different forms of infectious virion. Efficient release of enveloped virions, which promote systemic spread of infection within hosts, requires the VACV protein E2 but the molecular basis of E2 function remains unclear and E2 lacks sequence homology to any well-characterised family of proteins. We solved the crystal structure of VACV E2 to 2.3 Å resolution, revealing that it comprises two domains with novel folds: an N-terminal annular (ring) domain and a C-terminal head domain. The C-terminal head domain displays weak structural homology with cellular (pseudo)kinases but lacks conserved surface residues or kinase features, suggesting that it is not enzymatically active, and possesses a large surface basic patch that might interact with phosphoinositide lipid headgroups. Recent deep learning methods have revolutionised our ability to predict the three-dimensional structures of proteins from primary sequence alone. VACV E2 is an exemplar 'difficult' viral protein target for structure prediction, being comprised of multiple novel domains and lacking sequence homologues outside Poxviridae. AlphaFold2 nonetheless succeeds in predicting the structures of the head and ring domains with high and moderate accuracy, respectively, allowing accurate inference of multiple structural properties. The advent of highly accurate virus structure prediction marks a step-change in structural virology and beckons a new era of structurally-informed molecular virology.


2021 ◽  
Vol 23 (08) ◽  
pp. 352-365
Author(s):  
Vyas Sonal ◽  
◽  
Kaur Jasmine ◽  
Pahari Pratyay Kumar ◽  
Nain Parminder ◽  
...  

After past episodes of Zika, Nipah and Ebola viruses and also previous emergencies due to other viruses like swine flu and bird flu viruses, now in 21st century global disaster caused by nCoV virus. As the virus is still investigated for proper identification, there are very less option in choosing the proper detection method. So we have reviewed various article for giving an idea about pathogenesis and diagnostic methods. We had screened Google Scholar database with the keywords nCoV pathogenesis, molecular immune pathogenesis of COVID-19, virology of SARS-CoV-2, diagnosis of SARS-CoV-2 and advancement of nCoV diagnosis. In the final review we have included a total of 84 articles. As a result we have reviewed the molecular virology along with molecular pathogenesis of COVID-19 in human body. We have found various ongoing researches on detection of nCoV related to nucleic acid amplification test, different types of RT-qPCR, serological assay and different HRCT methods.


2021 ◽  
Vol 118 (32) ◽  
pp. e2101675118
Author(s):  
Cora N. Betsinger ◽  
Connor S.R. Jankowski ◽  
William A. Hofstadter ◽  
Joel D. Federspiel ◽  
Clayton J. Otter ◽  
...  

Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.


Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1512
Author(s):  
Nancy Palmerin ◽  
Farizeh Aalam ◽  
Romina Nabiee ◽  
Murali Muniraju ◽  
Javier Gordon Ogembo ◽  
...  

Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of multiple cancers in immunocompromised patients including two lymphoproliferative disorders associated with KSHV infection of B lymphocytes. Despite many years of research into the pathogenesis of KSHV associated diseases, basic questions related to KSHV molecular virology remain unresolved. One such unresolved question is the cellular receptors and viral glycoproteins needed for KSHV entry into primary B lymphocytes. In this study, we assess the contributions of KSHV glycoprotein H (gH) and the cellular receptor DC-SIGN to KSHV infection in tonsil-derived B lymphocytes. Our results show that (1) neither KSHV-gH nor DC-SIGN are essential for entry into any B cell subset, (2) DC-SIGN does play a role in KSHV entry into tonsil-derived B cells, but in all B cell subtypes alternative entry mechanisms exist, (3) KSHV-gH can participate in KSHV entry into centrocytes via a DC-SIGN independent entry mechanism, and (4) in the absence of KSHV-gH, DC-SIGN is required for KSHV entry into centrocytes. Our results provide a first glimpse into the complexity of KSHV entry in the lymphocyte compartment and highlight that multiple subset-dependent entry mechanisms are employed by KSHV which depend upon multiple cellular receptors and multiple KSHV glycoproteins.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zacharie Saint-Georges ◽  
Omar Dewidar

Dr. Marc-André Langlois, a cutting-edge virologist, Canada Research Chair in Molecular Virology and Intrinsic Immunity, and Professor in the Department of Biochemistry, Microbiology and Immunology at the University of Ottawa, received 1 million dollars in Canadian Institutes of Health Research (CIHR) funding to develop a nasal spray COVID-19 vaccine. We had the privilege of meeting with him virtually and having a fascinating and informative conversation on the COVID-19 pandemic, vaccines, and its effect on society.


2021 ◽  
Author(s):  
Andrea K. Thoma-Kress ◽  
Ronald C. Desrosiers ◽  
Michaela U. Gack ◽  
Jae U. Jung ◽  
Klaus Überla ◽  
...  

Bernhard Fleckenstein, Professor Emeritus and former Chair of the Institute of Clinical and Molecular Virology at the Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany, passed away on May 4 th , 2021.…


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