replication fitness
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Author(s):  
Nigeer Te ◽  
Jordi Rodon ◽  
Mónica Pérez ◽  
Joaquim Segalés ◽  
Júlia Vergara-Alert ◽  
...  

2021 ◽  
Author(s):  
Marlena Stadtmueller ◽  
Alexa Laubner ◽  
Fabian Rost ◽  
Sylke Winkler ◽  
Eva Patrasova ◽  
...  

SARS-CoV-2 evolution plays a significant role in shaping the dynamics of the COVD-19 pandemic. To monitor the evolution of SARS-CoV-2 variants, through international collaborations, we performed genomic epidemiology analyses on a weekly basis with SARS-CoV-2 samples collected from a border region between Germany, Poland and the Czech Republic in a global background. For identified virus mutant variants, active viruses were isolated and functional evaluations were performed to test their replication fitness and neutralization sensitivity against vaccine elicited serum neutralizing antibodies. Thereby we identified a new B.1.1.7 sub-lineage carrying additional mutations of nucleoprotein G204P and open-reading-frame-8 K68stop. Of note, this B.1.1.7 sub-lineage is the predominant B.1.1.7 variant in several European countries, such as Czech Republic, Austria and Slovakia. The earliest samples belonging to this sub-lineage were detected in November 2020 in a few countries in the European continent, but not in the UK. We have also detected its further evolution with extra spike mutations D138Y and A701V, which are signature mutations shared with the Beta and Gamma variants, respectively. Antibody neutralization assay of virus variant isolations has revealed that the variant with extra spike mutations is 3.2-fold less sensitive to vaccine-elicited antibodies as compared to other B.1.1.7 variants tested, indicating potential for immune evasion, but it also exhibited reduced replication fitness. The wide spread of this B.1.1.7 sub-lineage was related to the pandemic waves in early 2021 in various European countries. These findings about the emergence, spread, evolution, infection and transmission abilities of this B.1.1.7 sub-lineage add to our understanding about the pandemic development in Europe, and could possibly help to prevent similar scenarios in future.


2021 ◽  
Author(s):  
Bryan A Johnson ◽  
Yiyang Zhou ◽  
Kumari G Lokugamage ◽  
Michelle N Vu ◽  
Nathen E Bopp ◽  
...  

While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in SARS-CoV-2 nucleocapsid protein. Recreating the alpha variant mutation in an early pandemic (WA-1) background, we found that the R203K-G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. Importantly, the R203K-G204R mutation increases nucleocapsid phosphorylation, providing a molecular basis for these phenotypes. Notably, an analogous alanine substitution mutant also increases SARS-CoV-2 fitness and phosphorylation, suggesting that infection is enhanced through ablation of the ancestral RG motif. Overall, these results demonstrate that variant mutations outside spike are also key components in SARS-CoV-2 continued adaptation to human infection.


2021 ◽  
Author(s):  
Rajesh Thippeshappa ◽  
Patricia Polacino ◽  
Shaswath S Chandrasekar ◽  
Khanghy Truong ◽  
Anisha Misra ◽  
...  

We previously reported that a human immunodeficiency virus type 1 with a simian immunodeficiency virus vif substitution (HSIV-vif-NL4-3) could replicate in pigtailed macaques (PTMs), demonstrating that Vif is a species-specific tropism factor of primate lentiviruses. However, infections did not result in high peak viremia or setpoint plasma viral loads, as observed during SIV infection of PTMs. Here, we characterized variants isolated from one of the original infected animals with CD4 depletion after nearly four years of infection to identify determinants of increased replication fitness. In our studies, we found that the HSIV-vif clones did not express the HIV-1 Vpr protein due to interference from the vpx open reading frame in singly spliced vpr mRNA. To examine whether these viral genes contribute to persistent viral replication, we generated infectious HSIV-vif clones expressing either the HIV-1 Vpr or SIV Vpx protein. And then to determine viral fitness determinants of HSIV-vif, we conducted three rounds of serial in vivo passaging in PTMs, starting with an initial inoculum containing a mixture of CXCR4-tropic (Vpr- HSIV-vif-NL4-3 isolated at 196 (C/196) and 200 (C/200) weeks post-infection from a PTM with depressed CD4 counts) and CCR5-tropic HSIV (Vpr+ HSIV-vif derivatives based NL-AD8 and Bru-Yu2 and a Vpx expressing HSIV-vif-Yu2). Interestingly, all infected PTMs showed peak plasma viremia close to or above 105 copies/ml and persistent viral replication for more than 20 weeks. The passage 3 PTM showed peak viral loads greater than 105 viral RNA copies/ml. Infectious molecular clones (IMCs) recovered from the passage 3 PTM (HSIV-P3 IMCs) included mutations required for HIV-1 Vpr expression and those mutations encoded by the CXCR4-tropic HSIV-vifNL4-3 isolates C/196 and C/200. The data indicate that the biological isolates selected during long-term infection acquired HIV-1 Vpr expression to enhance their replication fitness in PTMs. Further passaging of HSIV-P3 IMCs in vivo may generate pathogenic variants with higher replication capacity, which will be a valuable resource as challenge virus in vaccine and cure studies.


2021 ◽  
Author(s):  
Prashant Ranjan ◽  
Neha ◽  
Chandra Devi ◽  
Garima Jain ◽  
Chandana Basu Mallick ◽  
...  

Abstract The existing panels of COVID-19 vaccines are based on the spike protein of earlier SARS-CoV-2 strain that emerged in Wuhan, China. However, the evolving nature of SARS-CoV-2 has resulted in emergence of new variants, thereby, posing a greater challenge in the management of the disease. India faced a deadlier second wave of infections very recently and genomic surveillance revealed that B.1.617 variant and its sub lineages are responsible for majority of the cases. These are highly infectious and possibly more lethal and therefore labelled as variants of concern by WHO. Hence, it’s crucial to determine if the current vaccines available can be effective against these variants. To address this, we performed molecular dynamics (MD) simulation on B.1.617 along with K417G variants and other RBD variants. We studied structural alteration of the spike protein and factors affecting antibody neutralization and immune escape. We found in seven of the 12 variants studied, there was a structural alteration in RBD region further affecting its stability and function. Docking analysis of RBD variants and wild type strain demonstrated increase in binding affinity with ACE2 (angiotensin 2 altered enzymes) receptor in these variants. Molecular interaction with CR3022 antibody revealed that binding affinity was less in comparison to wild type, with B.1.617 showing the least binding affinity. These findings from the extensive simulations provides novel mechanistic insights on the conformational dynamics and improves our understanding of the enhanced properties of these variants in terms of infectivity, transmissibility, neutralization potential, virulence and host-viral replication fitness.


2021 ◽  
Author(s):  
Jieshi Yu ◽  
Chen Huang ◽  
Zizhang Sheng ◽  
Zhao Wang ◽  
Feng Li ◽  
...  

The newly identified influenza D virus (IDV) of the Orthomyxoviridae family has a wide host range with broad geographical distribution. Despite the first appearance in U.S. pig herds in 2011, subsequent studies demonstrate that IDV is widespread in global cattle populations, supporting a theory that IDV utilizes bovines as a primary reservoir. Our investigation of the two reference influenza D viruses, D/swine/Oklahoma/1334/2011 (OK/11) isolated from swine and D/Bovine/Oklahoma/660/2013 (660/13) from cattle, revealed that 660/13 replicated to titers approximately 100-fold higher than those for OK/11 in multiple cell lines. By using a recently developed IDV reverse genetics system derived from low-titer OK/11, we generated recombinant chimeric OK/11 viruses in that one of the seven genome segments was replaced with its counterpart from high-titer 660/13 virus. Further characterization demonstrated that the replication level of the chimeric OK/11 virus was significantly increased only when harboring the 660/13 nucleoprotein (NP) segment. Finally, through both gain-of-function and loss-of-function experiments, we identified that one amino acid residue at position 381, located in the body domain of NP protein, was a key determinant for the replication difference between the low-titer OK/11 virus and the high-titer 660/13 virus. Taken together, our findings provide important insight into IDV replication fitness mediated by the NP protein, which should facilitate future study of infectious virus particle production mechanism of IDV. IMPORTANCE Little is known about virus infection and production mechanism for newly discovered influenza D virus (IDV) that utilizes bovines as a primary reservoir with frequent spillover to new hosts including swine. In this study, we showed that two well-characterized IDVs, 660/13 replicated more efficiently (approximately 100-fold higher) than OK/11. Using a recently developed IDV reverse genetics system, we identified viral nucleoprotein (NP) as a primary determinant of the different replication capacity observed between these two nearly identical viruses. Mechanistic investigation further revealed that a mutation at NP position 381 evidently modulated virus fitness. Taken together, these observations indicate that IDV NP protein performs a critical role in infectious virus particle production. Our study thus illustrates a NP-based mechanism for efficient IDV infection and production in vitro .


2021 ◽  
Author(s):  
Guido Papa ◽  
Janine Vetter ◽  
Michael Seyffert ◽  
Kapila Gunasekera ◽  
Giuditta De Lorenzo ◽  
...  

The rotavirus (RV) VP4 spike protrudes as a trimeric structure from the five-fold axes of the virion triple-layer. Infectious RV particles need to be proteolytically cleaved in VP4 into two subunits, VP8* and VP5*, constituting both the distal part and central body of the virus spike. Modification of VP4 has been challenging as it is involved in biological processes such as the interaction with sialic acid and integrins, cell tropism and hemagglutinin activity. Using RV reverse genetics, four loops in the lectin domain of the VP8* subunit were engineered independently to harbor a small biotin acceptor peptide (BAP) tag and then tested for their ability to rescue virus. Only a single recombinant virus, rRV/VP4-BAP, harboring VP4 with a modified loop at position K145-G150 was rescued. This rRV/VP4-BAP internalizes, replicates, and generates virus progeny, demonstrating that the VP4 spike of RV particles can be genetically manipulated by the incorporation of at least 15 exogenous amino acids. VP4-BAP had a similar distribution as VP4 in infected cells by localizing in the cytoskeleton and surrounding viroplasms. However, compared to wild-type RV, rRV/VP4-BAP featured a reduced replication fitness and impaired viroplasm stability. Upon treatment with 1,6-hexanediol, a drug disrupting liquid-liquid phase-separated condensates, the kinetic of rRV/VP4-BAP viroplasm recovery was delayed, and their size and numbers reduced when compared to viroplasms of wild type RV. Moreover, siRNA silencing of VP4 expression in RV strain SA11 showed similar recovery patterns as rRV/VP4-BAP, revealing a novel function of VP4 in viroplasm stability.


2021 ◽  
Author(s):  
Sushant Bhat ◽  
Joe James ◽  
Jean-Remy Sadeyen ◽  
Sahar Mahmood ◽  
Holly J Everest ◽  
...  

SUMMARYAn H7N9 low pathogenicity avian influenza virus (LPAIV) emerged through genetic reassortment between H9N2 and other LPAIVs circulating in birds in China. This virus causes inapparent clinical disease in chickens, but zoonotic transmission results in severe and fatal disease in humans. We evaluated the consequences of reassortment between the H7N9 and the contemporary H9N2 viruses of G1 lineage that are enzootic in poultry across the Indian sub-continent and the Middle East. Co-infection of chickens with these viruses resulted in emergence of novel reassortant H9N9 viruses carrying genes derived from both H9N2 and H7N9 viruses. These reassortant H9N9 viruses showed significantly increased replication fitness, enhanced pathogenicity in chicken embryos and the potential to transmit via contact among ferrets. Our study highlights that the co-circulation of H7N9 and H9N2 viruses could represent a threat for the generation of novel reassortant viruses with greater virulence in poultry and an increased zoonotic potential. Graphical AbstractIn BriefH9N2 viruses have a high propensity to reassort with other avian influenza viruses. We found that co-infection of chickens with H9N2 and H7N9 led to the emergence of reassortant viruses including the H9N9 subtype. Some reassortant H9N9 viruses exhibited increased replication fitness, increased pathogenicity in the chicken embryo, greater avidity for human and avian cell receptors, lower pH fusion and contact-transmission to ferrets. This study demonstrated the ability of viruses that already exist in nature to exchange genetic material, highlighting the potential emergence of viruses from these subtypes with increased zoonotic potential. There are nine H9 influenza A subtypes carrying different neuraminidase (NA) genes, including H9N9 viruses, while they are not common they do exist in nature as wildtypes (CDC).HighlightsCo-infection of chickens with H7N9 and H9N2 led to emergence of reassortant H9N9 virusesReassortant H9N9 viruses had an increased replication rate in avian and human cellsReassortant H9N9 viruses had a lower pH fusion and significantly higher receptor binding to α 2,3 sialoglycansReassortant H9N9 replicated in ferrets at similar levels compared to H7N9 and transmitted via direct contactFerrets exposed to reassortant H9N9 by aerosol contact were also found to be seropositiveExperimental simulation of events that may occur naturally with circulating viruses has demonstrated the risk of emergence of viruses with increased zoonotic potential.


2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Kathleen D. Engelman ◽  
Alan N. Engelman
Keyword(s):  

2020 ◽  
Author(s):  
Katja Klein ◽  
Immaculate Nankya ◽  
Gabrielle Nickel ◽  
Annette N. Ratcliff ◽  
Adam A.J. Meadows ◽  
...  

Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multi-virus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue while Envacute viruses penetrated the human tissue and established infection of CD4+ T cells more efficiently. Analysis of the replication fitness, as tested in peripheral blood mononuclear cells (PBMCs), showed similar replication fitness of Envacute and Envchronic viruses, which did not correlate with transmission fitness in penile tissue. Further, we observed that chimeric env viruses with higher replication in genital mucosal tissue (chronic Env viruses) had higher binding affinity to C-type lectins. Data presented herein suggests that the inoculating HIV-1 may be sequestered in the genital mucosal tissue (represented by chronic Env HIV-1) but that a single HIV-1 clone (e.g. acute Env HIV-1) can escape this trapped replication for systemic infection. Importance During heterosexual HIV-1 transmission, a genetic bottleneck occurs in the newly infected individual as the virus passes from the mucosa and leading to systemic infection of a single transmitted HIV-1 clone in the recipient. This bottleneck in the recipient has just been described and the mechanisms involved in this selection process have not been elucidated. However, understanding mucosal restriction is of the utmost importance to understanding dynamics of infections and to now design focused vaccines. Using our human penile and cervical mucosal tissue models for mixed HIV infections, we provide evidence that HIV-1 from acute/early as compared to chronic infection can more efficiently traverse the mucosal epithelium and transmitted to T cells, suggesting higher transmission fitness. These studies focused on the role of the HIV-1 envelope in transmission and provides strong evidence that HIV transmission may involve breaking the mucosal lectin trap.


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