RR:C19 Editorial: Immune Escape and Viral Evolution

Hepatitis C virus (HCV) has the propensity to cause chronic infection. Continuous immune escape has been proposed as a mechanism of intrahost viral evolution contributing to HCV persistence. Although the pronounced genetic diversity of intrahost HCV populations supports this hypothesis, recent observations of long-term persistence of individual HCV variants, negative selection increase, and complex dynamics of viral subpopulations during infection as well as broad cross-immunoreactivity (CR) among variants are inconsistent with the immune-escape hypothesis. Here, we present a mathematical model of intrahost viral population dynamics under the condition of a complex CR network (CRN) of viral variants and examine the contribution of CR to establishing persistent HCV infection. The model suggests a mechanism of viral adaptation by antigenic cooperation (AC), with immune responses against one variant protecting other variants. AC reduces the capacity of the host’s immune system to neutralize certain viral variants. CRN structure determines specific roles for each viral variant in host adaptation, with variants eliciting broad-CR antibodies facilitating persistence of other variants immunoreacting with these antibodies. The proposed mechanism is supported by empirical observations of intrahost HCV evolution. Interference with AC is a potential strategy for interruption and prevention of chronic HCV infection.

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Adaptation to host cell environment during experimental evolution of Zika virus

10.21203/rs.3.rs-492894/v1 ◽

2021 ◽

Author(s):

Vincent Grass ◽

Emilie Hardy ◽

Kassian Kobert ◽

Soheil Rastgou Talemi ◽

Elodie Décembre ◽

...

Keyword(s):

Host Cell ◽

Zika Virus ◽

Immune Escape ◽

Viral Evolution ◽

Time Lag ◽

Host Cells ◽

Host Responses ◽

Type I ◽

Zikv Infection ◽

Cellular Environment

Abstract Zika virus (ZIKV) infection can cause important developmental and neurological defects in Humans. Type I/III interferon responses control ZIKV infection and pathological processes, yet the virus has evolved various mechanisms to defeat these host responses. Here, we established a pipeline to delineate at high-resolution the genetic evolution of ZIKV in a controlled host cell environment. We uncovered that serially passaged ZIKV acquired increased infectivity and simultaneously developed a resistance to TLR3-induced restriction. We built a mathematical model that suggests that the increased infectivity is due to a reduced time-lag between infection and viral replication. We found that this adaptation is cell-type specific, suggesting that different cell environments may drive viral evolution along different routes. Deep-sequencing of ZIKV populations pinpointed mutations whose increased frequencies temporally coincide with the acquisition of the adapted phenotype. We functionally validated S455L, a substitution in ZIKV envelope (E) protein, recapitulating the adapted phenotype. Its positioning on the E structure suggests a putative function in protein refolding/stability. Taken together, our results uncovered ZIKV adaptations to the cellular environment leading to accelerated replication onset coupled with resistance to TLR3-induced antiviral response. Our work provides insights into Zika virus adaptation to host cells and immune escape mechanisms.

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ADCC-mediating non-neutralizing antibodies can exert immune pressure in early HIV-1 infection

PLoS Pathogens ◽

10.1371/journal.ppat.1010046 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1010046

Author(s):

Dieter Mielke ◽

Gama Bandawe ◽

Jie Zheng ◽

Jennifer Jones ◽

Melissa-Rose Abrahams ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Immune Escape ◽

Viral Evolution ◽

Neutralizing Antibody ◽

Protective Role ◽

Viral Escape ◽

Immune Pressure ◽

Control Virus ◽

Kinetics Of ◽

Hiv 1

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination.

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An overview of the ongoing challenges in SARS-CoV-2 global control

German Journal of Microbiology - Special Issue: Existence Battle: Viruses vs. Creatures ◽

10.51585/gjm.2021.2.0006 ◽

2021 ◽

Vol 1 (2) ◽

pp. 1-18

Author(s):

Awad A. Shehata1 ◽

Rokshana Parvin ◽

Abdou Nagy ◽

Ya Wang ◽

Turki Maher Azhar ◽

...

Keyword(s):

Public Health ◽

Side Effects ◽

Immune Escape ◽

Control Strategies ◽

Viral Evolution ◽

European Medicines Agency ◽

Gastrointestinal Microbiota ◽

Global Control ◽

Development Of Resistance ◽

Hygienic Measures

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has caused a severe global pandemic with major public health issues. Public health sectors implemented several control strategies, such as social distancing, hygienic measures, and the development of anti-viral drugs and vaccines. However, the situation is still critical due to several challenges facing the global control strategy. SARS-CoV-2 has undergone several mutations that will drive viral evolution, which might impact the virus’s transmissibility and pathogenicity and the immune escape and development of resistance to therapeutics. Moreover, although the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved several vaccines, however, some vaccines, especially vector-based vaccines, have rarely induced severe fatal side effects. These side effects led to widespread doubts about the safety of the coronavirus disease-19 (COVID-19) vaccines, which in turn dragged a certain proportion of the public from getting vaccinated. This review highlights some of the ongoing challenges in controlling the COVID-19 pandemic, including side effects of the developed vaccines, potential mechanisms for the development of thrombocytopenia, and the clinical impacts of the emerged SARS-CoV-2 variants on the pathogenesis of the virus and vaccine efficacy. Additionally, we discuss the comorbidity and the potential role of gastrointestinal microbiota in controlling SARS-CoV-2. Finally, we shed light on the substantial collateral health damage and unprecedented economic disaster caused by the lockdown.

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SARS-CoV-2 Entry Related Viral and Host Genetic Variations: Implications on COVID-19 Severity, Immune Escape, and Infectivity

International Journal of Molecular Sciences ◽

10.3390/ijms22063060 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3060

Author(s):

Szu-Wei Huang ◽

Sheng-Fan Wang

Keyword(s):

Genetic Variation ◽

Immune Escape ◽

Driving Forces ◽

Viral Evolution ◽

Genetic Variations ◽

Intercellular Adhesion Molecule ◽

Human Populations ◽

Host Proteins ◽

Risk Variants ◽

Geographical Regions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved to display particular patterns of genetic diversity in the genome across geographical regions. These variations in the virus and genetic variation in human populations can determine virus transmissibility and coronavirus disease 2019 (COVID-19) severity. Genetic variations and immune differences in human populations could be the driving forces in viral evolution. Recently emerged SARS-CoV-2 variants show several mutations at the receptor binding domain in the spike (S) glycoprotein and contribute to immune escape and enhanced binding with angiotensin 1-converting enzyme 2 (ACE2). Since ACE2 and transmembrane protease serine 2 (TMPRSS2) play important roles in SARS-CoV-2 entry into the cell, genetic variation in these host entry-related proteins may be a driving force for positive selection in the SARS-CoV-2 S glycoprotein. Dendritic or liver/lymph cell-specific intercellular adhesion molecule (ICAM)-3-grabbing non-integrin is also known to play vital roles in several pathogens. Genetic variations of these host proteins may affect the susceptibility to SARS-CoV-2. This review summarizes the latest research to describe the impacts of genetic variation in the viral S glycoprotein and critical host proteins and aims to provide better insights for understanding transmission and pathogenesis and more broadly for developing vaccine/antiviral drugs and precision medicine strategies, especially for high risk populations with genetic risk variants.

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Topology identifies emerging adaptive mutations in SARS-CoV-2

10.1101/2021.06.10.21258550 ◽

2021 ◽

Author(s):

Michael Bleher ◽

Lukas Hahn ◽

Juan Ángel Patiño-Galindo ◽

Mathieu Carrière ◽

Ulrich Bauer ◽

...

Keyword(s):

Immune Escape ◽

Early Stage ◽

Persistent Homology ◽

Viral Evolution ◽

Topological Data Analysis ◽

Adaptive Mutations ◽

Topological Measure ◽

Inference Techniques ◽

Early Occurrence ◽

New Mutations

The COVID-19 pandemic has lead to a worldwide effort to characterize its evolution through the mapping of mutations in the genome of the coronavirus SARS-CoV-2. As the virus spreads and evolves it acquires new mutations that could have important public health consequences, including higher transmissibility, morbidity, mortality, and immune evasion, among others. Ideally, we would like to quickly identify new mutations that could confer adaptive advantages to the evolving virus by leveraging the large number of SARS-CoV-2 genomes. One way of identifying adaptive mutations is by looking at convergent mutations, mutations in the same genomic position that occur independently. The large number of currently available genomes, more than a million at this moment, however precludes the efficient use of phylogeny-based techniques. Here, we establish a fast and scalable Topological Data Analysis approach for the early warning and surveillance of emerging adaptive mutations of the coronavirus SARS-CoV-2 in the ongoing COVID-19 pandemic. Our method relies on a novel topological tool for the analysis of viral genome datasets based on persistent homology. It systematically identifies convergent events in viral evolution merely by their topological footprint and thus overcomes limitations of current phylogenetic inference techniques. This allows for an unbiased and rapid analysis of large viral datasets. We introduce a new topological measure for convergent evolution and apply it to the complete GISAID dataset as of February 2021, comprising 303,651 high-quality SARS-CoV-2 isolates taken from patients all over the world since the beginning of the pandemic. A complete list of mutations showing topological signals of convergence is compiled. We find that topologically salient mutations on the receptor-binding domain appear in several variants of concern and are linked with an increase in infectivity and immune escape. Moreover, for many adaptive mutations the topological signal precedes an increase in prevalence. We demonstrate the capability of our method to effectively identify emerging adaptive mutations at an early stage. By localizing topological signals in the dataset, we are able to extract geo-temporal information about the early occurrence of emerging adaptive mutations. The identification of these mutations can help to develop an alert system to monitor mutations of concern and guide experimentalists to focus the study of specific circulating variants.

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Tracking genetic diversity of SARS-CoV-2 infections in Ghana after one year of surveillance

10.21203/rs.3.rs-1088719/v1 ◽

2021 ◽

Author(s):

Collins Morang'a ◽

Joyce Ngoi ◽

Jones Gyamfi ◽

Dominic Amuzu ◽

Benjamin Nuertey ◽

...

Keyword(s):

Immune Escape ◽

Temporal Dynamics ◽

Mutational Analysis ◽

Viral Evolution ◽

Novel Variants ◽

Community Transmission ◽

Spatio Temporal ◽

Alpha Variant ◽

One Year ◽

Second Wave

Abstract This study sequenced 1077 SARS-CoV-2 genomes from patient isolates (106 from arriving travellers and 971 from communities) to track the molecular evolution and spatio-temporal dynamics of the SARS-CoV-2 variants in Ghana. The data show that initial local transmission was dominated by B.1.1 lineages, but the second wave in Ghana was overwhelmingly driven by the Alpha variant, which was detected in community cases from January 2021, with Eta also contributing to reported cases. Subsequently, an unheralded variant under monitoring, B.1.1.318, dominated transmission from April to June 2021 before being displaced by Delta (B.1.1.617) and Delta Plus (AY.*) variants, which were introduced into community transmission in May 2021 and have remained dominant to date. Mutational analysis indicated that variants that took hold in Ghana harboured transmission enhancing and immune escape spike substitutions. The apparent rapid viral evolution observed demonstrate the potential for emergence of novel variants with greater mutational fitness.

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Increased Cytotoxic T-Lymphocyte Epitope Variant Cross-Recognition and Functional Avidity Are Associated with Hepatitis C Virus Clearance

Journal of Virology ◽

10.1128/jvi.02252-07 ◽

2008 ◽

Vol 82 (6) ◽

pp. 3147-3153 ◽

Cited By ~ 38

Author(s):

Daniel Yerly ◽

David Heckerman ◽

Todd M. Allen ◽

John V. Chisholm ◽

Kellie Faircloth ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Lymphocyte ◽

Immune Escape ◽

Cytotoxic T Lymphocyte ◽

Viral Evolution ◽

High Avidity ◽

Functional Avidity ◽

Ctl Responses

ABSTRACT Hepatitis C virus (HCV) clearance has been associated with reduced viral evolution in targeted cytotoxic T-lymphocyte (CTL) epitopes, suggesting that HCV clearers may mount CTL responses with a superior ability to recognize epitope variants and prevent viral immune escape. Here, 40 HCV-infected subjects were tested with 406 10-mer peptides covering the vast majority of the sequence diversity spanning a 197-residue region of the NS3 protein. HCV clearers mounted significantly broader CTL responses of higher functional avidity and with wider variant cross-recognition capacity than nonclearers. These observations have important implications for vaccine approaches that may need to induce high-avidity responses in vivo.

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Impact of Suboptimal APOBEC3G Neutralization on the Emergence of HIV Drug Resistance in Humanized Mice

Journal of Virology ◽

10.1128/jvi.01543-19 ◽

2019 ◽

Vol 94 (5) ◽

Cited By ~ 1

Author(s):

Matthew M. Hernandez ◽

Audrey Fahrny ◽

Anitha Jayaprakash ◽

Gustavo Gers-Huber ◽

Marsha Dillon-White ◽

...

Keyword(s):

Reverse Transcriptase ◽

Antiretroviral Treatment ◽

Immune Escape ◽

Viral Evolution ◽

Viral Fitness ◽

Humanized Mice ◽

Hiv Reverse Transcriptase ◽

Humanized Mouse Model ◽

Fitness Advantage ◽

Plasma Compartment

ABSTRACT HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized-mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, and HIV-ΔSLQ) that differ in their abilities to counteract APOBEC3G (A3G). Infected mice remained naive or were treated with the reverse transcriptase (RT) inhibitor lamivudine (3TC). Viremia, emergence of drug-resistant variants, and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time, HIV-45G replication was significantly reduced compared to that of HIV-WT in the absence of 3TC treatment. In contrast, treatment responses differed significantly between HIV-45G- and HIV-WT-infected mice. Antiretroviral treatment failed in 91% of HIV-45G-infected mice, while only 36% of HIV-WT-infected mice displayed a similar negative outcome. Emergence of 3TC-resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase gene (RT) and 6,985 vif sequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all the animals. Upon treatment, the composition of the plasma quasispecies rapidly changed, leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G-infected animals, but not in HIV-WT-infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but displayed a fitness advantage in the presence of antiretroviral treatment. IMPORTANCE Both viral (e.g., RT) and host (e.g., A3G) factors can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment in humanized mice.

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