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All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Within-Host Phenotypic Evolution and the Population-Level Control of Chronic Viral Infections by Treatment and Prophylaxis

Chronic viral infections can persist for decades spanning thousands of viral generations, leading to a highly diverse population of viruses with its own complex evolutionary history. We propose an expandable mathematical framework for understanding how the emergence of genetic and phenotypic diversity affects the population-level control of those infections by both non-curative treatment and chemo-prophylactic measures. Our frameworks allows both neutral and phenotypic evolution, and we consider the specific evolution of contagiousness, resistance to therapy, and efficacy of prophylaxis. We compute both the controlled and uncontrolled, population-level basic reproduction number accounting for the within-host evolutionary process where new phenotypes emerge and are lost in infected persons, which we also extend to include both treatment and prophylactic control efforts. We used these results to discuss the conditions under which the relative efficacy of prophylactic versus therapeutic methods of control are superior. Finally, we give expressions for the endemic equilibrium of these models for certain constrained versions of the within-host evolutionary model providing a potential method for estimating within-host evolutionary parameters from population-level genetic sequence data.

sensitivity analysis↗
DOE OSTI2023

Lower viral evolutionary pressure under stable versus fluctuating conditions in subzero Arctic brines

Climate change threatens Earth’s ice-based ecosystems which currently offer archives and eco-evolutionary experiments in the extreme. Arctic cryopeg brine (marine-derived, within permafrost) and sea ice brine, similar in subzero temperature and high salinity but different in temporal stability, are inhabited by microbes adapted to these extreme conditions. However, little is known about their viruses (community composition, diversity, interaction with hosts, or evolution) or how they might respond to geologically stable cryopeg versus fluctuating sea ice conditions. We used long- and short-read viromics and metatranscriptomics to study viruses in Arctic cryopeg brine, sea ice brine, and underlying seawater, recovering 11,088 vOTUs (~species-level taxonomic unit), a 4.4-fold increase of known viruses in these brines. More specifically, the long-read-powered viromes doubled the number of longer (≥25 kb) vOTUs generated and recovered more hypervariable regions by >5-fold compared to short-read viromes. Distribution assessment, by comparing to known viruses in public databases, supported that cryopeg brine viruses were of marine origin yet distinct from either sea ice brine or seawater viruses, while 94% of sea ice brine viruses were also present in seawater. A virus-encoded, ecologically important exopolysaccharide biosynthesis gene was identified, and many viruses (~half of metatranscriptome-inferred “active” vOTUs) were predicted as actively infecting the dominant microbial genera Marinobacter and Polaribacter in cryopeg and sea ice brines, respectively. Evolutionarily, microdiversity (intra-species genetic variations) analyses suggested that viruses within the stable cryopeg brine were under significantly lower evolutionary pressures than those in the fluctuating sea ice environment, while many sea ice brine virus-tail genes were under positive selection, indicating virus-host co-evolutionary arms races. Our results confirmed the benefits of long-read-powered viromics in understanding the environmental virosphere through significantly improved genomic recovery, expanding viral discovery and the potential for biological inference. Evidence of viruses actively infecting the dominant microbes in subzero brines and modulating host metabolism underscored the potential impact of viruses on these remote and underexplored extreme ecosystems. Microdiversity results shed light on different strategies viruses use to evolve and adapt when extreme conditions are stable versus fluctuating. Together, these findings verify the value of long-read-powered viromics and provide foundational data on viral evolution and virus-microbe interactions in Earth’s destabilized and rapidly disappearing cryosphere.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Quantitative stable isotope probing (qSIP)-informed metagenomics identifies viruses infecting chemoautotrophs

Aquatic environments absorb ~2.5 gigatonnes of atmospheric carbon each year1, more than the carbon stored in the atmosphere, soils, and all biomass combined. Primary producers transform this dissolved inorganic carbon into biomass that can subsequently flow into other trophic levels, or be released back into the environment through viral lysis. While there is substantial knowledge about the diversity and activity of viruses infecting photoautotrophic primary producers and the ecosystem impact, little is known about viruses infecting chemoautotrophs, representing a gap in our understanding of key processes driving microbial carbon cycling. Here, we combine metagenomics with quantitative 12/13C stable isotopic probing (qSIP) mesocosm experiments in a marine-derived meromictic pond to quantify population-specific isotopic enrichment, identify key chemoautotrophic primary producers, and virus-host dynamics. Isotopically enriched carbon is tracked from the genomes of chemoautotrophs to putative viruses, showing that active populations of hydrogen/sulfur-oxidizing chemoautotrophs (Thiomicrorhabdus, Hydrogenovibrio, Sulfurimonas, Sulfurovum) are targeted by viruses. This work provides the foundation for revealing the diversity and activity of viruses infecting globally-widespread chemoautotrophs. Our study sheds light on trophic interactions that impact microbial carbon cycling in aphotic environments and builds toward biogeochemical models that incorporate viral impacts on chemoautotrophic microbial communities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Viromics approaches for the study of viral diversity and ecology in microbiomes

Viruses are found across all ecosystems and infect every type of organism on Earth. Traditional culture-based methods have proven insufficient to explore this viral diversity at scale, driving the development of viromics, the sequence-based analysis of uncultivated viruses. Viromics approaches have been particularly useful for studying viruses of microorganisms, which can act as crucial regulators of microbiomes across ecosystems. They have already revealed the broad geographic distribution of viral communities and are progressively uncovering the expansive genetic and functional diversity of the global virome. Moving forward, large-scale viral ecogenomics studies combined with new experimental and computational approaches to identify virus activity and host interactions will enable a more complete characterization of global viral diversity and its effects.

Ecology↗
DOE OSTI2023

Giant Virus Infection Signatures Are Modulated by Euphotic Zone Depth Strata and Iron Regimes of the Subantarctic Southern Ocean

Viruses can alter the abundance, evolution, and metabolism of microorganisms in the ocean, playing a key role in water column biogeochemistry and global carbon cycles. Large efforts to measure the contribution of eukaryotic microorganisms (e.g., protists) to the marine food web have been made, yet the in situ activities of the ecologically relevant viruses that infect these organisms are not well characterized. Viruses within the phylum Nucleocytoviricota (“giant viruses”) are known to infect a diverse range of ecologically relevant marine protists, yet how these viruses are influenced by environmental conditions remains under-characterized. By employing metatranscriptomic analyses of in situ microbial communities along a temporal and depthresolved gradient, we describe the diversity of giant viruses at the Southern Ocean Time Series (SOTS), a site within the subpolar Southern Ocean. Using a phylogeny-guided taxonomic assessment of detected giant virus genomes and metagenome-assembled genomes, we observed depth-dependent structuring of divergent giant virus families mirroring dynamic physicochemical gradients in the stratified euphotic zone. Analyses of transcribed metabolic genes from giant viruses suggest viral metabolic reprogramming of hosts from the surface to a 200-m depth. Lastly, using on-deck incubations reflecting a gradient of iron availability, we show that modulating iron regimes influences the activity of giant viruses in the field. Specifically, we show enhanced infection signatures of giant viruses under both iron-replete and iron-limited conditions. Collectively, these results expand our understanding of how the water column’s vertical biogeography and chemical surroundings affect an important group of viruses within the Southern Ocean

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Computationally Selected Multivalent HIV-1 Subtype C Vaccine Protects Against Heterologous SHIV Challenge

Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy trial to date to demonstrate any efficacy. Genetic signatures suggested that antibodies targeting the variable loop 2 (V2) of the HIV-1 envelope played an important protective role. The ALVAC prime and protein boost follow-up trial in southern Africa (HVTN702) failed to show any efficacy. One hypothesis for this is the greater diversity of subtype C viruses in southern Africa relative to CRF01_AE in Thailand. Methods: Here, we determined whether an ALVAC prime with computationally selected gp120 boost immunogens maximizing coverage of diversity of subtype C viruses in the variable V1 and V2 regions (V1V2) improved the protection of non-human primates (NHPs) from a heterologous subtype C SHIV challenge compared to more traditional regimens. Results: An ALVAC prime with Trivalent subtype C gp120 boosts resulted in statistically significant protection from repeated intrarectal SHIV challenges compared to the control. Evaluation of the immunogenicity of each vaccine regimen at the time of challenge demonstrated that different gp120 combination boosts elicited similar high magnitudes of gp120 and breadth of V1V2-binding antibodies, as well as strong Fc-mediated immune responses. Low-to-no neutralization of the challenge virus was detected. A Cox proportional hazard analysis of five pre-selected immune parameters at the time of challenge identified ADCC against the challenge envelope as a correlate of protection. Systems serology analysis revealed that immune responses elicited by the different vaccine regimens were distinct and identified further correlates of resistance to infection. Conclusions: Computationally designed vaccines with maximized subtype C V1V2 coverage mediated protection of NHPs from a heterologous Tier-2 subtype C SHIV challenge.

Immunology↗
DOE OSTI2026

Cryo-EM visualization of viruses from partially irrigated soils

Viruses are numerically the most abundant forms on Earth, and most are present in soil. Even though viruses are highly abundant in soil and critical to rhizosphere function, visualizing the diverse morphotypes within soil has been challenging. The difficulty is primarily due to the heterogenous nature of isolated suspensions that typically contain nanometer to micron scale debris which renders protein crystallography for structural studies unfeasible and hinders cryo-electron microscopy due to ice thickness and contrast issues. Here we employed and compared a simple spin filtration method to cleanup solutions of extracted viruses for direct observation with cryo-electron microscopy. The method employs common physical biochemical separation steps to remove large and small debris which dramatically improves image quality and preservation of structural features to permit visualizing morphotypes not typically seen with conventional negative stain approaches. In addition to tailed and non-tailed polyhedral phages, several under reported or novel morphotypes of soil viruses are directly visualized as a particle library with both 2D and 3D information.

cryo-EM↗
DOE OSTI2023

A novel candidate hepatitis C virus genotype 4 subtype identified by next generation sequencing full-genome characterization in a patient from Saudi Arabia

Background and aim: Hepatitis C virus (HCV) infection is a major global public health concern, being a leading cause of chronic liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The virus is classified into 8 genotypes and 93 subtypes, each displaying distinct geographic distributions. Genotype 4 is the most predominant in the Middle East and Eastern Mediterranean and is associated with high rates of hepatitis C infection worldwide. This study used next-generation sequencing to fully characterize the HCV genome and identify a novel subtype within genotype 4 isolated from a 64-year-old Saudi man diagnosed with hepatitis C. Methods: We analyzed the complete genome of the 141-HCV isolate using whole-genome sequencing. Results: Our phylogenetic reconstructions, based on the entire genome of HCV-4 strains, revealed that the 141-HCV isolate formed a distinct group within the genotype 4 classification, providing valuable new insights into the variability of HCV. Conclusion: This discovery of a previously unclassified HCV subtype within genotype 4 sheds light on the ongoing evolution and diversity of the virus. Such knowledge has significant implications for diagnostic and therapeutic approaches, as different subtypes may exhibit varying drug sensitivities and resistance profiles.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Soil viral diversity, ecology and climate change

Soil viruses are highly abundant and have important roles in the regulation of host dynamics and soil ecology. Climate change is resulting in unprecedented changes to soil ecosystems and the life forms that reside there, including viruses. In this Review, we explore our current understanding of soil viral diversity and ecology, and we discuss how climate change (such as extended and extreme drought events or more flooding and altered precipitation patterns) is influencing soil viruses. Finally, here, we provide our perspective on future research needs to better understand how climate change will impact soil viral ecology.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat

The N-heptad repeat (NHR) of the HIV-1 gp41 prehairpin intermediate (PHI) is an attractive potential vaccine target with high sequence conservation across diverse strains. However, despite the potency of NHR-targeting peptides and clinical efficacy of the NHR-targeting entry inhibitor enfuvirtide, no potently neutralizing NHR-directed monoclonal antibodies (mAbs) nor antisera have been identified or elicited to date. The lack of potent NHR-binding mAbs both dampens enthusiasm for vaccine development efforts at this target and presents a barrier to performing passive immunization experiments with NHR-targeting antibodies. To address this challenge, we previously developed an improved variant of the NHR-directed mAb D5, called D5_AR, which is capable of neutralizing diverse tier-2 viruses. Building on that work, here we present the 2.7Å-crystal structure of D5_AR bound to NHR mimetic peptide IQN17. We then utilize protein language models and supervised machine learning to generate small (n < 100) libraries of D5_AR variants that are subsequently screened for improved neutralization potency. We identify a variant with 5-fold improved neutralization potency, D5_FI, which is the most potent NHR-directed monoclonal antibody characterized to date and exhibits broad neutralization of tier-2 and −3 pseudoviruses as well as replicating R5 and X4 challenge strains. Additionally, our work highlights the ability of protein language models to efficiently identify improved mAb variants from relatively small libraries.

Biopolymers↗
DOE OSTI2024

The protein structurome of Orthornavirae and its dark matter

Metatranscriptomics is uncovering more and more diverse families of viruses with RNA genomes comprising the viral kingdom Orthornavirae in the realm Riboviria. Thorough protein annotation and comparison are essential to get insights into the functions of viral proteins and virus evolution. In addition to sequence- and hmm profile-based methods, protein structure comparison adds a powerful tool to uncover protein functions and relationships. We constructed an Orthornavirae “structurome” consisting of already annotated as well as unannotated (“dark matter”) proteins and domains encoded in viral genomes. We used protein structure modeling and similarity searches to illuminate the remaining dark matter in hundreds of thousands of orthornavirus genomes. The vast majority of the dark matter domains showed either “generic” folds, such as single α-helices, or no high confidence structure predictions. Nevertheless, a variety of lineage-specific globular domains that were new either to orthornaviruses in general or to particular virus families were identified within the proteomic dark matter of orthornaviruses, including several predicted nucleic acid-binding domains and nucleases. In addition, we identified a case of exaptation of a cellular nucleoside monophosphate kinase as an RNA-binding protein in several virus families. Notwithstanding the continuing discovery of numerous orthornaviruses, it appears that all the protein domains conserved in large groups of viruses have already been identified. The rest of the viral proteome seems to be dominated by poorly structured domains including intrinsically disordered ones that likely mediate specific virus-host interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Expanding standards in viromics: in silico evaluation of dsDNA viral genome identification, classification, and auxiliary metabolic gene curation

Viruses influence global patterns of microbial diversity and nutrient cycles. Though viral metagenomics (viromics), specifically targeting dsDNA viruses, has been critical for revealing viral roles across diverse ecosystems, its analyses differ in many ways from those used for microbes. To date, viromics benchmarking has covered read pre-processing, assembly, relative abundance, read mapping thresholds and diversity estimation, but other steps would benefit from benchmarking and standardization. Here we use in silico-generated datasets and an extensive literature survey to evaluate and highlight how dataset composition (i.e., viromes vs bulk metagenomes) and assembly fragmentation impact (i) viral contig identification tool, (ii) virus taxonomic classification, and (iii) identification and curation of auxiliary metabolic genes (AMGs). The in silico benchmarking of five commonly used virus identification tools show that gene-content-based tools consistently performed well for long (≥3 kbp) contigs, while k -mer- and blast-based tools were uniquely able to detect viruses from short (≤3 kbp) contigs. Notably, however, the performance increase of k -mer- and blast-based tools for short contigs was obtained at the cost of increased false positives (sometimes up to ~5% for virome and ~75% bulk samples), particularly when eukaryotic or mobile genetic element sequences were included in the test datasets. Furthermore, for viral classification, variously sized genome fragments were assessed using gene-sharing network analytics to quantify drop-offs in taxonomic assignments, which revealed correct assignations ranging from ~95% (whole genomes) down to ~80% (3 kbp sized genome fragments). A similar trend was also observed for other viral classification tools such as VPF-class, ViPTree and VIRIDIC, suggesting that caution is warranted when classifying short genome fragments and not full genomes. Finally, we highlight how fragmented assemblies can lead to erroneous identification of AMGs and outline a best-practices workflow to curate candidate AMGs in viral genomes assembled from metagenomes. Together, these benchmarking experiments and annotation guidelines should aid researchers seeking to best detect, classify, and characterize the myriad viruses ‘hidden’ in diverse sequence datasets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

NCBI’s Virus Discovery Codeathon: Building “FIVE” —The Federated Index of Viral Experiments API Index

Viruses represent important test cases for data federation due to their genome size and the rapid increase in sequence data in publicly available databases. However, some consequences of previously decentralized (unfederated) data are lack of consensus or comparisons between feature annotations. Unifying or displaying alternative annotations should be a priority both for communities with robust entry representation and for nascent communities with burgeoning data sources. To this end, during this three-day continuation of the Virus Hunting Toolkit codeathon series (VHT-2), a new integrated and federated viral index was elaborated. This Federated Index of Viral Experiments (FIVE) integrates pre-existing and novel functional and taxonomy annotations and virus–host pairings. Variability in the context of viral genomic diversity is often overlooked in virus databases. As a proof-of-concept, FIVE was the first attempt to include viral genome variation for HIV, the most well-studied human pathogen, through viral genome diversity graphs. As per the publication of this manuscript, FIVE is the first implementation of a virus-specific federated index of such scope. FIVE is coded in BigQuery for optimal access of large quantities of data and is publicly accessible. Many projects of database or index federation fail to provide easier alternatives to access or query information. To this end, a Python API query system was developed to enhance the accessibility of FIVE.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structures of honeybee-infecting Lake Sinai virus reveal domain functions and capsid assembly with dynamic motions

Understanding the structural diversity of honeybee-infecting viruses is critical to maintain pollinator health and manage the spread of diseases in ecology and agriculture. We determine cryo-EM structures of $T$ = 4 and $T$ = 3 capsids of virus-like particles (VLPs) of Lake Sinai virus (LSV) 2 and delta-N48 LSV1, belonging to tetraviruses, at resolutions of 2.3–2.6 Å in various pH environments. Structural analysis shows that the LSV2 capsid protein (CP) structural features, particularly the protruding domain and C-arm, differ from those of other tetraviruses. The anchor loop on the central β-barrel domain interacts with the neighboring subunit to stabilize homo-trimeric capsomeres during assembly. Delta-N48 LSV1 CP interacts with ssRNA via the rigid helix α1’, α1’–α1 loop, β-barrel domain, and C-arm. Cryo-EM reconstructions, combined with X-ray crystallographic and small-angle scattering analyses, indicate that pH affects capsid conformations by regulating reversible dynamic particle motions and sizes of LSV2 VLPs. C-arms exist in all LSV2 and delta-N48 LSV1 VLPs across varied pH conditions, indicating that autoproteolysis cleavage is not required for LSV maturation. The observed linear domino-scaffold structures of various lengths, made up of trapezoid-shape capsomeres, provide a basis for icosahedral $T$ = 4 and $T$ = 3 architecture assemblies. These findings advance understanding of honeybee-infecting viruses that can cause Colony Collapse Disorder.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1 109 and BMLF1 280 , show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Influenza A Virus Multicycle Replication Yields Comparable Viral Population Emergence in Human Respiratory and Ocular Cell Types

While primarily considered a respiratory pathogen, influenza A virus (IAV) is nonetheless capable of spreading to, and replicating in, numerous extrapulmonary tissues in humans. However, within-host assessments of genetic diversity during multicycle replication have been largely limited to respiratory tract tissues and specimens. As selective pressures can vary greatly between anatomical sites, there is a need to examine how measures of viral diversity may vary between influenza viruses exhibiting different tropisms in humans, as well as following influenza virus infection of cells derived from different organ systems. Here, we employed human primary tissue constructs emulative of the human airway or corneal surface, and we infected both with a panel of human- and avian-origin IAV, inclusive of H1 and H3 subtype human viruses and highly pathogenic H5 and H7 subtype viruses, which are associated with both respiratory disease and conjunctivitis following human infection. While both cell types supported productive replication of all viruses, airway-derived tissue constructs elicited greater induction of genes associated with antiviral responses than did corneal-derived constructs. We used next-generation sequencing to examine viral mutations and population diversity, utilizing several metrics. With few exceptions, generally comparable measures of viral diversity and mutational frequency were detected following homologous virus infection of both respiratory-origin and ocular-origin tissue constructs. Expansion of within-host assessments of genetic diversity to include IAV with atypical clinical presentations in humans or in extrapulmonary cell types can provide greater insight into understanding those features most prone to modulation in the context of viral tropism.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Extreme dimensions — how big (or small) can tailed phages be?

Bacteriophages (phages), that is, viruses that infect bacteria, represent an extremely diverse, yet under-characterized, group of viruses. Although most known phages harbour genomes that are shorter than 200 kb packaged into capsids with a diameter under 100 Å, more and more ‘extremely large’ phages are being discovered. Early reports of phages with genomes larger than 200 kb defined them as ‘jumbo phages’1. Phylogenetic analysis of these jumbo phages revealed that they form distinct and cohesive groups with multiple independent origins. This suggested that jumbo phages are not merely mistakes or aberrations of smaller phages that got too big, but that large genome size is generally a stable trait. In fact, a larger genome can be advantageous; almost all jumbo phages encode their own specific transcription factors, at least some parts of the replication machinery, and many also have their own tRNA genes, which enables increased independence from their host. Here, large genomes also provide more flexibility in terms of transcription strategy; smaller phage genomes tend to have a strict modular genome structure to increase efficiency, whereas jumbo phage genomes may be much less organized in the absence of a strong selection pressure to maintain a compact genome.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Nucleic Acid-Based Sensing Techniques for Diagnostics and Surveillance of Influenza

Influenza virus poses a threat to global health by causing seasonal outbreaks as well as three pandemics in the 20th century. In humans, disease is primarily caused by influenza A and B viruses, while influenza C virus causes mild disease mostly in children. Influenza D is an emerging virus found in cattle and pigs. To mitigate the morbidity and mortality associated with influenza, rapid and accurate diagnostic tests need to be deployed. However, the high genetic diversity displayed by influenza viruses presents a challenge to the development of a robust diagnostic test. Nucleic acid-based tests are more accurate than rapid antigen tests for influenza and are therefore better candidates to be used in both diagnostic and surveillance applications. We review various nucleic acid-based techniques that have been applied towards the detection of influenza viruses in order to evaluate their utility as both diagnostic and surveillance tools. We discuss both traditional as well as novel methods to detect influenza viruses by covering techniques that require nucleic acid amplification or direct detection of viral RNA as well as comparing advantages and limitations for each method. There has been substantial progress in the development of nucleic acid-based sensing techniques for the detection of influenza virus. However, there is still an urgent need for a rapid and reliable influenza diagnostic test that can be used at point-of-care in order to enhance responsiveness to both seasonal and pandemic influenza outbreaks.

59 BASIC BIOLOGICAL SCIENCES↗