Virus-host Protein Interactions Research Articles

Proteomes, kinases and signalling pathways in virus-induced filopodia, as potential antiviral therapeutics targets.

SummaryFilopodia are thin finger‐like protrusions at the surface of cells that are internally occupied with bundles of tightly parallel actin filaments. They play significant roles in cellular physiological processes, such as adhesion to extracellular matrix, guidance towards chemo‐attractants and in wound healing. Filopodia were recently reported to play important roles in viral infection including initial viral attachment to host cells, cell surfing, viral trafficking, internalization, budding, virus release and spread to other cells in a form that would avoid the host immune system. The detailed virus‐host protein interactions underlying most of these processes remain to be elucidated. This review will describe some reported virus‐host protein interactions on filopodia with the aim of identifying potential new anti‐virus therapeutic targets. Exploring this research area may lead to the development of novel classes of anti‐viral therapeutics that can block signalling pathways used by the virus to trigger filopodia formation. Successful compounds would inhibit initial virus attachment, formation of filopodia, expression of putative virus binding protein, extracellular virus trafficking, and budding.

Insights on cross-species transmission of SARS-CoV-2 from structural modeling.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 31 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic and confirmed cases of cross-species transmission, the question of the extent to which this transmission is possible emerges, as well as what molecular features distinguish susceptible from non-susceptible animal species. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also allow us to predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

Invasion of the Nervous System.

In vertebrates, the nervous system (NS) is composed of a peripheral collection of neurons (the peripheral nervous system, PNS), a central set found in the brain and spinal cord (the central nervous system, CNS). The NS is protected by rather complicated multi-layer barriers that allow access to nutrients and facilitate contact with the peripheral tissues, but block entry of pathogens and toxins. Virus infections usually begin in peripheral tissues and if these barriers are weakened, they can spread into the PNS and more rarely into the CNS. Most viral infections of the NS are opportunistic or accidental pathogens that gain access via the bloodstream (e.g., HIV and various arboviruses). But a few have evolved to enter the NS efficiently by invading neurons directly and by exploiting neuronal cell biology (e.g., rhabdoviruses and alphaherpesviruses). Most NS infections are devastating and difficult to manage. Remarkably, the alphaherpesviruses establish life-long quiescent infections in the PNS, with rare but often serious CNS pathology. In this review, we will focus on how alphaherpesviruses gain access to and spread in the NS, with particular emphasis on bidirectional transport and spread within and between neurons and neural circuits, which is regulated by complex viral-host protein interactions. Finally, we will describe the wide use of alphaherpesviruses as tools to study nerve connectivity and function in animal models.

Pathways involved in viral oncogenesis: New perspectives from virus-host protein interactomics

Oncogenic viruses are among the apparent causes of cancer-associated mortality. It was estimated that 12% to 15% of human malignancies are linked to oncoviruses. Although modernist strategies and traditional genetic studies have defined host-pathogen interactions of the oncoviruses, their host functions which are critical for the establishment of infection still remain mysterious. However, over the last few years, it has become clear that infections hijack and modify cellular pathways for their benefit. In this context, we constructed the virus-host protein interaction networks of seven oncoviruses (EBV, HBV, HCV, HTLV-1, HHV8, HPV16, and HPV18), and revealed cellular pathways hijacking as a result of oncogenic virus infection. Several signaling pathways/processes such as TGF-β signaling, cell cycle, retinoblastoma tumor suppressor protein, and androgen receptor signaling were mutually targeted by viruses to induce oncogenesis. Besides, cellular pathways specific to a certain virus were detected. By this study, we believe that we improve the understanding of the molecular pathogenesis of viral oncogenesis and provide information in setting new targets for treatment, prognosis, and diagnosis.

A dual controllability analysis of influenza virus-host protein-protein interaction networks for antiviral drug target discovery

BackgroundHost factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. In this context, controllability analyses aim to identify key regulating host factors of the infected cell’s progression. This knowledge can be utilized in further biological analysis to understand disease dynamics and isolate proteins for study as drug target candidates.ResultsBoth topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. Functional analysis finds overlap of results with previous siRNA studies of host factors involved in influenza replication, NF-kB pathway and infection relevance, and roles as interferon regulating genes. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets.ConclusionsSeasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year with a constant threat of pandemic infection. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. These results are beneficial to future studies of influenza virus, both experimental and computational, and provide evidence that the combination of topology and controllability analyses may be valuable for future efforts in drug target discovery.

Targeting Virus-host Protein Interactions: Feature Extraction and Machine Learning Approaches.

Targeting critical viral-host Protein-Protein Interactions (PPIs) has enormous application prospects for therapeutics. Using experimental methods to evaluate all possible virus-host PPIs is labor-intensive and time-consuming. Recent growth in computational identification of virus-host PPIs provides new opportunities for gaining biological insights, including applications in disease control. We provide an overview of recent computational approaches for studying virus-host PPI interactions. In this review, a variety of computational methods for virus-host PPIs prediction have been surveyed. These methods are categorized based on the features they utilize and different machine learning algorithms including classical and novel methods. We describe the pivotal and representative features extracted from relevant sources of biological data, mainly include sequence signatures, known domain interactions, protein motifs and protein structure information. We focus on state-of-the-art machine learning algorithms that are used to build binary prediction models for the classification of virus-host protein pairs and discuss their abilities, weakness and future directions. The findings of this review confirm the importance of computational methods for finding the potential protein-protein interactions between virus and host. Although there has been significant progress in the prediction of virus-host PPIs in recent years, there is a lot of room for improvement in virus-host PPI prediction.

Host cell interactome of PB1 N40 protein of H5N1 influenza A virus in chicken cells

H5N1 influenza A virus (IAV) causes seasonal epidemics that represent a worldwide threat to public health. IAV relies on host factors for viral replication. PB1 N40 is translated from the fifth starting code (AUG) of PB1 mRNA, which is the product of the ribosomal scan omission. Here, we report the interactome landscape of H5N1 IAV PB1 N40 protein in chicken cells. The interacting complexes were captured by co-immunoprecipitation and analyzed by mass spectrometry. We identified 135 proteins as PB1 N40-interacting proteins. GO and Pathway analysis showed that proteins with biological functions such as protein localization and viral transcription and proteins related to signaling pathways of DNA replication and cell cycle were significantly enriched in virus–host interactions, suggesting the potential roles of them in infection with H5N1 IAV. Comparative analysis among H1N1 and H5N1 revealed conservation of the virus–host protein interaction between different subtypes or strains of influenza virus. ARCN1 was identified as a host interacting factor of H5N1 IAV PB1 N40 protein, which is the component of the coatomer. Knockdown of ARCN1 significantly decreased the titer of H5N1 IAV in chicken cells. Biological significanceInfluenza A virus (IAV) is a great threat to public health and avian production. However, the manner in which avian IAV recruits the host cellular machinery for replication and how the host antagonizes the IAV infection was previously poorly understood. Here we present the viral-host interactome of the H5N1 IAV PB1 N40 protein and reveal its involvement with dozens of important host genes during the course of IAV infection.

Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network.

We have mapped a global network of virus-host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV- but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.Significance: In this study, we created a protein-protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474-89. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

Global Interactomics Uncovers Extensive Organellar Targeting by Zika Virus

Zika virus (ZIKV) is a membrane enveloped Flavivirus with a positive strand RNA genome, transmitted by Aedes mosquitoes. The geographical range of ZIKV has dramatically expanded in recent decades resulting in increasing numbers of infected individuals, and the spike in ZIKV infections has been linked to significant increases in both Guillain-Barré syndrome and microcephaly. Although a large number of host proteins have been physically and/or functionally linked to other Flaviviruses, very little is known about the virus-host protein interactions established by ZIKV. Here we map host cell protein interaction profiles for each of the ten polypeptides encoded in the ZIKV genome, generating a protein topology network comprising 3033 interactions among 1224 unique human polypeptides. The interactome is enriched in proteins with roles in polypeptide processing and quality control, vesicle trafficking, RNA processing and lipid metabolism. >60% of the network components have been previously implicated in other types of viral infections; the remaining interactors comprise hundreds of new putative ZIKV functional partners. Mining this rich data set, we highlight several examples of how ZIKV may usurp or disrupt the function of host cell organelles, and uncover an important role for peroxisomes in ZIKV infection.

HIV-1 Nef-POTEE; A novel interaction modulates macrophage dissemination via mTORC2 signaling pathway

AimsHuman immunodeficiency virus −1 [HIV-1] Nef, localizes in different cellular compartments and modulates several cellular pathways. Nef promotes virus pathogenicity through alteration in cell surface receptor expression, apoptosis, protein trafficking etc. Nef regulates viral pathogenesis through interaction with different host proteins. Thus, molecular mechanisms of pathogenesis could be deciphered by identifying novel Nef interacting proteins. Main methodsHIV-1 Nef interacting proteins were identified by pull down assay and MALDI-TOF analysis. The interaction was further validated through mammalian two hybrid assay. Functional role of this interaction was identified by immunoprecipitation assay, cell invasion and cell migration studies. Fold Change in mRNA levels of CD163, CD206, CCL17 and CCL18 was analyzed using qPCR. Key findingsIn current study, C. elegans protein ACT4C and its human homolog POTEE was identified to be interacting with Nef. This interaction activates mTORC2 complex, which in-turn activates AKT and PKC-α. The activation of mTORC2 complex was found to be initiated by the interaction of Nef, mTORC2, Rictor to POTEE. The cellular phenotype and functions affected by Nef-POTEE interaction resulted in significant increase in cell invasion and migration of macrophages (MΦ). SignificanceMΦ is primary target of HIV-1 infection where HIV-1 replicates and polarizes immunosuppressive M2 phenotype. Combine effect of M2 phenotype and Viral-host protein interactions compromise the MΦ associated physiological functions. Infected MΦ dissemination into other system also leads to HIV-1 induced malignancies. Therefore, targeting POTEE-Nef interaction can lead to formulating better therapeutic strategy against HIV-1.

Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx-DDB1 Interaction.

Background & AimsHepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein–protein interaction was considered as a new molecular target of HBV treatment.MethodsTo identify candidate compounds that target the HBx–DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes.ResultsWe show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx–DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV.ConclusionsThese results indicate that NTZ, which targets an HBV-related viral–host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure.

Respiratory Syncytial Virus Matrix (M) Protein Interacts with Actin In Vitro and in Cell Culture.

The virus–host protein interactions that underlie respiratory syncytial virus (RSV) assembly are still not completely defined, despite almost 60 years of research. RSV buds from the apical surface of infected cells, once virion components have been transported to the budding sites. Association of RSV matrix (M) protein with the actin cytoskeleton may play a role in facilitating this transport. We have investigated the interaction of M with actin in vitro and cell culture. Purified wildtype RSV M protein was found to bind directly to polymerized actin in vitro. Vero cells were transfected to express full-length M (1–256) as a green fluorescent protein-(GFP) tagged protein, followed by treatment with the microfilament destabilizer, cytochalasin D. Destabilization of the microfilament network resulted in mislocalization of full-length M, from mostly cytoplasmic to diffused across both cytoplasm and nucleus, suggesting that M interacts with microfilaments in this system. Importantly, treatment of RSV-infected cells with cytochalasin D results in lower infectious virus titers, as well as mislocalization of M to the nucleus. Finally, using deletion mutants of M in a transfected cell system, we show that both the N- and C-terminus of the protein are required for the interaction. Together, our data suggest a possible role for M–actin interaction in transporting virion components in the infected cell.

The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA.

The papillomavirus E2 protein executes numerous essential functions related to viral transcription, replication of viral DNA, and viral genome maintenance. Because E2 lacks enzymatic activity, many of these functions are mediated by interactions with host cellular proteins. Unbiased proteomics approaches have successfully identified a number of E2-host protein interactions. We have extended such studies and have identified and validated the cellular proteins structural maintenance of chromosome 5 (SMC5) and SMC6 as interactors of the viral E2 protein. These two proteins make up the core components of the SMC5/6 complex. The SMC5/6 complex is a member of the conserved structural maintenance of chromosomes (SMC) family of proteins, which are essential for genome maintenance. We have examined the role of SMC5/6 in various E2 functions. Our data suggest that SMC6 is not required for E2-mediated transcriptional activation, E1/E2-mediated transient replication, or differentiation-dependent amplification of viral DNA. Our data, however, suggest a role for SMC5/6 in viral genome maintenance.IMPORTANCE The high-risk human papillomaviruses (HPVs) are the etiological cause of cervical cancer and the most common sexually transmitted infection. While the majority of infections may be asymptomatic or cause only benign lesions, persistent infection with the oncogenic high-risk HPV types may lead to serious diseases, such as cervical cancer, anogenital carcinoma, or head and neck oropharyngeal squamous cell carcinoma. The identification of virus-host protein interactions provides insights into the mechanisms of viral DNA persistence, viral genome replication, and cellular transformation. Elucidating the mechanism of early events in the virus replication cycle as well as of integration of viral DNA into host chromatin may present novel antiviral strategies and targets for counteracting persistent infection. The E2 protein is an important viral regulatory protein whose functions are mediated through interactions with host cell proteins. Here we explore the interaction of E2 with SMC5/6 and the functional consequences.

Hybrid experimental‐mathematical methods for probing dynamic proteome organization during viral infections

Every year, a major cause of human disease and death worldwide is infection with the various viral pathogens that are intrinsic to our ecosystem. The outcomes of viral infections derive from dynamic virus‐host cell interactions that function either in promoting virus replication or in host defense against invading pathogens. An essential component of these virus‐host interactions is spatial organization. Eukaryotic viruses replicate within highly organized host cells that compartmentalize their vast cellular proteomes within organelles. Alterations in organelle shape, composition, function, and dynamics are prominent features of virus replication cycles, although the knowledge of the mechanisms involved remains limited.This presentation will describe the integration of experimental studies, mathematical modeling and inference methods for understanding the dynamic regulation of organelles during viral infection. The experimental methods presented will include live‐cell microscopy and quantitative mass spectrometry‐based proteomics for characterizing both organelle changes and virus‐host protein interactions during the progression of an infection. These studies discovered 1) dynamic changes in organelle composition, 2) translocation of cellular proteins from one subcellular compartment to another, and 3) temporal virus‐host protein interactions within organelles that induce alterations in host biological pathways (Figure 1).The value of these integrative methods is demonstrated by the identification of mechanisms through which viruses remodel subcellular organelle function to suppress host defense and promote viral replication. Furthermore, our findings are starting to uncover how viruses regulate the dynamics of organelle biogenesis during infection. Overall, these studies highlight how integrative omic technologies can help paint a picture of the pathogen's life cycle and aid in the future development of antiviral therapies.Support or Funding InformationNIH grants GM114141 and HL127640, and Mallinckrodt Scholar AwardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Defining Pharmacological Targets by Analysis of Virus-Host Protein Interactions.

Viruses are obligate parasites that depend on cellular factors for replication. Pharmacological inhibition of essential viral proteins, mostly enzymes, is an effective therapeutic alternative in the absence of effective vaccines. However, this strategy commonly encounters drug resistance mechanisms that allow these pathogens to evade control. Due to the dependency on host factors for viral replication, pharmacological disruption of the host-pathogen protein–protein interactions (PPIs) is an important therapeutic alternative to block viral replication. In this review we discuss salient aspects of PPIs implicated in viral replication and advances in the development of small molecules that inhibit viral replication through antagonism of these interactions.

Molecular Recognition Features in Zika Virus Proteome

Viruses have compact genomes that encode limited number of proteins in comparison to other biological entities. Interestingly, viral proteins have shown natural abundance of either completely disordered proteins that are recognized as intrinsically disorder proteins (IDPs) or partially disordered segments known as intrinsically disordered protein regions (IDPRs). IDPRs are involved in interactions with multiple binding partners to accomplish signaling, regulation, and control functions in cells. Tuning of IDPs and IDPRs are mediated through post-translational modification and alternative splicing. Often, the interactions of IDPRs with their binding protein partner(s) lead to transition from the state of disorder to ordered form. Such interaction-prone protein IDPRs are identified as molecular recognition features (MoRFs). Molecular recognition is an important initial step for the biomolecular interactions and their functional proceedings. Although previous studies have established occurrence of the IDPRs in Zika virus proteome, which provide the functional diversity and structural plasticity to viral proteins, the MoRF analysis has not been performed as of yet. Many computational methods have been developed for the identification of the MoRFs in protein sequences including ANCHOR, MoRFpred, DISOPRED3, and MoRFchibi_web server. In the current study, we have investigated the presence of MoRF regions in structural and non-structural proteins of Zika virus using an aforementioned set of computational techniques. Furthermore, we have experimentally validated the intrinsic disorderness of NS2B cofactor region of NS2B–NS3 protease. NS2B has one of the longest MoRF regions in Zika virus proteome. In future, this study may provide valuable information while investigating the virus host protein interaction networks.

Foot-and-mouth disease virus 5’-terminal S fragment is required for replication and modulation of the innate immune response in host cells

The S fragment of the FMDV 5’ UTR is predicted to fold into a long stem-loop structure and it has been implicated in virus-host protein interactions. In this study, we report the minimal S fragment sequence required for virus viability and show a direct correlation between the extent of the S fragment deletion mutations and attenuated phenotypes. Furthermore, we provide novel insight into the role of the S fragment in modulating the host innate immune response. Importantly, in an FMDV mouse model system, all animals survive the inoculation with the live A24 FMDV-S4 mutant, containing a 164 nucleotide deletion in the upper S fragment loop, at a dose 1000 higher than the one causing lethality by parental A24 FMDV, indicating that the A24 FMDV-S4 virus is highly attenuated in vivo. Additionally, mice exposed to high doses of live A24 FMDV-S4 virus are fully protected when challenged with parental A24 FMDV virus.

Review of computational methods for virus-host protein interaction prediction: a case study on novel Ebola-human interactions.

Identification of potential virus–host interactions is useful and vital to control the highly infectious virus-caused diseases. This may contribute toward development of new drugs to treat the viral infections. Recently, database records of clinically and experimentally validated interactions between a small set of human proteins and Ebola virus (EBOV) have been published. Using the information of the known human interaction partners of EBOV, our main objective is to identify a set of proteins that may interact with EBOV proteins. Here, we first review the state-of-the-art, computational methods used for prediction of novel virus–host interactions for infectious diseases followed by a case study on EBOV–human interactions. The assessment result shows that the predicted human host proteins are highly similar with known human interaction partners of EBOV in the context of structure and semantics and are responsible for similar biochemical activities, pathways and host–pathogen relationships.

Protein-Protein Interactions in Virus-Host Systems.

To study virus–host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions—viral–viral or host–host interactions—are constantly targeted and inhibited by exogenous interfaces mediating viral–host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these “hub proteins” evolve. “Party hubs” have multiple interfaces; they establish simultaneous/stable (domain–domain) interactions, and tend to evolve slowly. On the other hand, “date hubs” have few interfaces; they establish transient/weak (domain–motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein–protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus–host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus–host protein interactions.

Influenza A Virus-Host Protein Interactions Control Viral Pathogenesis.

The influenza A virus (IAV), a member of the Orthomyxoviridae family, is a highly transmissible respiratory pathogen and represents a continued threat to global health with considerable economic and social impact. IAV is a zoonotic virus that comprises a plethora of strains with different pathogenic profiles. The different outcomes of viral pathogenesis are dependent on the engagement between the virus and the host cellular protein interaction network. The interactions may facilitate virus hijacking of host molecular machinery to fulfill the viral life cycle or trigger host immune defense to eliminate the virus. In recent years, much effort has been made to discover the virus–host protein interactions and understand the underlying mechanisms. In this paper, we review the recent advances in our understanding of IAV–host interactions and how these interactions contribute to host defense and viral pathogenesis.