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A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus.

ABSTRACT: Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin (HA) glycoprotein, which is the major antigen on the surface of the virus. The HA is composed of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines and novel therapeutics.

SUBMITTER: Wu NC

PROVIDER: S-EPMC5573227 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus.

Wu Nicholas C NC Wilson Ian A IA

Journal of molecular biology 20170623 17

Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin (HA) glycoprotein, which is the major antigen on the surface of the virus. The HA is composed of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino acid substitutions and continual addition of glycosylation s ...[more]

PMID: 28648617

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Project description:Influenza is a contagion that has plagued mankind for many decades, and continues to pose concerns every year, with millions of infections globally. The frequent mutations and recombination of the influenza A virus (IAV) cast a looming threat that antigenically novel strains/subtypes will rise with unpredictable pathogenicity and fear of it evolving into a pandemic strain. There have been four major influenza pandemics, since the beginning of twentieth century, with the great 1918 pandemic being the most severe, killing more than 50 million people worldwide. The mechanisms of IAV infection, host immune responses, and how viruses evade from such defensive responses at the molecular and structural levels have been greatly investigated in the past 30?years. While this has advanced our understanding of virus-host interactions and human immunology, and has led to the development of several antiviral drugs, they have minimal impact on the clinical outcomes of infection. The heavy use of these drugs has also imposed selective pressure on IAV to evolve and develop resistance. Vaccination remains the cornerstone of public health efforts to protect against influenza; however, rapid mass-production of sufficient vaccines is unlikely to occur immediately after the beginning of a pandemic. This, therefore, requires novel therapeutic strategies against this continually emerging infectious virus with higher specificity and cross-reactivity against multiple strains/subtypes of IAVs. This review discusses essential virulence factors of IAVs that determine sustainable human-to-human transmission, the mechanisms of viral hijacking of host cells and subversion of host innate immune responses, and novel therapeutic interventions that demonstrate promising antiviral properties against IAV. This hopefully will promote discussions and investigations on novel avenues of prevention and treatment strategies of influenza, that are effective and cross-protective against multiple strains/subtypes of IAV, in preparation for the advent of future IAVs and pandemics.

Project description:Influenza A viruses (IAV) are responsible for recurrent influenza epidemics and occasional devastating pandemics in humans and animals. They belong to the Orthomyxoviridae family and their genome consists of eight (-) sense viral RNA (vRNA) segments of different lengths coding for at least 11 viral proteins. A heterotrimeric polymerase complex is bound to the promoter consisting of the 13 5'-terminal and 12 3'-terminal nucleotides of each vRNA, while internal parts of the vRNAs are associated with multiple copies of the viral nucleoprotein (NP), thus forming ribonucleoproteins (vRNP). Transcription and replication of vRNAs result in viral mRNAs (vmRNAs) and complementary RNAs (cRNAs), respectively. Complementary RNAs are the exact positive copies of vRNAs; they also form ribonucleoproteins (cRNPs) and are intermediate templates in the vRNA amplification process. On the contrary, vmRNAs have a 5' cap snatched from cellular mRNAs and a 3' polyA tail, both gained by the viral polymerase complex. Hence, unlike vRNAs and cRNAs, vmRNAs do not have a terminal promoter able to recruit the viral polymerase. Furthermore, synthesis of at least two viral proteins requires vmRNA splicing. Except for extensive analysis of the viral promoter structure and function and a few, mostly bioinformatics, studies addressing the vRNA and vmRNA structure, structural studies of the influenza A vRNAs, cRNAs, and vmRNAs are still in their infancy. The recent crystal structures of the influenza polymerase heterotrimeric complex drastically improved our understanding of the replication and transcription processes. The vRNA structure has been mainly studied in vitro using RNA probing, but its structure has been very recently studied within native vRNPs using crosslinking and RNA probing coupled to next generation RNA sequencing. Concerning vmRNAs, most studies focused on the segment M and NS splice sites and several structures initially predicted by bioinformatics analysis have now been validated experimentally and their role in the viral life cycle demonstrated. This review aims to compile the structural motifs found in the different RNA classes (vRNA, cRNA, and vmRNA) of influenza viruses and their function in the viral replication cycle.

Dataset Information

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus.

Publications

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus.

Similar Datasets

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