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Jun Prof Redmond Smyth

Genome Architecture and Evolution of RNA viruses

The Helmholtz Junior research group of Redmond Smyth investigates how RNA viruses regulate their replication and evolution using non-coding RNA structures within their genomes.

Our research and approach

RNA viruses are a major threat to human health and responsible for millions of deaths each year. Their replication is orchestrated by the RNA genome, which encodes for viral proteins needed to hijack the host cell. Traditionally, infectious disease research has focused on blocking viral replication by inhibiting these proteins. However, we now appreciate that the genomes of RNA viruses are not just passive carriers of protein coding information, but active participants in the viral infection process through the action of non-coding RNA. We study the structure and function of viral non-coding RNA, with the goal of harnessing the resulting knowledge in the design of next generation RNA-based therapies.

Team members

Liqing Ye

Liqing Ye

PhD Student

Patrick Bohn

Patrick Bohn

PhD Student

Shazeb Ahmad

Shazeb Ahmad

PhD Student

Uddhav Ambi

Uddhav Ambi

PhD Student

Charlene Börtlein

Charlene Börtlein

Technical Assistant

Research projects

RNA is a versatile molecule. It is a messenger for protein synthesis, but also a carrier of non-coding elements that regulate cellular activity through specific interactions with proteins, small molecules, and even other nucleic acids. RNA viruses exploit these non-coding RNA elements at almost every stage of their replication cycle, using them to influence splicing, protein translation, evasion of host cell defences, viral evolution and accessibility towards drug binding. Consequently, non-coding RNA represents an extremely attractive target for antiviral intervention, with the potential to revolutionize the treatment of infectious disease.

We use an integrative structural, functional and evolutionary approach to discover and mechanistically characterize non-coding RNA structures involved in viral replication and evolution. As in the protein world, it is often the higher order structure of the RNA, rather than primary sequence, that determines its function. Currently, how RNA structure drives diverse biological functions is not yet fully understood. Moreover, RNA readily undergoes structural changes, allowing it to switch between different functions, between different on/off states, or to adopt specific folds in different environments or in the presence of ligands. RNA dynamics have traditionally frustrated RNA structural characterization by biochemical and biophysical approaches. Our research focuses on unravelling the relationship between RNA structure and function, and we are actively working on new methods to investigate RNA structural dynamics. In the long term, we plan to use this knowledge to rationally develop small molecule drugs that interfere with RNA structure as a novel antiviral strategy.

We are also interested in how RNA structure constrains viral evolution. Retroviruses, such as HIV, package two copies of their RNA genome into each virion leading to recombination (template switching) and the formation of genome chimeras during replication. Another widespread strategy, seen in rotaviruses and influenza viruses, is genome segmentation leading to reassortment. Reassortment and recombination are non-random processes that are known to depend on RNA sequence and structure, but the underlying mechanisms are poorly understood. We study these mechanisms with the goal of improving disease prevention and control strategies. At the population level, we hope to understand the emergence of novel viral strains, such as how potentially pandemic influenza arises from genetic reassortment in humans, pigs or birds. At an individual level, we want to understand how RNA structure leads to immune evasion and the generation of multiple drug resistant viruses. Through our fundamental research we seek to rationally manipulate recombination and reassortment for the development of safer gene therapy vectors, as well as powerful new vaccine platforms.

Publications

2019

The evolution of RNA structural probing methods: From gels to next-generation sequencing

Mailler E, Paillart J, Marquet R, Smyth RP, Vivet-Boudou V (2019)

Wiley Interdisciplinary Reviews: RNA, 10 (2): 1518

2018

In cell mutational interference mapping experiment (in cell MIME) identifies the 5' polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging

Smyth RP, Smith MR, Jousset A, Despons L, Laumond G, Decoville T, Cattenoz P, Moog C, Jossinet F, Mougel M, …, Kleist M, Marquet R (2018)

Nucleic Acids Research, 46 (9): 57

RNA Structure - A Neglected Puppet Master for the Evolution of Virus and Host Immunity

Smyth RP, Negroni M, Lever AM, Mak J, Kenyon JC (2018)

Frontiers in Immunology, 9: 2097

Structural and Functional Motifs in Influenza Virus RNAs

Ferhadian D, Contrant M, Printz-Schweigert A, Smyth RP, Paillart J, Marquet R (2018)

Frontiers in Microbiology, 9: 559

2017

HIV-1 Pr55Gag binds genomic and spliced RNAs with different affinity and stoichiometry

Bernacchi S, Abd El-Wahab EW, Dubois N, Hijnen M, Smyth RP, Mak J, Marquet R, Paillart J (2017)

RNA Biology, 14 (1): 90-103

2016

HIV-1 Mutation and Recombination Rates Are Different in Macrophages and T-cells

Cromer D, Schlub TE, Smyth RP, Grimm AJ, Chopra A, Mallal S, Davenport MP, Mak J (2016)

Viruses, 8 (4): 118

A step forward understanding HIV-1 diversity

Smyth RP, Negroni M (2016)

Retrovirology, 13: 27

The Life-Cycle of the HIV-1 Gag-RNA Complex

Mailler E, Bernacchi S, Marquet R, Paillart J, Vivet-Boudou V, Smyth RP (2016)

Viruses, 8 (9): 248

MIMEAnTo: profiling functional RNA in mutational interference mapping experiments

Smith MR, Smyth RP, Marquet R, Kleist M (2016)

Bioinformatics, 32 (21): 3369-3370

2015

Mutational interference mapping experiment (MIME) for studying RNA structure and function

Smyth RP, Despons L, Huili G, Bernacchi S, Hijnen M, Mak J, Jossinet F, Weixi L, Paillart J, Kleist M, Marquet R (2015)

Nature Methods, 12 (9): 866-72

Evaluation of anti-HIV-1 mutagenic nucleoside analogues

Vivet-Boudou V, Isel C, El Safadi Y, Smyth RP, Laumond G, Moog C, Paillart J, Marquet R (2015)

The Journal of Biological Chemistry, 290 (1): 371-83

Properties of HIV-1 associated cholesterol in addition to raft formation are important for virus infection

Hawkes D, Jones KL, Smyth RP, Pereira CF, Bittman R, Jaworowski A, Mak J (2015)

Virus Research, 210: 18-21

2014

Specific recognition of the HIV-1 genomic RNA by the Gag precursor

Abd El-Wahab EW, Smyth RP, Mailler E, Bernacchi S, Vivet-Boudou V, Hijnen M, Jossinet F, Mak J, Paillart J, Marquet R (2014)

Nature Communications, 5: 4304

Identifying recombination hot spots in the HIV-1 genome

Smyth RP, Schlub TE, Grimm AJ, Waugh C, Ellenberg P, Chopra A, Mallal S, Cromer D, Mak J, Davenport MP (2014)

Journal of Virology, 88 (5): 2891-902

Fifteen to twenty percent of HIV substitution mutations are associated with recombination

Schlub TE, Grimm AJ, Smyth RP, Cromer D, Chopra A, Mallal S, Venturi V, Waugh C, Mak J, Davenport MP (2014)

Journal of Virology, 88 (7): 3837-49

2013

Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth RP, Mak J, Dorrell L (2013)

Journal of Immunological Methods, 391 (1-2): 174-8

Intracellular Dynamics of HIV Infection

Petravic J, Ellenberg P, Chan M, Paukovics G, Smyth RP, Mak J, Davenport MP (2013)

Journal of Virology, 88 (2): 1113-24

A functional sequence-specific interaction between influenza A virus genomic RNA segments

Gavazzi C, Yver M, Isel C, Smyth RP, Rosa-Calatrava M, Lina B, Moulès V, Marquet R (2013)

Proceedings of the National Academy of Sciences of the United States of America, 110 (41): 16604-9

2012

The Origin of Genetic Diversity in HIV-1

Smyth RP, Davenport MP, Mak J (2012)

Virus Research, 169 (2): 415-29

2011

8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription

Vivet-Boudou V, Isel C, Sleiman M, Smyth RP, Ben Gaied N, Barhoum P, Laumond G, Bec G, Götte M, Mak J, …, Burger A, Marquet R (2011)

PLOS One, 6 (11): 27456

Early events of HIV-1 infection: can signaling be the next therapeutic target?

Jones KL, Smyth RP, Pereira CF, Cameron PU, Lewin SR, Jaworowski A, Mak J (2011)

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 6 (2): 269-83

Labeling of multiple HIV-1 proteins with the biarsenical-tetracysteine system

Pereira CF, Ellenberg PC, Jones KL, Fernandez TL, Smyth RP, Hawkes DJ, Hijnen M, Vivet-Boudou V, Marquet R, Johnson I, Mak J (2011)

PLOS One, 6 (2): 17016

2010

Accurately measuring recombination between closely related HIV-1 genomes

Schlub TE, Smyth RP, Grimm AJ, Mak J, Davenport MP (2010)

PLOS Computational Biology, 6 (4): 10007

Reducing chimera formation during PCR amplification to ensure accurate genotyping

Smyth RP, Schlub TE, Grimm A, Venturi V, Chopra A, Mallal S, Davenport MP, Mak J (2010)

Gene, 469 (1-2): 45-51

2009

The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNA

Keating CP, Hill MK, Hawkes DJ, Smyth RP, Isel C, Le S, Palmenberg AC, Marshall JA, Marquet R, Nabel GJ, Mak J (2009)

Nucleic Acids Research, 37 (3): 945-56

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