- Moleculaire virologie
- RNA virus-gastheer interacties
- Chikungunya virus onderzoek
- Zika virus onderzoek
- Ontwikkeling antivirale middelen
- Chikungunya and Zika virus replication and virus-host interactions
- Chikungunya and Zika virus antivirals
- Novel (broad-spectrum and host-directed) antiviral strategies
Chikungunya virus: a serious emerging pathogen
Chikungunya virus (CHIKV) is a re-emerging human pathogen that is transmitted by mosquitoes, mainly Aedes aegypti and the Asian Tiger mosquito Aedes albopictus. CHIKV causes a fever that usually resolves within several days and extreme joint pains that can be severely debilitating and may persist for months or years. In 2005 CHIKV became “world news” when a massive outbreak struck the French island of La Reunion, resulting in the infection of one third of its population. Since then CHIKV has caused outbreaks of unprecedented proportions and it is estimated that over 4 million people have been infected. Up to 2013 these large outbreaks only occurred in Asia and Africa, but in December 2013, locally-transmitted CHIKV infections were reported from the island of St Martin in the Caribbean. CHIKV then also spread to the Dutch island of St Maarten and many other islands in the Caribbean. Subsequently, the virus spread widely over mainland Central and South America, infecting over 1 million people in about a year’s time. Hundreds of infected travelers have returned to Europe, which in 2007 led to a small locally-transmitted CHIKV outbreak in Italy and a few locally acquired infections in France in 2010 and 2014 and Spain in 2015.
The impact of CHIKV
Emerging viruses like CHIKV can have a serious impact, not only on the quality of life of individual patients, but also on society and economy. There are currently no registered vaccines or antiviral drugs available to prevent or treat CHIKV infections. The millions of people that have suffered or are still experiencing the painful and debilitating consequences of CHIKV infections and the expected further geographic dispersal of the virus make it painfully clear that vaccines and antiviral therapy are desperately needed.
Zika virus: from neglected pathogen to major public health concern
Zika virus (ZIKV) is a flavivirus that, like CHIKV, dengue virus, and several other important human pathogens, is transmitted by (Aedes) mosquitoes. The virus has been known since 1947, when it was isolated from a sentinel monkey in the Zika forest in Uganda. Zika virus mostly causes asymptomatic infections and when symptomatic mainly causes mild disease characterized by fever, conjunctivitis, headache, skin rash, mild joint pains and oedema. For decades the virus has only caused (enzootic) infections on a limited scale, mainly in equatorial Africa and Asia. In 2013 ZIKV caused large outbreaks on several islands in the Pacific Ocean. In 2015 ZIKV spread to South and Central America, where it caused a massive outbreak that affected millions of people in countries like Brazil, Suriname, Colombia, Venezuela, Mexico, and many Caribbean islands. During this pandemic, ZIKV infections in pregnant women were linked to microcephaly (birth defect) and in adults there might be a link with the with neurologic condition Guillain–Barré syndrome. More research is required to establish whether ZIKV is really the cause of these serious complications. ZIKV is now considered a serious international public health problem due to the scale of the ZIKV pandemic and the rare but very serious consequences that the virus might have in probably a limited group of patients. There are currently no vaccines or antiviral drugs on the market to prevent or treat ZIKV infections.
The quest for antivirals
RNA viruses (viruses with RNA as their genetic material) form the largest group of viruses, which includes many important human pathogens. Vaccines and effective antiviral therapy against CHIKV, ZIKV, and many other medically important RNA viruses are still lacking. This stresses the importance of advancing our knowledge of the replication, transmission, and pathogenesis of these viruses, to develop drugs, novel antiviral strategies, and prepare us for new outbreaks of (yet unknown) viruses that will undoubtedly occur in the future.
Traditionally, viral proteins have been the primary targets for antiviral drug development, with the inherent risk of the emergence of drug resistance due to the high mutation rate of RNA viruses. Due to their relatively small genomes with limited coding capacity, RNA viruses strongly rely on and exploit numerous host cell processes and molecules for their replication, while simultaneously counteracting or evading antiviral responses. A better understanding of these virus-host interactions can (and already does) form the basis for new approaches in antiviral therapy: the targeting of host factors to block virus replication and/or pathogenesis. This ‘host-directed’ approach could circumvent the emergence of antiviral drug resistance, since host factors -unlike viral drug targets- are unlikely to mutate during antiviral therapy.
Our research is aimed at better understanding CHIKV and ZIKV replication and virus-host interactions, with the ultimately goal to develop novel antiviral strategies (based on targeting host factors). Therefore, we have developed a variety of tools to study various aspects of CHIKV replication, including infectious clones to perform reverse genetics experiments and in vitro assays to study viral RNA synthesis. We are also performing mode of action studies on a variety of antiviral compounds, often in collaboration with international partners, using our expertise and CHIKV research tools. CHIKV is a BSL-3 pathogen and all research with infectious CHIKV is carried out in our state-of-the-art high-containment lab. We have a variety of tools available, including several clinical isolates from the 2015-2016 outbreak in the Americas to study ZIKV. We are collaborating with various academic and non-academic partners in research that should lead to a better understanding of ZIKV pathogenesis, improved diagnostics, antivirals and vaccines. Our research is supported by EU-funded projects like SILVER, EUVIRNA, ANTIVIRALS, SysVirDrug and ZIKAlliance.
Martijn van Hemert (1971) obtained his MSc degree (cum laude) in Molecular Biology at the Leiden University Faculty of Natural Sciences in 1995 and a PhD degree from Leiden University in 2001. After post-doctoral research on the so-called “14-3-3 proteins”, he joined the nidovirus research group of prof. dr. E.J. Snijder at the LUMC department of Medical Microbiology in 2004, to study the replication and transcription complexes of SARS-coronavirus and equine arteritis virus. Since 2009 Martijn heads the alphavirus research group, which studies CHIKV replication and virus-host interactions with the ultimate goal of developing antiviral strategies against CHIKV and other RNA viruses (broad-spectrum antivirals). He was and is involved in various teaching activities related to molecular virology and virus-host interactions and in supervising several PhD and undergraduate students.
Pietilä MK, Albulescu IC, van Hemert MJ*, Ahola T*. Polyprotein Processing as a Determinant for in Vitro Activity of Semliki Forest Virus Replicase (2017). Viruses 9: pii: E292.
Hwu JR, Gupta NK, Tsay SC, Huang WC, Albulescu IC, Kovacikova K, van Hemert MJ. Bis(benzofuran-thiazolidinone)s and bis(benzofuran-thiazinanone)s as inhibiting agents for chikungunya virus (2017). Antiviral Res. 146:96-101.
de Wilde AH, Snijder EJ, Kikkert M, van Hemert MJ. Host Factors in Coronavirus Replication (2017). Curr Top Microbiol Immunol. doi: 10.1007/82_2017_25: 1-42.
van Boheemen S, Tas A, Anvar SY, van Grootveld R, Albulescu IC, Bauer MP, Feltkamp MC, Bredenbeek PJ, van Hemert MJ. Quasispecies composition and evolution of a typical Zika virus clinical isolate from Suriname (2017). Sci Rep. 7:2368
Albulescu IC, Kovacikova K, Tas A, Snijder EJ, van Hemert MJ. Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles (2017). Antiviral Res. 143:230-236
Delang L, Li C, Tas A, Quérat G, Albulescu IC, De Burghgraeve T, Guerrero NA, Gigante A, Piorkowski G, Decroly E, Jochmans D, Canard B, Snijder EJ, Pérez-Pérez MJ, van Hemert MJ, Coutard B, Leyssen P, Neyts J. The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection (2016). Sci Rep. 6: 31819
Hoornweg TE, van Duijl-Richter MK, Ayala Nuñez NV, Albulescu IC, van Hemert MJ, Smit JM. Dynamics of Chikungunya Virus Cell Entry Unraveled by Single-Virus Tracking in Living Cells (2016). J Virol. 90:4745-4756.
Albulescu IC, van Hoolwerff M, Wolters LA, Bottaro E, Nastruzzi C, Yang SC, Tsay SC, Hwu JR, Snijder EJ, van Hemert MJ. Suramin inhibits chikungunya virus replication through multiple mechanisms. Antiviral Res. 2015;121:39-46.
de Wilde AH, Wannee KF, Scholte FE, Goeman JJ, Ten Dijke P, Snijder EJ, Kikkert M, van Hemert MJ. A kinome-wide siRNA screen identifies proviral and antiviral host factors in SARS-coronavirus replication, including PKR and early secretory pathway proteins. J Virol. 2015; 89:8318-33.
Treffers EE, Tas A, Scholte FE, Van MN, Heemskerk MT, de Ru AH, Snijder EJ, van Hemert MJ*, van Veelen PA*. Temporal SILAC-based quantitative proteomics identifies host factors involved in chikungunya virus replication. Proteomics 2015; 15:2267-80.
Scholte FE, Tas A, Albulescu IC, Zusinaite E, Merits A, Snijder EJ, van Hemert MJ. Stress granule components G3BP1 and G3BP2 play a proviral role early in Chikungunya virus replication. J Virol. 2015; 89:4457-4469.
Fros JJ, Major LD, Scholte FE, Gardner J, van Hemert MJ, Suhrbier A, Pijlman GP. Chikungunya virus nsP2-mediated host shut-off disables the unfolded protein response. J Gen Virol. 2015; 96:580-9.
Albulescu IC, Tas A, Scholte FE, Snijder EJ, van Hemert MJ. An in vitro assay to study chikungunya virus RNA synthesis and the mode of action of inhibitors. J Gen Virol. 2014; 95:2683-92.
Delang L, Segura Guerrero N, Tas A, Quérat G, Pastorino B, Froeyen M, Dallmeier K, Jochmans D, Herdewijn P, Bello F, Snijder EJ, de Lamballerie X, Martina B, Neyts J*, van Hemert MJ*, Leyssen P. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J Antimicrob Chemother. 2014; 69:2770-84.
Li Y, Treffers EE, Napthine S, Tas A, Zhu L, Sun Z, Bell S, Mark BL, van Veelen PA, van Hemert MJ, Firth AE, Brierley I, Snijder EJ, Fang Y. Transactivation of programmed ribosomal frameshifting by a viral protein. Proc Natl Acad Sci U S A. 2014; 111:E2172-81.
Olagnier D, Scholte FE, Chiang C, Albulescu IC, Nichols C, He Z, Lin R, Snijder EJ, van Hemert MJ, Hiscott J. Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response. J Virol. 2014; 88:4180-94.
Scholte FE, Tas A, Martina BE, Cordioli P, Narayanan K, Makino S, Snijder EJ, van Hemert MJ. Characterization of Synthetic Chikungunya Viruses Based on the Consensus Sequence of Recent E1-226V Isolates. PLoS One. 2013; 8:e71047.
de Wilde AH, Li Y, van der Meer Y, Vuagniaux G, Lysek R, Fang Y, Snijder EJ, van Hemert MJ. Cyclophilin inhibitors block arterivirus replication by interfering with viral RNA synthesis. J Virol. 2013; 87:1454-64.
de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, Thiel V, Narayanan K, Makino S, Snijder EJ, van Hemert MJ. Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol. 2011; 92:2542-8.
te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010; 6:e1001176.
van Hemert MJ, van den Worm SH, Knoops K, Mommaas AM, Gorbalenya AE, Snijder EJ. SARS-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro. PLoS Pathog. 2008; 4:e1000054.
van Hemert MJ, de Wilde AH, Gorbalenya AE, Snijder EJ. The in vitro RNA synthesizing activity of the isolated arterivirus replication/transcription complex is dependent on a host factor. J Biol Chem. 2008; 283:16525-36.
All publications by Martijn J. van Hemert in PubMed
Leids Universitair Medisch Centrum
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