|Year : 2013 | Volume
| Issue : 5 | Page : 762-765
Approaches to the treatment of disease induced by chikungunya virus
Jayaram Bettadapura, Lara J Herrero, Adam Taylor, Suresh Mahalingam
Emerging Viruses & Inflammation Research Group, Institute for Glycomics, Griffith University, Queensland, Australia
|Date of Submission||15-Oct-2013|
|Date of Web Publication||9-Jan-2014|
Emerging Viruses & Inflammation Research Group, Institute for Glycomics Griffith University (Gold Coast Campus), Queensland 4222
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Chikungunya virus, a re-emerging mosquito-borne alphavirus, causes fever, rash and persistent arthralgia/arthritis in humans. Severe outbreaks have occurred resulting in infections of millions of people in Southeast Asia and Africa. Currently there are no antiviral drugs or vaccines for prevention and treatment of chikungunya infections. Herein we report the current status of research on antiviral drugs and vaccines for chikungunya virus infections.
Keywords: Antivirals - arthralgia - chikungunya - CHIKV - vaccines
|How to cite this article:|
Bettadapura J, Herrero LJ, Taylor A, Mahalingam S. Approaches to the treatment of disease induced by chikungunya virus. Indian J Med Res 2013;138:762-5
|How to cite this URL:|
Bettadapura J, Herrero LJ, Taylor A, Mahalingam S. Approaches to the treatment of disease induced by chikungunya virus. Indian J Med Res [serial online] 2013 [cited 2021 Sep 22];138:762-5. Available from: https://www.ijmr.org.in/text.asp?2013/138/5/762/124694
| Introduction|| |
Chikungunya virus (CHIKV) is an arthropod-borne virus belonging to the Family, Togaviridae, and genus, Alphavirus. In this group of 29 viruses, six cause arthralgia and arthritis upon infection in humans. These six viruses are CHIKV, Ross River virus (RRV), Semliki Forest virus (SFV), o'nyong-nyong virus (ONNV), Sindbis virus (SINV) and Mayaro virus (MAYV). CHIKV was first isolated from a febrile patient in Tanzania in 1952  . The name chikungunya means "that which bends up" and refers to the contorted posture adopted by infected patients. Symptomatic CHIKV infections are characterised by fever, rashes and arthralgia leading to arthritis. In the last 50 years there have been frequent outbreaks of CHIKV disease in Asia and Africa. In 2005-2006 an outbreak that occurred in La Réunion Island resulted in approximately 260,000 cases of CHIKV associated fever with 237 deaths reported  . Additionally, in 2006-2007 around 1.5 million cases of CHIKV disease were reported in India  . Through viral adaptation CHIKV has broadened its vector competence and therefore increased its potential to cause human disease. A single mutation, A226E in the envelope protein 1 (E1) of CHIKV, now allows Aedes albopictus as well as
Ae. aegypti mosquitoes to transmit CHIKV  .
Currently there are no vaccines or antivirals for the prevention or treatment of CHIKV infections. Treatment is symptomatic with analgesics, antipyretics and non-steroidal anti-inflammatory agents. Passive immunization with human IgGs derived from CHIKV infected patients has been shown to be protective in mice against CHIKV challenge  . This approach may prove effective for the prevention and treatment of neonates who are at the risk of infection from viraemic mothers. However, this is not cost-effective and it is critical to develop antiviral drugs and/or vaccines for the control of CHIKV infections.
Owing to the recent outbreaks of CHIKV in Asia, Africa and La Réunion island there has been a renewed interest in the development of antiviral drugs and vaccines to manage CHIKV infections. In this article, we report on the advancements made towards the development of anti-inflammatory agents, antivirals and vaccines for the efficient control of CHIKV infections.
| Antiviral compounds|| |
Chloroquine phosphate was reported to be effective in the treatment of chronic CHIKV arthritis  . However, in a clinical trial of chloroquine in CHIKV infected patients, no difference was observed between the placebo group and the treatment group  . Maheshwari et al have also reported that in a mouse model, chloroquine enhances alphavirus replication and aggravates disease pathogenesis. Ribavirin, an antiviral agent was used to treat CHIKV induced arthritis in a small cohort of patients and was found to be beneficial in resolving joint and soft tissue swelling  . Briolant et al have reported a synergistic effect of ribavirin and interferon-α in the inhibition of CHIKV and SFV replication in cell culture. Recently Rulli et al  have reported using bindarit, a small molecule anti-inflammatory drug, in a mouse model to effectively treat CHIKV induced arthritis. Bindarit has also been demonstrated to have significant effect in ameliorating RRV induced arthritis  .
An additional 356 compounds (natural and clinically approved drugs) were initially screened for their antiviral effects using a CHIKV replicon cell line  . A recombinant CHIKV with Rluc (Renilla luciferase) fused with nonstructural protein 3 (CHIKV-Rluc) was constructed and used to validate the most active compounds from the initial screening studies. Out of 12 selected compounds, coumarin 30 was found to be the most potent in inhibiting the replication of CHIKV-RLuc virus (IC 50 value of 6.4 μM). Arbidol, licensed for the treatment of influenza and other respiratory infections, was found to be effective in inhibiting CHIKV replication in Vero and MRC-5 cell lines (IC 50 <10μg/ml)  . Recently, screening of a highly purified natural compound library for inhibition of CHIKV replication identified 44 inhibitors  . Among the selected compounds, harringtone, a cephalotoxine alkaloid, was found to be a potent inhibitor of CHIKV infection with an EC 50 value of 0.24 μM. This drug was found to inhibit the early stages of CHIKV replication. As this was also found to inhibit SINV replication suggesting the drug may be effective against other alphaviruses. In another study, an optimal homology model of CHIKV nonstructural protein 2(nsp2) protease was created using comparative modelling approach. Based on the active site of nsP2 model, a virtual screening was performed with commercially available compounds subsequently 26 compounds were evaluated for the anti-CHIKV activity in a cell culture assay  .
| Vaccines|| |
Several approaches have been undertaken to develop an effective vaccine against CHIKV infections. Levitt et al described the development of an attenuated strain of CHIKV (181/25) obtained by serial passage in MRC-5 cells. This vaccine candidate was tested in both mice and non-human primates and was found to protect the animals against challenge with parent virus. However, in Phase II trials the vaccine caused mild transient arthralgia in some of vaccinees  . Recent attempts to develop a CHIKV vaccine have used formalin inactivated vaccine  , virus like particles (VLPs)  and DNA vaccines , . Immunization with VLPs and DNA vaccines resulted in immunogenicity and protected the mice and non-human primates against subsequent challenge with CHIKV.
Chimaeric viruses containing Venezeulean equine encephalitis virus (VEEV) or Eastern equine encephalitis virus (EEEV) or SINV non-structural proteins with CHIKV structural proteins elicited neutralizing antibodies and protected the mice against CHIKV challenge  . However, these viruses still had the ability to infect mosquitoes and attenuation was dependent on an intact interferon response in mice. Another chimaeric vaccine using VEEV strain TC-83 and encepahalomyocarditis virus (EMCV) IRES (internal ribosome entry site) in the subgenomic promoter was developed to reduce the transmission to mosquitoes. The EMCV IRES sequence cannot efficiently drive translation in arthropod cells. This vaccine was poorly immunogenic and lacked neutralizing antibody response  . Recently Chattopadhyay et al developed a chimaeric vaccine using a vesiculostomatitis virus (VSV) backbone and CHIKV structural proteins (VSV∆G-CHIKV). This VSV∆G-CHIKV chimaeric virus induced a good neutralizing antibody response and protected mice against CHIKV infection.
Plante et al designed a vaccine by introducing the EMCV IRES sequence into the CHIKV subgenomic promoter. This reduced the replication of the vaccine strain in mosquitoes and was highly immunogenic in mice. This vaccine is now undergoing preclinical trials in non-human primates.
| Short interfering RNA (siRNA) and short hairpin RNAs (shRNA)|| |
siRNAs and shRNAs against envelope protein E1, nsP3, capsid and nsP1 proteins of the CHIKV have been used to inhibit the replication of CHIKV in mammalian cells with promising results , . Furthermore, in vivo studies have shown that shRNA E1 offers a strong and sustained protection against CHIKV infection in suckling mice.
| Other therapeutic options|| |
Studies on the role of mannose binding lectin (MBL) in RRV-induced arthritis in mice  suggest that MBL may be a target for therapeutic intervention in the treatment of alphavirus induced arthritis/myositis. Inhibitors targeting the MBL pathway of complement may be useful in the treatment of alphavirus induced diseases. Additionally, a peptide corresponding to the autophagy inducing peptide, beclin, has been shown to be effective against CHIKV infections in cell culture and in mice  .
A recent study on gene profiling has revealed a significant overlap of differentially expressed genes involved in the inflammatory processes of both CHIKV- induced arthritis and rheumatoid arthritis (RA). Thus, new drugs being developed for RA might also be beneficial for the treatment of alphavirus induced arthritis  .
| Conclusions|| |
Chikungunya fever is a global health problem and several outbreaks have occurred in the last 50 years in Asia and Africa. Recent outbreaks in La Réunion and Italy have raised the awareness of the need to develop effective antiviral drugs or vaccines against CHIKV. Although many antiviral compounds have been shown to be effective in cell culture, very few compounds have been evaluated in animal models. Intensive studies are needed to evaluate the effect of appropriate compounds in animal models and humans.
| Acknowledgment|| |
This study was supported by a grant from the Australian National Health and Medical Research Council (NHMRC Project Grant 508600).
| References|| |
|1.||Robinson MC. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53. I. Clinical features. Trans R Soc Trop Med Hyg 1955; 49 : 28-32 . |
|2.||Renault P, Solet, JL, Sissoko D, Balleydier E, Larrieu S,Filleul L, et al. A major epidemic of chikungunya virus infection on Reunion Island, France, 2005-2006. Am J Trop Med Hyg 2007; 77 : 727-31. |
|3.||Arankalle VA, Shrivastava S, Cherian S, Gunjikar RS, Walimbe AM, Jadhav SM, et al. Genetic divergence of Chikungunya viruses in India (1963-2006) with special reference to the 2005-2006 explosive epidemic. J Gen Virol 2007; 88 : 1967-76. |
|4.||Tsetsarkin KA, Vanlandingham DL, McGee CE, Higgs SA. Single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog 2007; 3 : e201. |
|5.||Couderc T, Khandoudi N, Grandadam M, Visse C, Gangneux N, Bagot S, et al. Prophylaxis and therapy for Chikungunya virus infection. J Infect Dis 2009; 200 : 516-23. |
|6.||Brighton, SW. Chloroquine phosphate treatment of chronic Chikungunya arthritis. An open pilot study. S Afr Med J1984; 66 : 217-8 . |
|7.||De Lamballerie X, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, et al. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis 2008; 8 : 837-9. |
|8.||Maheshwari RK, Srikantan V, Bhartiya D. Chloroquine enhances replication of Semliki Forest virus and encephalomyocarditis virus in mice. J Virol 1991;65 : 992-5. |
|9.||Ravichandran R, Manian M. Ribavirin therapy for Chikungunya arthritis. J Infect Dev Ctries 2008; 2 : 140-2. |
|10.||Briolant S, Garin D, Scaramozzino N, Jouan A, Crance JM. In vitro inhibition of Chikungunya and Semliki Forest viruses replication by antiviral compounds: synergistic effect of interferon-alpha and ribavirin combination. Antiviral Res 2004; 61 : 111-7. |
|11.||Rulli NE, Rolph MS, Srikiatkhachorn A, Anantapreecha S, Guglielmotti A, Mahalingam S. Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis. J Infect Dis 2011; 204 : 1026-30. |
|12.||Rulli NE, Guglielmotti A, Mangano G, Rolph MS, Apicella C, Zaid A, et al. Amelioration of alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteins. Arthritis Rheum 2009; 60 : 2513-23. |
|13.||Pohjala L, Utt A, Varjak M, Lulla A, Merits A, Ahola T, et al. Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS One 2011; 6 : e28923. |
|14.||Delogu I, Pastorino B, Baronti C, Nougairède A, Bonnet E, de Lamballerie X. In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutant. Antiviral Res 2011; 90 : 99-107. |
|15.||Kaur P, Thiruchelvan M, Lee RC, Chen H, Chen KC, Ng ML, et al. Inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob Agents Chemother 2013; 57 : 155-67. |
|16.||Bassetto M, De Burghgraeve T, Delang L, Massarotti A, Coluccia A, Zonta N, et al. Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus. Antiviral Res 2013; 98 : 12-8. |
|17.||Levitt NH, Ramsburg HH, Hasty SE, Repik PM, Cole FE Jr, Lupton HW. Development of an attenuated strain of chikungunya virus for use in vaccine production. Vaccine 1986; 4 : 157-62. |
|18.||Edelman R, Tacket CO, Wasserman SS, Bodison SA, Perry JG, Mangiafico JA. Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD 218. Am J Trop Med Hyg 2000; 62 : 681-5. |
|19.||Tiwari M, Parida M, Santhosh SR, Khan M, Dash PK, Rao PV. Assessment of immunogenic potential of Vero adapted formalin inactivated vaccine derived from novel ECSA genotype of Chikungunya virus. Vaccine 2009; 27 : 2513-22. |
|20.||Akahata W, Yang ZY, Andersen H, Sun S, Holdaway HA, Kong WP, et al. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat Med 2010; 16 : 334-8. |
|21.||Muthumani K, Lankaraman KM, Laddy DJ, Sundaram SG, Chung CW, Sako E, et al. Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine 2008; 26 : 5128-34. |
|22.||Mallilankaraman K, Shedlock DJ, Bao H, Kawalekar OU, Fagone P, Ramanathan AA, et al. A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. PLoS Negl Trop Dis 2011; 5 : e928 . |
|23.||Weaver SC, Osorio JE, Livengood JA, Chen R, Stinchcomb DT. Chikungunya virus and prospects for a vaccine. Expert Rev Vaccines 2012; 11 : 1087-101. |
|24.||Plante K, Wang E, Partidos CD, Weger J, Gorchakov R, Tsetsarkin, K, et al. Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism. PLoS Pathog 2011; 7 : e1002142. |
|25.||Chattopadhyay A, Wang E, Seymour R, Weaver SC, Rose JK. A chimeric vesiculo/alphavirus is an effective alphavirus vaccine. J Virol 2013; 87 : 395-402. |
|26.||Dash PK, Tiwari M, Santhosh SR, Parida M, Lakshmana Rao PV. RNA interference mediated inhibition of Chikungunya virus replication in mammalian cells. Biochem Biophys Res Commun 2008; 376 : 718-22 . |
|27.||Lam S, Chen KC, Ng MM, Chu JJ, Expression of plasmid-based shRNA against the E1 and nsP1 genes effectively silenced Chikungunya virus replication. PLoS One 2012; 7 : e46396. |
|28.||Gunn BM, Morrison TE, Whitmore AC, Blevins LK, Hueston L, Fraser RJ, et al. Mannose binding lectin is required for alphavirus-induced arthritis/myositis. PLoS Pathog 2012; 8 : e1002586. |
|29.||Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z, Kinch L, et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 2013; 494 : 201-6. |
|30.||Nakaya HI, Gardner J, Poo YS, Major L, Pulendran B, Suhrbier A. Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis. Arthritis Rheum 2012; 64 : 3553-63. |