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Article history:
Received 22 April 2014
Accepted 25 August 2014
Keyword:
Chikungunya
a b s t r a c t
Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family that causes chronic and incapacitating arthralgia in human populations. Since its discovery in 1952, CHIKV was responsible for sporadic
and infrequent outbreaks. However, since 2005, global Chikungunya outbreaks have occurred, inducing
some fatalities and associated with severe and chronic morbidity. Chikungunya is thus considered as
an important re-emerging public health problem in both tropical and temperate countries, where the
distribution of the Aedes mosquito vectors continues to expand. This review highlights the most recent
advances in our knowledge and understanding of the epidemiology, biology, treatment and vaccination
strategies of CHIKV.
2014 Elsevier B.V. All rights reserved.
1. Introduction
Chikungunya virus (CHIKV) is an alphavirus from the Togaviridae family, which is transmitted by Aedes mosquitoes, and causes
epidemic arthritis or arthralgia together with fever and rash. It is
part of the Semliki Forest virus antigenic complex that also contains ONyong Nyong, Mayaro and Ross River viruses [1]. CHIKV
is a positive-sense, single-stranded RNA virus of about 11.8 kb
(Fig. 1). There are three main genotypes, West African, Central/East
African (C/EA), and Asian, the names reecting the initial geographic restriction of each type. Since CHIKV was rst isolated in
Tanzania in 1952 [2], the disease was mainly conned to localized
outbreaks in Asia and Africa, sometimes with hundreds of thousands of cases [3]. In 2005, a C/EA strain of CHIKV, which likely
Fig. 1. Genomic structure of CHIKV and expected function of the produced proteins.
CHIKV has a typical alphavirus genomic organization: 5 -nsP1-nsP2-nsP3-nsP4junction region-C-E3-E2-6K-E1-poly (A)-3 with two open reading frames (ORFs).
The 5 end of the genome has a 7-methylguanosine cap and there is a polyadenylation signal at the 3 end. The 5 ORF is translated from genomic RNA and encodes
four non-structural proteins (nsP1, 2, 3 and 4) encoding for the synthesis of RNA
capping, helicase protease, RNA and RNA dependent RNA polymerase [121]. The 3
ORF is translated from a subgenomic 26S RNA and encodes a polyprotein that is
processed as the capsid protein (C), two surface envelope glycoproteins (E1 and E2),
a small peptide designated E3, and two proteins with ion-channel activity, 6K and
the transframe protein [53,122].
145
Fig. 2. Biological life cycle of Chikungunya virus with interconnection between rural
and urban cycles. In Africa, the CHIKV transmission cycle is considered as sylvatic
and enzoonotic, and human infections are due to occasional spillovers and happen
mostly in rural zones. Urban CHIKV introduction is thought to be due to human
migrations. In Asia, outbreaks occur mostly in urban areas, and virus maintenance
is associated with continuous introduction of the virus into new areas and new
nave human populations. In relation to type of cycle (urban vs. rural), the mosquito
vectors involved are different.
146
Fig. 3. Geographical distribution of reported outbreaks of chikungunya virus infection in African and Asian regions. Each country presenting CHIKV outbreaks is colored
differently in relation to the outbreaks dates: in green the old outbreaks countries (corresponding to the countries presenting outbreaks only before 2004), in blue countries
touched by outbreaks before and after 2004 and in red the new outbreaks countries (corresponding to the countries where outbreaks occurred only since or after 2004).
to spread during the early stages of the disease [35]. Viral protein recruitment of cell components is prominent, as highlighted
in the selection of ubiquinated capsid by the autophagy receptor p62 promoting cell survival, and the binding of human NDP52
(but not mouse) to nsP2, which promotes viral replication [36].
This may explain the exquisite differences observed in the nonhuman primate and mouse models despite a general involvement
of macrophages in viral persistence [31,3739].
In contrast to new-world alphaviruses, CHIKV RNA packaging
signal was found in the nsP2 sequence, not in nsP1, and is recognized by chikungunya capsid [40]. Moreover, a mutation in nsP2
protease (P718S) showed a role in inhibition of JAK-STAT signaling following IFN type 1 cell activation [41], probably by inhibiting
nsP2 nuclear localization [42]. Another in vitro study, comparing
CHIKV and Sindbis, showed that for CHIKV nsP4, but not Sindbis, the RNA dependent RNA polymerase might specically inhibit
phosphorylation of cellular eIF2a and thus modulate the unfolded
protein response to control the host cells fate [43]. The nsP3 protein
seems to be the most exible protein of the viral genome, as it is the
only place where protein markers can be stably inserted without
modifying CHIKV viral replication [44]. Evolution however seems
to maintain a role in intracellular structure which may vary largely
between alphaviruses and support the need to explore the CHIKV
nsp3 [45]. Specically, CHIKV nsP3 blocks stress granule assembly
by recruitment of G3BP into cytoplasmic foci, and amphiphysin2, which is involved in efcient viral RNA synthesis [46,47]. Some
of these functions are shared within the SFV alphavirus subgroup
[45,47]. Furthermore, nsP3 may play a role in host cell specicity, as
introducing the Onyong nyong nsP3 gene within a CHIKV backbone
allowed a vector shift to Anopheles [21].
In addition to nsP3, motifs in the viral envelope are involved in
the capacity to bind and infect various host cells. Concerning the
vector shift, from Ae. aegypti to Ae. albopictus, so important in the
current outbreaks, the E1-E226V mutation is major, [4851] but
epistatic mutations in E2 (E2-D60G and E2-I211T) may modulate
this effect and even explain the absence of adaptation of the Asian
virus strain to Ae. albopictus [49]. Surprisingly other E1E2 mutant
viruses obtained by truncation of the trans-membrane part of E2
(TMB position AA 374 to 383) remained infectious in mosquito cells
but are attenuated in the vertebrate susceptible host, showing a
complex relationship between infection and pathogenic capacity
[52]. A recent study identied a transframe protein related to the
structural protein 6K which plays a role in particle release in addition to E3 [53,54]. Recently, it was demonstrated that mutants E2
(E2-E166K) in CHIKV viruses, probably found in virus quasi-species,
are able to counteract IFN-induced genes like OAS-3 and ZAP and
in addition trigger a quasi-pure apoptosis phenotype in vitro ([32];
P. Desprs unpublished). Of note, because the packaging of viruses
not only involves the structural proteins but also some of the nonstructural ones, compensatory mutations were observed in nsP
genes as recently described for VEEV nsP2 [42,55].
4. Advances in immuno-virology: mechanisms of
pathogenesis
Following the bite of an infected mosquito, CHIKV is injected
into blood capillaries and dermis. During this intradermal stage,
CHIKV infects the most common cells of connective tissues, epithelial cells and dermal broblasts (Fig. 4). These cells have been shown
to be susceptible to infection and allow viral production [56,57].
Thus viruses produced by both host broblasts and mosquitoes
enter the blood vessels. During the acute phase of infection, CHIKV
antigens can be detected in vivo in blood monocytes [58]. However, it seems that monocytes become a signicant target for CHIKV
only when high levels of virus are present in the circulation. Even
if these cells might be infected, they did not produce substantial
levels of new viruses [58]. This step corresponds to the acute stage
of the CHIKV infection, which can last up to 12 days [59]. At this
stage, viral load can be extremely high, at >108 copies/mL [60]
(Figs. 4 and 5). Because of their extensive distribution among the
147
Fig. 4. Chikungunya infection pathogenesis model. Following the bite of an infected mosquito, CHIKV is injected into blood capillaries and dermis. During this intradermal
stage, CHIKV infects human epithelial cells and dermal broblasts. Blood monocytes and macrophages then become infected with CHIKV and viral replication happens
(>108 copies/m). Monocytes are then responsible for viral dissemination and systemic infection. The principal secondary infection sites are muscles and joints, endothelial
cells of the liver and the brain and macrophages and stroma cells of the spleen and lymph nodes. Immune responses are also induced, with high production of IFN- and
liberation of several cytokines and chemokines.
148
Fig. 5. Chikungunya virus infection evolution and clinical diagnosis. After transmission of CHIKV through an infected mosquito bite, a period of incubation begins for
24 days on average. Then, an abrupt clinical onset is observed which lasts between
7 and 10 days. During this time, viral load may be extremely high, exceeding 108 viral
copies/ml of blood, and is followed by activation of innate immunity leading to high
levels of interferon (IFN). Anti-CHIKV antibodies can be detected in patients shortly
after symptoms onset, usually from 4 to 6 days for IgM, and remain detectable for
several weeks to several months. IgG are detectable only a few days later (715
days), and persist for life.
are not widely available in most endemic countries. Both methods are most useful in the rst 7 days of acute symptoms, when
viremia is present before IgM becomes detectable (Fig. 5). Numerous conventional and real-time RT-PCR assays have been described
[60,86]. Peak viremia levels are seen at days 13 of symptoms and
RNA from non-viable virus can still be detected in the presence of
antibodies as late as day 12 [60]. Apart from increased sensitivity
compared to conventional PCR, real-time PCR also allows viral load
quantication, which warrants further study as a potential indicator of prognosis. At present, conicting data exist as to whether
higher viral loads are associated with increased [38] or reduced risk
of persistent arthralgia [87], or if there is no link [83]. An alternative
for diagnosis during the early stages of infection is antigen detection, of which there are two reports, [88], [89] although further
evaluation of performance is required.
CHIKV patients often do not present early in infection; in Sri
Lanka and Malaysia, patients presented at a median of 45 days [90]
(Sam, unpublished). The serological detection of IgM is thus important. However, the limited data available on use of commercial kits
in a clinical setting are disappointing. A commercial immunouorescence assay had a sensitivity of 76% at day 5 and 100% at
day 7 [91], but most diagnostic laboratories in endemic areas are
unlikely to have a uorescence microscope. Other ELISA and rapid
immunochromatographic tests (ICT) performed poorly, with sensitivity rates of 022% before day 7, and 1783% after day 7, when
retrospective diagnosis is of less clinical value [90,92], [93]. Furthermore, performance of the tests is affected by the match between
the antigen used in the assay and the circulating CHIKV strain, presumably leading to differences in IgM binding. In Singapore, an ICT
using recombinant E1-226A had a sensitivity of 77% for samples collected at days 57 during an outbreak of CHIKV bearing E1-226A;
during a later outbreak of CHIKV with E1-226V, sensitivity fell to
0% [91]. The use of CHIKV antigens of C/EA origin in ICTs may also
explain the poor sensitivities of 2053% in Indonesia, where the
Asian genotype of CHIKV was circulating [92]. Currently available
CHIKV IgM kits therefore are either unsuited, or cannot be solely
relied upon for diagnosis of acute infection.
There remains a need for simple, affordable, sensitive and specic diagnostic tests for CHIKV in developing countries, for the
different periods over which a patient may present, preferably at
the point of care. For early presentations of <7 days, an RNA/antigen
detection assay would be appropriate. Loop-mediated isothermal
amplication is a possible option for resource-limited settings,
as it can be performed in a single tube at a single temperature
in a water-bath, with greater sensitivity than conventional PCR
[94]. For presentations after >5 days, an IgM assay is necessary
[86]. Recently, patients antibody responses to CHIKV proteins have
been characterized, showing that linear epitopes at the N terminus
of E2 glycoprotein induce early antibodies that persist, although
binding may be affected by a K252Q change which can occur
naturally [95]. Further work is needed to identify and validate wellconserved antigens that may be reliably used for serological assays.
All new assays will then require subsequent testing with wellcharacterized samples in different settings with genetically diverse
circulating strains.
149
Acknowledgments
The authors are grateful to Dr. Philippe Desprs for helpful comments and for providing unpublished data. We are also thankful to
Caroline Petitdemange from CIRMF for help in editing the text and
gures.
Funding
PR and ICS received funding from the European Unions Seventh Framework Program ICRES (Grant Agreement No. 261202).
ICS was funded by University Malaya (UMRG grant RG526-13HTM
and PPP Grant PG030-2012B) and the Ministry of Higher Education,
Malaysia (FRGS Grant FP036-2013A).
Competing interests
The authors declare they have no competing interest.
Ethical approval
Not required.
150
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