Alexander Gold - CAEV Literature Review for Industry

Caprine Arthritis Encephalitis Virus: a review
Alexander Gold1
and Sarah Wootton1
1
Department of Pathobiology
Ontario Veterinary College
University of Guelph
June 29, 2012
Revised August 27, 2012

CAPRINE ARTHRITIS‐ENCEPHALITIS VIRUS: A REVIEW FOR THE ONTARIO GOAT ASSOCIATION  2 
 
Part I – Introduction to Caprine Arthritis and Encephalitis
Caprine arthritis and encephalitis (CAE) is a widely disseminated lentiviral disease of goats that
is caused by the caprine arthritis encephalitis virus (CAEV). Infection with CAEV adversely
affects the quality of life of infected animals, is associated with decreased milk production, and
poses a barrier to exportation of goats from North America. Thus, there is an urgent need to
establish prevention and control strategies to combat this disease.
CLINICAL SIGNS
CAEV infection causes a significant production limiting disease in goats due predominantly to
indurative mastitis (hard udder due to the deposition of vast quantities of connective tissue in
the udder as part of the immune response) in which milk production is diminished or abrogated
altogether. CAEV infection of synovial tissues causes severe polyarthritis in adult goats 1 to 2
years of age and is the most common form of the disease (24). Affected goats gradually lose
weight and develop enlarged joints, particularly the carpal, hocks, and stifle. Early in the course
of the disease, affected animals may show progressive and sometimes irregular, leg lameness,
however, as the disease progresses, affected goats may walk on their knees or refuse to rise.
Less commonly, the virus will infect choroid plexus of kids 2 to 4 months of age and will lead to
leukoencephalomyelitis and coagulative encephalopathy. Lameness, ataxia and hind limb
placing deficits are the initial signs of encephalomyelitis, and numerous other neurological
deficits develop over time. Other less observed signs include interstitial pneumonia and chronic
wasting. It is important to note that most infections are subclinical and seroconversion of an
infected animal occurs between 3 months and several years (24).
TRANSMISSION
CAEV is predominantly transmitted through colostrum and milk from the doe to her kid, and a
single oral exposure may be sufficient for infection (13). Both free virus and virus-infected cells

 
(macrophages) are present in the milk and colostrum of infected lactating does, however it is not
known which form of the virus is responsible for infection (6). Interestingly, in a group of kids
separated from their mothers at birth and fed only pasteurized or synthetic milk, a small
percentage of animals still seroconverted indicating that transmission may occur from doe to
fetus prior to or during the birth process (5, 13). Transmission through fomites and close contact
has also been observed (13). Additionally, farm equipment may play a role in transmission as
milking machines have an established role in the spread of mastitis causing organisms (27).
Travassos et al. demonstrated that the semen of infected bucks contains replication competent
CAEV, suggesting the possibility of sexual transmission (42). However, Blacklaws et al. found
that semen from seropositive bucks does not seem to represent a serious risk factor (5).
It is important to note that an individual goat’s susceptibility to viral infection may vary depending
on heritable genetic variations. The first study to reveal a genetic predisposition to CAEV-
induced arthritis in the goat was published by Ruff and Lazary (1988) in which they reported a
genetic linkage between MHC class I gene products and susceptibility to CAEV (35). Further
evidence supporting a genetic predisposition to small ruminant lentivirus infections has been
obtained through the study of a highly related virus called Maedi-Visna Virus (MVV), which
predominantly infects sheep. Berriatua et al. found that risk of seroconversion to MVV was 50%
lower in offspring from a seronegative ewe over 4 years of age, suggesting that the 4-year-old
seronegative ewes and their lambs may harbor some genetic resistance to MVV (4). A recent
analysis of single nucleotide polymorphisms (SNPs) to identify genetic risk factors for MVV
infection discovered that variation in the ovine gene TMEM154 was associated with infection
(19). Interestingly, sheep homozygous for this mutation remained seronegative for MVV despite
being housed with seropositive sheep for over 11 years (19).

 
PATHOGENESIS
The pathogenesis of CAEV is not well understood. CAEV is a member of the retrovirus family
of lentiviruses, so named because of their slow infections (lente is Latin for “slow”). These
viruses show the remarkable ability to infect cells that are not actively dividing. CAEV, through
its various routes of transmission, enters the blood stream, targeting monocytes and some
dendritic cells (15). Monocytes are an immature form of white blood cell that travels through the
bloodstream until they are signaled to migrate into the peripheral tissues. This migration
triggers their maturation into macrophages: cells that engulf and digest foreign particles and
invading cells. CAEV initially remains dormant inside the circulating monocytes. The virion
matures as the monocyte matures into a macrophage (16). Virus replication within the white
blood cells induces a local inflammatory response leading to the various clinical signs. The
virus buds from the macrophages and infects local tissues. Pathogenesis predominantly occurs
in the synovial membranes (arthritis), choroid plexus (encephalitis), and mammary glands
(mastitis).
With respect to arthritis, CAEV infection has been shown to increase the percentage of dividing
macrophages in the synovial fluid of goats as much as sixfold and this increase in macrophage
cell division correlates with joint swelling and increased numbers of synovial fluid macrophages
(20). In a subsequent study, infection by CAEV was shown to increase the reactivity of
lymphocytes and macrophages to immune and non-immune stimuli, possibly contributing to the
increased likelihood of progressive arthritis in infected animals (3). Moreover, studies have
shown that CAEV infection of macrophages can dysregulate cytokine expression in these cells,
which can in turn modulate the accessory functions of infected macrophages and the antiviral
immune response in vivo (21). A practical implication of this phenomenon is that trauma to the
joints, due to poor environmental and/or housing conditions, may stimulate CAEV infected
macrophages thereby exacerbating the disease.

 
DIAGNOSIS
Early diagnosis of CAEV is essential for prevention of infection and control of the disease.
Numerous laboratory tests are capable of detecting CAEV from blood or tissue samples, many
of which are labour intensive and not useful for widespread screening purposes; for example
radioimmuoprecipitation assay (RIPA), radioimmuno assay (RIA) and western blotting (WB).
Currently, agar immunodiffusion (AGID) and enzyme-linked immunosorbent assay (ELISA) are
the two internationally prescribed tests. In 2004, Peterhans et al. found that AGID was 91%
sensitive and 100% specific to RIA (29), and in 2005 de Andres et al. found AGID to be 76%
sensitive and 98% specific to ELISA. This clearly indicates that ELISA is the technique of
choice for all antibody-based detection methods and is ideal for performing regular screens.
Typically, DNA based analysis through use of polymerase chain reaction (PCR) and sequencing
would be the gold standard, however as a retrovirus, CAEV has a large amount of genomic
heterogeneity thereby diminishing the sensitivity of currently designed primers to amplify
different strains. Furthermore, CAEV maintains extremely low viral loads in the host, decreasing
the probability of collecting viral DNA from an infected animal. Interestingly, PCR can be
positive in seronegative animals due to late seroconversion and reported seroreversion of
infected animals (12). ELISA complimented with DNA testing is the best diagnostic strategy,
however an initial screening of the local antigenic and genetic variation is recommended to
optimize the sensitivity of these assays. Isolation of viral DNA is best from peripheral blood
mononuclear cells over milk, colostrum, semen and synovial fluid (14).
PREVALENCE
There is currently no data to indicate the prevalence of CAEV in Ontario goat herds. Upon
examination of the literature, it is typical to see high seroprevalence in goat populations prior to
control and eradication measures being implemented. For example, prior to implementation of
a national eradication program, Switzerland reported a seroprevalence of 83% in 1989 (38). In

 
1992, a prevalence study involving goats across 28 states in the United States of America
reported 31% seropositivity with at least one infected animal in 73% of the farms (11). Based
on the literature and reports from local veterinarians, it is expected that the seroprevalence of
CAEV in Ontario is high. In 1984, a global serological survey found Canada to be 65% positive
or higher for CAEV (1).
TREATMENT AND CONTROL
Currently there is no specific treatment available for CAEV infected goats, only supportive care
of the individual animals and infection control for the herd are employed (24). Arthritic changes
may be managed with non-steroidal anti-inflammatories, additional bedding and regular foot
trimming. Secondary bacterial infections associated with interstitial pneumonia can be treated
with antimicrobial therapy, and high quality, easily digestible feed given to seropositive goats
may delay onset of chronic wasting (24).
The most effective mechanism for prevention and control of a virus is usually vaccination.
Currently, no vaccine is available for CAEV. Initially, researchers attempted to produce a live
attenuated vaccine with limited success (28). More recently, the focus has moved towards viral
clones, genetically modified viruses, and recombinant plasmids. Cheevers et al. in 2003
demonstrated that vaccination with plasmid DNA encoding CAEV envelope and surface
antigens would suppress infection and the development of arthritis (8). Goats infected with
proviral DNA or virus with the tat gene removed, a transcriptional activator, maintained a
persistent infection of the vaccine strain conferring significant protection against wildtype CAEV
infection (18). Furthermore, a non-pathogenic MVV clone decreased viral load and delayed
lesion development in sheep after challenge and this was associated with production of
antibodies (41). The current prototype vaccines may confer significant protection, however,
they have not been successful in preventing infection.

 
Control and eradication programs begin by determining the current seroprevalence of the virus
in the population. This can then be used as a reference to indicate change over the course of
the program. Isolating kids from their mothers at birth prevents nursing and can eliminate the
primary form of transmission, however this strategy will not be effective unless the kids are fed
only pasteurized colostrum or milk (56° for 60 min), cow colostrum or milk, or commercial milk
replacers. Kids should be reintroduced back into the herd between weaning and their first
lactation. Following these strategies will significantly decrease the rate of infection, however
seroconversion will continue to occur (24, 25, 29, 34). Transmission can occur through
numerous other routes including close contact, shared farm equipment such as feed and water
troughs as well as milking equipment (27). Annual or semi-annual screening of each herd is
recommended, and seropositive and seronegative animals should be separated. All shared
farm equipment should be thoroughly disinfected using phenolic or quaternary ammonium
compounds. Eventually seropositive animals should be culled. In farms with a moderately high
seroprevalence, rate of seroconversion can be lower than that of culling. If approximately 15 to
20% of the herd is culled each year, then it is possible to gradually decrease seroprevalence
without increasing the rate of culling (4).
It is recommended that continuous screening of the farms be linked to an accreditation program
and according to one study (33), accreditation should be applied when the seroprevalence is
<10%. The number and frequency of retests required to definitively reach SRLV-free status
varies between countries and ranges from 2–5 tests, carried out every 6 months, yearly or every
2 years (26). Both CAEV and MVV should be jointly controlled in order to avoid viral spread
between species as mixed sheep/goat flocks involving CAEV-negative goats and seropositive
sheep may lead to goat re-infections (7). The OIE (World Organisation for Animal Health)
recommends that goats shipped between farms must test seronegative for 30 days before
transfer, and the originating farm should have been seronegative for 3 consecutive years.

 
Additionally, breeding bucks must be seronegative before they are bred or their semen is
entered into artificial insemination programs. If there is interest in maintaining the genetic lines
of seropositive animals, neonates can be obtained by caesarean section (26) or immediately
after birth, eliminating physical contact with the mother (5). These kids should be fed, as
discussed earlier, with uninfected milk and colostrum or milk replacement (4). If possible, when
starting a new herd, it is recommended to use kids born to mothers who have tested
seronegative for several years, as there is evidence to suggest that they may have some
genetic resistance to infection (4).
Producers should also be aware of the possibility of cross-species transmission between sheep
and goats. CAEV has a very high genetic similarity to the sheep MVV, and there is evidence for
natural cross species transmission (38, 39). MVV and CAEV are often lumped into the group
known as small ruminant lentiviruses. MVV has been shown under experimental conditions to
transfer both from sheep to goat, and from goat to sheep (2). Furthermore sheep were
experimentally shown to be susceptible to CAEV infection, and mixing sheep and goats was
unfavorable in eradication programs (2).
Part II - The Molecular Biology of CAEV
GENOME STRUCTURE
CAEV is a lentivirus in the family Retroviridae. Its genome is a linear, single stranded, positive
sense RNA molecule approximately 9kb in length that is packaged in duplicate within a
nucleocapsid surrounded by lipid envelope (22, 36) (Fig. 1). The genome is flanked by long
terminal repeat regions (LTRs) that carry out enhancer, promoter, and transcription initiation
functions. There are four key genes (5'-gag-pro-pol-env-3') present on the genome (Fig. 1).
gag is the “group specific antigen” and contains the sequence for three proteins: matrix, major

 
capsid protein and the nucleocapsid protein, all important for forming the protein coat on the
virus. pro codes for a protease responsible for cleaving the precursor polyproteins (like Gag)
into their functional units (like matrix, capsid and nucleocapsid). pol is a gene which codes for
the reverse transcriptase and the viral integrase, together functioning to reverse transcribe the
viral RNA genome into DNA and then insert a double stranded DNA copy of the viral genome
into a host chromosome. env is a gene which codes for the envelope glycoprotein, which is
subsequently cleaved into the surface and the transmembrane proteins.
Figure 1. Organization of the CAEV genome and virion. The 5′ and 3′ long terminal repeats
(LTRs) are shown as white boxes. ORFs encoding the canonical Gag, Pro, Pol and Env
proteins are shown in grey whereas the ORFs encoding the auxillary nonstructural proteins, Vif
(viral infectivity factor), Tat (transcriptional trans-activator protein) and Rev, are represented by
black boxes. Note that the Rev protein is encoded by two reading frames found within the env
gene. The Gag-Pro-Pol polyprotein is cleaved into the matrix (MA), capsid (CA), nucleocapsid
(NC), protease (PR), reverse transcriptase (RT), and integrase (IN), while Env is cleaved into
the surface (SU) subunit and the transmembrane (TM) subunit.

 
GENETIC AND ANTIGENIC VARIATION
CAEV is a member of a group of viruses known as small ruminant lentiviruses (SRLV) that
includes MVV. This group is discussed as a “genetic continuum” due to the close genetic
relationship between its members (22). In a large study examining a number of SRLV
sequence databases, Zanoni reported 22% divergence in env and only 16% divergence in gag
and pol (43). This variability is similar to that seen upon examination of world wide HIV
sequences (23).
Retroviruses have RNA genomes that must be copied into DNA before their genes can be
expressed. The DNA versions of their genomes are later copied into RNA before packaging
into new virions. Reverse transcriptase has a high error rate when transcribing RNA into DNA
since unlike other DNA polymerases it has no proofreading capability. Mutations accumulate
1x105
to 1x106
times faster than replication with conventional DNA polymerases, leading to at
least one mutation each time the virus replicates (31). Retroviruses contain diploid genomes
and thus are able to undergo recombination between RNA copies packaged within the same
virus particle (9), and recombination between CAEV and MVV has been demonstrated in vivo
by coinfection of goats (30). This high rate of mutation allows for a large amount of divergence,
forming many different strains of virus. Genetic recombination allows for horizontal transfer of
mutations between different members of this grouping, ultimately producing a widely varying,
but highly related cluster of viruses.
Early phylogenetic studies based on short sequences of nucleic acids suggested that SRLV
could be divided into six clades (I to VI) with no clear separation of SRLV strains from goats or
sheep (43). Clade I contains the prototype Icelandic visna virus and related MVV strains. Clade
II consists of North American lentivirus strains isolated from sheep. Clade III consists of
Norwegian SRLV, and clade IV of French SRLV. Clade V contains French and Swiss CAEV
strains, North American prototype strains, and North American ovine lentivirus strains (MVV).

 
Clade VI contains French SRLV. In this analysis, clades III to VI contained SLRV sequences
from both sheep and goats, while clades I and II were more species-specific suggesting that
SRLV may cross the species barrier with ease (43).
In 2004, SRLV were reclassified into four principal sequence groups, A-D (which differ by 25–
37%), based on analysis of a longer genetic sequence comprising 1.8 kb of the gag–pol region
(38). Group A is comprised of a large heterogeneous group that clusters around the prototype
MVV isolates: SA-OMVV (South Africa) (32), EV1(Scotland) (37), and 1514 (Iceland) (40).
Group B contains viruses related to the prototype CAEV isolate from the USA, CAEVCork (10).
Sequence groups A and B contain viruses from both sheep and goats and are divided further
into subtypes which differ by 15–27%. Group A contains at least seven subtypes and group B
at least two subtypes. Of interest, recombination between a group A MVV and a group B CAEV
has recently been demonstrated in goats infected with both viruses (30). Group C contains
Norwegian CAEV isolates represented by the full-length sequence AF322109 (17). These three
groups; A, B and C, are roughly equidistant to each other, with pairwise distances of around
30% for the 1.8 kb gag–pol sequence. Goat isolate 5668 from Switzerland was as distant from
the other groups as they were among themselves and thus was designated as group D.
Interestingly, this molecular analysis revealed that Swiss strains in subtype B1 differed no more
from US, French, or Brazilian strains than from each other, suggesting virus spread through
international livestock trade. Furthermore, infection of goats by subtypes A3 or A4 was
significantly associated with reported contact with sheep, which also harbor these subtypes,
thus indicating frequently occurring sheep-to-goat transmission (38).

 
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