Small ruminant lentivirus infections and diseases

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Veterinary Microbiology xxx (2015) xxx–xxx

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Veterinary Microbiology journal homepage: www.elsevier.com/locate/vetmic

Small ruminant lentivirus infections and diseases E. Minguijóna , R. Reinab , M. Pérezc , L. Polledod, M. Villoriaa , H. Ramíreze, I. Leginagoikoaa , J.J. Badiolaf , J.F. García-Marínd , D. de Andrésb , L. Lujánf , B. Amorenab , R.A. Justea,* a

Department of Animal Health, NEIKER-Tecnalia, Berreaga 1, 48160 Derio, Vizcaya, Spain Institute of Agrobiotechnology (CSIC-UPNA-Government of Navarra), Avenida de Pamplona 123, 31192 Mutilva, Spain Department of Anatomy, Embryology and Genetics. University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain d Pathological Anatomy Section, Animal Health Department, Veterinary School, University of León, 24007 León, Spain e Facultad de Estudios Superiores Cuautitlán. UNAM. Laboratorio de Virología, Genética y Biología Molecular, Campo 4. Veterinaria.Carretera Cuautitlán– Teoloyucan, Km 2.5. San Sebastián Xhala, Cuautitlán Izcalli, CP.54714 Mexico f Department of Animal Pathology, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain b c

A R T I C L E I N F O

Keywords: Caprine artritis encephalitis Control Diagnosis Epidemiology Maedi Pathogenesis Small ruminant lentivirus SRLV Visna

A B S T R A C T

Small ruminant lentiviruses include viruses with diverse genotypes that frequently cross the species barrier between sheep and goats and that display a great genetic variability. These characteristics stress the need to consider the whole host range and to perform local surveillance of the viruses to opt for optimum diagnostic tests, in order to establish control programes. In the absence of effective vaccines, a comprehensive knowledge of the epidemiology of these infections is of major importance to limit their spread. This article intends to cover these aspects and to summarise information related to characteristics of the viruses, pathogenesis of the infection and description of the various syndromes produced, as well as the diagnostic tools available, the mechanisms involved in transmission of the pathogens and, finally, the control strategies that have been designed until now, with remarks on the drawbacks and the advantages of each one. We conclude that there are many variables influencing the expected cost and benefits of control programs that must be evaluated, in order to put into practice measures that might lead to control of these infections. ã 2015 Elsevier B.V. All rights reserved.

1. Introduction Discovery of Visna/maedi virus (VMV) can be considered a scientific feat, because it was the first case of a virus that replicated so slowly and caused a disease with such an apparently long incubation period. The virus was first isolated by Sigurdsson and collaborators in 1960 during the epidemic of slow diseases that swept Iceland in the 1940s after the importation of 20 Karakul rams from the Animal Breeding Department of the University of Halle (Germany), which were distributed through the island with the aim to improve sheep production (Pálsson, 1990). Although the animals came from a scientific institution where no disease had been observed and had passed through a long quarantine, they harboured the infectious agents for three chronic diseases: paratuberculosis, sheep pulmonary adenocarcinoma and visna/ maedi (VM). The first two were known to clinicians from the

* Corresponding author. E-mail address: [email protected] (R.A. Juste).

scientific literature existing at that time, but the third had characteristics totally unknown to scientists and therefore the descriptive names given by the local shepherds, ‘visna’ (wasting) and ‘maedi’ (breathlessness), became from then on the universal names for small ruminant lentivirus (SRLV) diseases overriding names given in other countries to the respiratory form. Since then, the infection has been found in all small ruminant producing countries, with a few exceptions according to species and production system (Thormar, 2013). Beyond the substantial losses associated to clinical diseases caused by small ruminant lentiviruses, the effects of subclinical infections have been the subject of controversy, because the slow course of the infection creates a whole spectrum of disease progression that cannot be differentiated following current in vitro diagnostic criteria. This has hampered the financial justification of control programs at a large scale outside highly genetically selected flocks. The relevant caprine disease is a more recent discovery, since the disease, caprine arthritis and encephalitis (CAE), and its retroviral aetiology were first described by Cork et al. in the United States in 1974 (Cork et al., 1974) and the virus (CAEV) was isolated

http://dx.doi.org/10.1016/j.vetmic.2015.08.007 0378-1135/ ã 2015 Elsevier B.V. All rights reserved.

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in 1980 (Crawford et al., 1980). Caprine arthritis and encephalitis was soon reported in other countries, where its negative effects seemed to be even more apparent, than those in sheep, and pressed for the implementation of control programs. VMV and CAEV are currently referred to as small ruminant lentiviruses, due to phylogenetic proximity and natural interspecies transmission between sheep and goats. In this article, we review the main features of small ruminant lentiviruses, the lesions and signs associated with the infection in sheep and goats, the diagnostic challenges posed for an efficient control and a summary of different strategies to control small ruminant lentivirus infections. 2. Lentiviruses: general characteristics The non-oncogenic genus Lentivirus belongs to the family Retroviridae, subfamily Orthoretrovirinae. Retroviruses are characterised by ability to reversely transcribe the viral RNA to double stranded DNA (dsDNA) through the action of reverse transcriptase (RT). The genus Lentivirus includes the immunodeficiency viruses of humans (HIV), the immunodeficiency viruses of simians (SIV), the immunodeficiency viruses of felines (FIV) and the immunodeficiency viruses of bovines (BIV), the equine infectious anemia virus (EIAV) and the small ruminant lentiviruses (SRLVs).

Small ruminant lentivirus virions (Fig. 1) have a diametre of 80– 100 nm and from inside out comprise nucleocapsid (NC), capsid (CA), matrix (MA) and envelope (ENV). Inside the NC are the genome (two positive single strand RNA chains of 8.4–9.2 kb), nearly 30 RT molecules with helical symmetry and the enzymes protease (PR) and integrase (IN). CA surrounds the NC, has an icosahedral morphology about 60 nm in diametre and is surrounded by MA. Finally, the virion has an outer envelope formed by a lipid bilayer of cellular origin and the ENV glycoproteins: transmembrane (TM), in a transmembrane position, and surface (SU), projecting outwards (Pétursson et al., 1992; Murphy et al., 1999). Lentiviruses are composed of approximately 60% protein, 35% lipids, 3% carbohydrates and 1% RNA (Pétursson et al., 1992). All lentiviruses have the same basic genetic organisation, with the genome of the provirus presenting a non-coding long terminal repeat (LTR) at both ends (Fig. 1). Between the LTRs there are three structural genes: gag (encoding NC, CA and MA proteins), pol (encoding RT, PR and IN) and env (encoding the TM and SU ENV glycoproteins). Lentiviruses also encode accessory genes, of which presence/absence and characteristics may vary according to the species (e.g., vif, rev, vpr -like are present in small ruminant lentiviruses; HIV includes in addition vpu, tat, nef and vpx).

Fig. 1. Structure of virions and genome of small ruminant lentiviruses: (a) virions, (b) viral genome, (c) HIV-1 virus genome, included for comparison.

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In contrast to other retroviruses, the proviral DNA of lentiviruses is transcribed in the cell nucleus where the viral genomes are produced. The infected cells contain few (often only one) provirus copies integrated into the host cell DNA. The remaining linear dsDNA viral molecules (100–200 copies) in the infected cell cytoplasm could be linked to the cytolytic effect that lentiviruses may exhibit, which is not observed in oncovirusinfected cells (Pétursson et al., 1992). The retrotranscription mechanism seems to be prone to errors and therefore, lentivirus replication involves a high frequency of point mutations, often insertions and deletions, all of which are estimated in a range of 0.1–2 mutations per genome and replication cycle. Among the structural genes of lentiviruses, gag, pol and certain parts of the env are relatively conserved, but other parts of env, primarily antibody-binding regions, are highly variable (Pétursson et al., 1992; Murphy et al., 1999). The polypurine tract (PPT), the rev response element (RRE) and other elements involved in replication and packaging of the viral genome are also relatively conserved among lentiviruses. Mutation leads to a high variability of sequences even within a single individual, jointly forming a quasispecies. The concept of quasispecies was proposed by Manfred Eigen and is defined as a population of genetic variants of which one is dominant. The type of virus that originally infects the animal persists and coexists with new variants, but disease progression is not always linked to the emergence of new variants (Murphy et al., 1999). Recombination is an early event occurring in co-infected cells before integration, during reverse transcription, leading to genetic variability. Together, lentivirus mutation and recombination frequencies exceed by far those of any other animal viruses (Murphy et al., 1999) (2.8 times in HIV1). Compared to mutation, recombination is a strong evolutionary force as it can assemble

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beneficial genetic combinations, jointly remove deleterious mutations and facilitate viral genome adaptability, integration and persistence. In the absence of recombination, lentiviruses tend to accumulate deleterious mutations. With regard to cell tropism and type of disease triggered, lentiviruses can be classified into two groups. In one group (HIV, FIV and SIV), viruses replicate in lymphocytes and macrophages, causing an acquired immunodeficiency syndrome and a disease that affects lungs, central nervous system (CNS) and gastrointestinal tract. In the other group, viruses (SRLV, EIAV and BIV) replicate in macrophages, but do not infect lymphocytes. These viruses cause a slow disease of the reticuloendothelial system, mammary gland, central nervous system, lung and/or joints and, while not triggering the classical immunodeficiency syndrome that involves a severe lymphocyte depletion in blood, infection may eventually lead to death of the animal. Typical effects of lentiviral infections may differ between species, these being: in horses (EIAV), cyclic infection in the first year with haemolytic anemia and sometimes encephalopathies—in sheep and goats (SRLV), interstitial pneumonia, encephalitis, mastitis and/or arthritis—in cattle (BIV), lymphadenopathy—in cats (FIV), immunodeficiency and opportunistic pathogen infections—in simians (SIV), immunodeficiency, encephalopathy and opportunistic pathogen infections—in humans (HIV), immunodeficiency, encephalopathy, myelopathy and opportunistic pathogen infections (Leroux and Mornex, 2008). 3. Genetic diversity of small ruminant lentiviruses Genetic variability is a key feature of small ruminant lentivirus genome and its knowledge, besides shedding light on the host– virus interactions, is essential for accurate diagnosis and molecular epidemiology studies. Small ruminant lentiviruses quasi-species

Fig. 2. Phylogenetic tree generated using small ruminant lentivirus complete sequences obtained from GenBank illustrating main genotypes (A–E) and subtypes (accession number of isolate and country of origin are indicated; CHI: China; ENG: England; ICE: Iceland; ITA: Italy; MEX: Mexico; NOR: Norway; POR: Portugal; SOA: South Africa; SPA: Spain; SWI: Switzerland; USA: United States of America).

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are continuously generated through mutation, recombination and selection pressure by the host immune system. Accordingly, reemergence of early forms and prevalence of dominant mutants are common events in small ruminant lentiviruses (reviewed in Ramírez et al., 2013). Small ruminant lentiviruses hypermutation is due to the lack of a proof-reading capacity in the RT enzyme and to the cytosine-to-uracyl deamination in the reversely transcribed single-stranded DNA (minus strand). This is attributed to APOBEC3 editing enzymes, which once packaged into lentiviral virions induce cytosine deamination, which leads to G-to-A mutations in the plus strand. Further mutation mechanisms might be found in macrophages (SRLV targets), since they present high dUTP:dTTP ratios, thus providing dUTP that can be incorporated into DNA. Small ruminant lentivirus variability is a tool of the virus to evade the host immune response and ensure the persistence of infection (Narayan et al., 1977a,b); moreover, it may be involved in the transgression of species barrier, as observed in wild ruminant species infected experimentally (mouflon) or naturally (ibex). This variability has led to the formation of small ruminant lentivirus heterogeneous groups with variable host range and pathogenic properties, and has obvious implications in the design of diagnostic tests and vaccine development (Murphy et al., 1999). Ancestors of small ruminant lentiviruses have been located in Turkey (Muz et al., 2012). Accordingly, Turkish VMV sequences appear to precede the establishment of the various strains associated with migration of sheep from the Middle East to Europe thousands years ago, leading to virus diversification. Small ruminant lentiviruses have been classified into five genetic groups (A–E) (Fig. 2) that differ from each other in 25–37% of their nucleotide sequences. Genotypes A, B and E, originally described in sheep (A) or goats (B and E), may further be distributed into different subtypes (A1–A15, B1–B3, E1–E2) (Fig. 2). Genotype C is

present in goats and sheep from Norway and genotype D, which may be considered as a genotype A exhibiting divergence in pol gene (reviewed in Ramírez et al., 2013), is also geographically restricted to Spain and Switzerland. New subtypes constantly appear as more local strains are analysed, which outlines the continuous need for surveillance of diagnostic and vaccination designs (Cardinaux et al., 2013; de Andrés et al., 2013). Genetic information useful for these designs is available at GenBank, including full genome sequences from goats: CAEV-CO (Narayan et al., 1980; Saltarelli et al., 1990), 1GA (Gjerset et al., 2006, 2007), Gansu (Qu et al., 2005), Shanxi (Huang et al., 2012), FESC-752 (Ramírez et al., 2011), Seui (Reina et al., 2010), Roccaverano (Reina et al., 2009b) and A4 (Shah et al., 2004) viruses, or sheep: Fonni (Bertolotti et al., 2011), Volterra (Bertolotti et al., 2011), 496 (Glaria et al., 2009), SA-OMVV (Querat et al., 1990), KV1514 (Andresson et al., 1993), KV1772 (Sonigo et al., 1985), LV1 (Staskus et al., 1991), EV1 (Sargan et al., 1991), P1OLV (Fevereiro and Barros, 2004), 85/34 (Karr et al., 1996) and 697 (Glaria et al., 2012) viruses. New partial sequences are being described in America, Europe and Asia. Types B, C and D and some A subtypes (A1, A3, A4, A5, A6, A9, A11, A12 and A13) have been found in both sheep and goats, whilst other subtypes have only been reported only in sheep (A2, A15) or goats (A7, A8, A10, A14, E1, E2) (Fig. 3). However, as more viral sequences are obtained, these ‘single-species subtypes’ may tend to disappear, infecting both species (Ramírez et al., 2013). 4. Virus tropism Small ruminant lentiviruses tropism depends on host–virus interactions occurring at different levels: cellular (at the stages of receptor/entry, pre-integration, integration, post-integration of

Fig. 3. Small ruminant species where small ruminant lentivirus types and subtypes have been detected.

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the viral genome into the host DNA), organ/tissue or host (individual/breed/species). In vivo, infection remains latent until the monocyte, the main target cell for small ruminant lentiviruses, which acts as a ‘Trojan horse’ to spread the virus in the body, differentiates into macrophage, triggering viral transcription. In vitro, clear differences in virus replication have been found according to the origin of tissue. Viruses isolated from brain cells replicate more rapidly in sheep choroid plexus cells, compared to isolates from lung; this difference being related to differences in env and LTR regions. Differences in permissiveness have been found in vitro between particular heterologous cell lines from various species (chicken, hamster, human, monkey, quail), which are permissive to small ruminant lentivirus infection, and Chinese hamster ovary cells, which are non-permissive to infection. Small ruminant lentiviruses are highly variable phenotypically in cells of homologous origin (from small ruminants) regarding the replicative capacity in vitro and generation of cytopathic effects. Frequently, sheep isolates are classified phenotypically as rapid/high, as they replicate rapidly, besides inducing the formation of syncytia and/or cell lysis, and when cultured, supernatants reach high titres; in contrast, isolates from goats are often slow/low viruses, growing slowly and yielding low titres. However, VMV-like and CAEV-like viruses of intermediate phenotypes have been isolated from both sheep and goats. High small ruminant lentivirus production can be achieved in vitro in macrophages and in fibro-epithelial synovial membrane cells and choroid plexus cells from goats or sheep (Glaria et al., 2009). Other cell types permissive to small ruminant lentivirus infection are microglia (Adebayo et al., 2008), dendritic cells (Ryan et al., 2000), epithelial cells from lung (Carrozza et al., 2003), mammary gland (Bolea et al., 2006), third eye lid (Capucchio et al., 2003), kidney (Angelopoulou et al., 2006), uterus and epididymis (Ali Al Ahmad et al., 2012; Lamara et al., 2013), endothelium, smooth myocytes (Leroux et al., 1995; Carrozza et al., 2003), granulosa cells (Lamara et al., 2001) and parenchyma cells from the liver or heart (Brellou et al., 2007). 5. Genetic compartmentalisation and diversification of small ruminant lentiviruses within an individual The genetic differences generated between virus populations from different tissues/organs within a host quasispecies may lead to virus compartmentalisation within the individual. In lentiviruses such as HIV, compartmentalisation has been shown by studying particular hypervariable genomic regions (V3) of the env gene involved in receptor binding. In small ruminant lentivirus genomes, five variable (V1–V5) and four conserved (C1–C4) regions have been identified in the envelope protein. The small ruminant lentivirus env hypervariable region (V4), structurally and functionally analogous to the V3 region of HIV, is likely involved in colonisation of various organs (lung, mammary gland, brain, joints). Small ruminant lentivirus V4 mutations during early infection give rise to different viral subpopulations (Ramírez et al., 2012), as shown in other lentiviruses. V4–V5 sequence analysis reveals that small ruminant lentivirus compartmentalises in the mammary gland of goats and sheep compared to small ruminant lentivirus from blood-derived cells and colostrum. Similarly, a study on small ruminant lentivirus genotype A (ENV V4-C4V5 region) in a visna outbreak showed compartmentalisation in the central nervous system, lung and mammary gland (Ramírez et al., 2012). In that study, the most probable common ancestors (infecting viruses) within the animal were proviruses from alveolar macrophages and peripheral blood mononuclear cells, compatible with the existence of a respiratory infection route. In the visna outbreak, neuroinvasion within the organism involved microevolution after initial infection with small ruminant lentivirus through

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respiratory secretions, but small ruminant lentivirus diversification, adaptation and/or compartmentalisation in the brain may be independent from events occurring in lymphoid tissues or other organs, where the virus is exposed to more intense/diverse immunologic pressures. High viral mutation rate and differences in selective pressures may result in divergent evolution of the virus, affecting tropism and pathogenesis. 6. Innate immune response against small ruminant lentiviruses Once the virus enters the target cell, molecules of the innate and adaptive immunity start host restriction. Innate immunity molecules, e.g., TRIM5, bind viral capsids, inhibiting integration and post-integration steps of the virus cycle, whilst others, e.g., APOBEC, mutate the viral genome. Thus, lack of productive infection is not due only to lack of functional receptors, since both post-entry restriction factors may also be responsible. But the virus Vif protein may neutralise APOBEC-encoded A3Z3 proteins, irrespective of the host species (sheep, humans, macaques, cows, cats). Variations in TRIM5 and APOBEC have important effects in defining the specificity of the virus target (Jáuregui et al., 2012). Virus and host co-evolve according to innate and adaptive immune pressures, to reach a balance favouring (virus) or opposing (host) infection. Of note, the heterologous restriction by innate immunity factors is often more extended and potent than the homologous one; this finding may have new prophylactic and therapeutic implications against lentiviral infections. 7. Adaptive immune response against small ruminant lentiviruses The monocyte/macrophage lineage represents a bridge between innate and adaptive immunity against small ruminant lentiviruses. The most widely known viral antigens triggering specific adaptive immune responses are the ENV and GAG proteins, which are processed and exhibited to the immune system by antigen presenting cells, e.g., monocytes and macrophages. As a result, small ruminant lentivirus antigens trigger adaptive immune responses, and thus production of helper T cells (Th), cytotoxic T lymphocytes (CTL) and B-cell derived antibodies, all being antigenspecific and highly dependent on small ruminant lentivirus heterogeneity. Due to this high small ruminant lentivirus diversity, a variety of specificities in the immune response elements is needed to face infection (Blacklaws, 2012); these cause serious difficulties for designing diagnostic tools (molecular and immunological) and vaccines (Peterhans et al., 2004; Reina et al., 2009a). Noteworthy, small ruminant lentivirus specific antibodies are produced for life (with titre variations) and appear to be mainly IgG1 (Blacklaws, 2012) (Th2 profile, not too efficient against viral infections). On the other hand, CTL responses to small ruminant lentiviruses have been found relatively weak and uncommon among infected individuals, in spite of the known role of CTL in defence against viral infections. Furthermore antigen presentation, which involves B7 co-stimulatory molecules, appears to be failing in small ruminant lentivirus clinical disease, since in these, B7 transcript levels and T cell specific proliferative recall responses are significantly decreased (Reina et al., 2007) in contrast to the increase observed during the asymptomatic phase of infection. It appears that, as a result of decreased B7 levels, T cells become anergic, unable to mount recall responses. This indicates existence of an immunodeficiency in small ruminant lentivirus clinical disease, which hampers different recall responses, so important in vaccination and defence against most pathogens. Thus, in spite of lymphocyte accumulation in some organs, possible anergy impedes defence against the virus.

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In sum, the binomial relationship between virus and host involves a constant interplay sculptured by virus mutation/ recombination events, the host genetic variability in innate and adaptive immunity and selection forces implemented on both, host and virus. A concerted action between these three elements mainly defines the profiles of virus populations, viral tropism for cells, tissues and hosts as well as the immune responses and the final outcome of infection. 8. Slow infection pathogenesis in sheep and goats 8.1. The respiratory, locomotive and mammary syndromes Small ruminant lentiviruses induce a systemic infection in sheep and goats that may affect in parallel and in an immunomediated manner an array of target organs, such as lung, central nervous sytem, mammary gland and joints. The clinical affection appears to depend on the tropism of the small ruminant lentivirus strain, the species affected and the genetic background of each breed or animal. In general, one of the target organs is mainly affected, but it is not rare to find several of them affected in the same animal, varying in severity. In both, sheep and goats, only the respiratory and neurologic syndromes lead the animal to a cachectic stage and death, either by impairment of the respiratory function or by a general alteration of the nervous system. The locomotive and mammary syndrome alone do not generally result in cachexia or death, although they can cause several degrees of locomotive difficulty (mostly in goats) or a decreased milk production leading to undernourished lambs or kids. Thus, animals with locomotive or mammary syndromes are prematurely culled due to suboptimal production. The respiratory syndrome was the first that has been associated to small ruminant lentivirus infection in sheep and has also been described in goats. This syndrome is considered to be the most relevant with regard to prevalence and financial significance in sheep, whereas it seems infrequent in domestic goats. The clinical syndrome is caused by interstitial pneumonia that increases thickness of the alveolar septa and progressively reduces air exchange capacity of affected lungs (Cutlip et al., 1979). Long-term consequences are increased respiratory rate and progressive loss of bodyweight. Chronically affected lungs show a grey discoloration, have a markedly increased size and weight and are accompanied by a severe chronic lymphadenitis seen as tumefaction of the mediastinal lymph nodes. At this stage, the appearance of miliary, grey spots on the pulmonary pleural surface in a focal to diffuse pattern is often evident (Fig. 3). Histopathological examination demonstrates an accumulation of inflammatory round cells (mostly lymphocytes) throughout the lung parenchyma and appearance of hyperplastic lymphoid follicles around blood vessels and airways, observed macroscopically as grey spots when located under the pleura. The infection is located within macrophages, but the number of infected cells is rarely numerous. The mammary syndrome affects both small ruminant species and has important financial and epidemiological consequences. It was first described in 1985 in both sheep and goats. Henceforth, milk was recognised as a very efficient and important source of infection in newborns, including those fed with small ruminant lentivirus-contaminated bulk tank milk from infected does (Van der Molen et al., 1985). The syndrome involves a periacinar diffuse interstitial mastitis that often appears with intense fibrosis profoundly modifying normal acinar structure. This is likely due to replication of small ruminant lentiviruses in macrophages or epithelial cells of the acini (Bolea et al., 2006), triggering an intense inflammatory reaction, which most often involves lymphocytes, and eventually effacing acinar epithelial cells, thus reducing milk production. Again, hyperplastic lymphoid follicles are found

scattered throughout the parenchymal tissue in the acinis and around lactiferous ducts. Clinical signs associated to this form are difficult to detect, as the mammary gland shows a diffuse and nonpainful hardening and tumefaction, mostly observed after delivery, which can only be confirmed by palpation (Van der Molen et al., 1985). The syndrome is a significant contributor in the ‘milk-drop syndrome’ seen in ewes (Giadinis et al., 2012) and should always be taken into account in the differential diagnosis of mammary diseases (Fragkou et al., 2014). Milk does not show changes in organoleptic characteristics and, often, the only way of suspecting a problem is a newborn’s suboptimal growth linked to the reduced milk yield. It seems that somatic cell counts in milk are not dramatically increased, as would have seemed expected in a case of mammary inflammation, although increased cell counts have been reported in some goat studies (Sánchez et al., 2001). The locomotive syndrome was also described by the 1980s in both small ruminant species and it is undoubtedly the hallmark of small ruminant lentivirus disease in goats (Narayan and Cork, 1985). The syndrome is based on a potential multifocal arthritis, although the carpal joints is the one more frequently affected, leading to marked lameness. Other possible locations in this species are the tarsal joints, the metatarsal and metacarpal joints, the nuchal ligament and the vertebral joints. In sheep, small ruminant lentivirus-induced inflammations in locations other than the carpal or metacarpal joints are rare. The clinical small ruminant lentivirus arthritis can be severe, the animal showing enlarged affected joints, chronic proliferative synovitis, fibrosis of the articular capsule and erosion and destruction of cartilage in advanced stages of the process (Fig. 4). Histopathologic examination demonstrates a severe subsynovial inflammatory process composed of lymphocytes, diffuse fibrosis and a proliferative reaction of the synovial membrane. In sheep, recent data indicate that the clinical affection is mild in most cases, even in the presence of enlarged carpal joints (Pérez et al., 2015); this might to some degree explain the apparent lack of diagnosis of this form in many highly-infected flocks. Also in sheep, recent data obtained in Spain indicates that the virus recovered from such lesions belongs to subtype B2, which is a CAEV-like (B) genotype first described in goats and not a VMV-like (group A) genotype first described in sheep. This presence of a B genotype in sheep can be related to the management practice of keeping goats in the flock in order to feed orphan lambs, thus allowing the interspecies transmission to happen.

Fig. 4. Characteristic lung lesions in the respiratory form of small ruminant lentivirus infection in sheep: overall size and weight is about twice that of uninfected lung; close-up of the miliary spots on the lung surface.

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8.2. The neurologic syndrome Neuropathogenesis of the disease begins with the VMV infection of the central nervous system and the viral migration in monocytes through the blood–brain barrier or choroid plexus, based on the ‘Trojan horse’ paradigm (Georgsson et al., 1989), or even on the infection of the perivascular macrophages (Polledo et al., 2012). After the viral invasion, chronic non-purulent inflammatory lesions of the neuroparenchyma are caused showing various neurological signs, e.g., progressive ataxia, hind limb weakness with stumbling gait, progressive incoordination, which can lead to total paralysis and recumbency with the animal nevertheless remaining alert (Pálsson, 1990; Benavides et al., 2006). This form was first reported in Iceland in 1957 (Sigurdsson et al., 1957) and subsequently has been reported in several other countries, in most of them as sporadic cases, usually accompanying the respiratory form (Pritchard et al., 1995; Benavides et al., 2006). However, outbreaks with high number of clinical cases have been reported in the Iceland epidemic, some regions in Spain and in a few flocks in United Kingdom. The main and common feature in these cases is the increased incidence risk of infection: over 60% or even over 90%, running in parallel with a high incidence of respiratory disease. Breed or genetic predisposition has also been mentioned, with these nervous forms being more commonly observed in milk production breeds (Georgsson et al., 1976). However, as these sheep tend to be managed indoors, there is also a possibility that infection can spread more easily. This is a factor that could also have accounted for the cases in Iceland, where sheep are kept in close quarters in winter huts. On the other hand, strain genotype has been isolated from a nervous clinical case, such as the VMV-like (A), involved in an outbreak of the nervous form of the disease, and strain genotype could be associated with this syndrome (Glaria et al., 2012). There is a wide spectrum of central nervous system lesions, regarding cellular types, extension and location. This could be related to immune responses mounted in both, experimental and natural VMV infections (Polledo et al., 2012), like in those by SIV and HIV (Freel et al., 2011). The primary lesion in the brain or spinal cord is a non-suppurative encephalitis, predominantly periventricular and paraventricular, accompanied by demyelination (Sigurdsson et al., 1957; Benavides et al., 2009). Mononuclear infiltration of the choroid plexus may also result in the development of ectopic lymphoid follicles (Cutlip et al., 1979). Three main patterns of infiltrate distribution can be observed in the same animal (Benavides et al., 2009): (a) vascular pattern, where mononuclear cells are arranged around blood vessels forming perivascular cuff, (b) infiltrative pattern, where a non-purulent infiltration of the neuroparenchyma accompanying perivascular cuffing, and (c) malacic pattern, where demyelination is the main feature. In recent studies, we have observed coexistence of lesional patterns in different organs in practically all cases studied. As a consequence, the predominant clinical manifestation would depend on the severity and extension that the inflammatory lesions reach in one of the organs affected compared to those in others. For instance, in the case of respiratory forms it is also possible to observe minimal and very focal lesions in central nervous system with no clinical signs, or vice versa. It is noteworthy that there is a wide spectrum of central nervous system lesions, with regard to cellular types, extension and location (Polledo et al., 2011, 2012). This could be related to the individual immune response, both in experimental or natural cases of MVV infection (Polledo et al., 2011, 2012), as in other related lentivirus infections, e.g. SIV and HIV (Freel et al., 2011). The importance of cell-mediated immunity with regard to severity of the central nervous system lesions has been

Fig. 5. Enlargement of the carpal joints in an advanced case of ovine small ruminant lentivirus infection; inset: marked proliferation and inflammation of the synovial membrane.

demonstrated in a sheep infected intracerebrally with MVV (Torsteinsdottir et al., 1992) and in natural cases (Polledo et al., 2011, 2012). Thus, an imbalance in the immune response, whether excessive or deficient, would result in lesion development (Polledo et al., 2011; Blacklaws, 2012), leading to two main lesion cell composition patterns: (a) a lymphocytic type (Fig. 5), characterised by presence of an infiltrate with CD8+ T lymphocytes with scarce viral antigen or (b) a histiocytic type (Fig. 6), with more extensive malacic areas, numerous macrophages, B cells and abundant viral antigen presence (Polledo et al., 2011). These observations suggest that development of histiocytic or lymphocytic type lesions could be related to a greater or lesser resistance to viral replication. In this way, in the lymphocytic lesions, the immune response would be more effective as opposed to the viral replication (Fig. 7). The abundant CD8+ T lymphocytes in this type of lesions may be effector cytotoxic cells (CTLs) that could specifically destroy virusinfected targets and would control the infection, as reported in SIV and HIV infections (Freel et al., 2011). On the other hand, the immune response would be defective in the histiocytic lesions, where abundant macrophages and B cells would fail to control viral replication (Polledo et al., 2011, 2012). These macrophages express CD163 compatible with a macrophage M2 differentiation pathway

Fig. 6. Lymphocytic lesion characterised by abundant CD8+ T lymphocytes in the inflammatory infiltrate of the central nervous system, as revealed by CD8-specific labelling (H–E as background).

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target organs of small ruminant lentiviruses are joints, lung, central nervous system and mammary gland, these points should be carefully checked, in order to detect the above described lesions. 9.2. Virus detection

Fig. 7. Histiocytic type of lesion in the central nervous system with abundant macrophage-like cells (H–E).

associated with viral replication and persistence, antibody production that fails to control infection, and the progression of the inflammatory response. Serological antibody response against MVV was significantly reduced in animals with lymphocytic encephalitis lesions when compared to animals with histiocytic lesions. This fact could be related to ineffective humoral response in the histiocytic lesions as related to viral replication B cells and macrophages observed in histiocytic lesion and could contribute to deterioration of tissue lesions (Polledo et al., 2011, 2012). On the other hand, after viral invasion of the neuroparenchyma, viral replication at tissue level could be controlled by effective lymphocytic immune response represented by the lymphocytic types, in a similar way as has happened in other slow ruminant infection, e.g. paratuberculosis where histiocytic/multibacillary patterns show high numbers of mycobacteria and serum antibody, while in the lymphocytic patterns a strong cellular immune response with scarce mycobacteria tends to be the rule (Pérez et al., 1999). These lesion differences could determine the initial, asymptomatic, latent and clinical phases of the nervous form of the disease (Polledo et al., 2011, 2012). 9. Detection of the infection 9.1. Clinical signs and lesions Accurate diagnosis of small ruminant lentivirus infection is of major importance in terms of epidemiological research, control programs and safe small ruminant international trade according to the World Organisation for Animal Health (OIE) recommendations. These objectives might be hampered by the high genetic and biological variation of small ruminant lentiviruses, but, in general, small ruminant lentivirus infections are efficiently detected by serological methods that can be complemented by molecular techniques (de Andrés et al., 2005). Until isolation of the causative virus, the diagnosis of the associated diseases was based on clinical and pathological observations, the description of which provided the name of the disease: ovine progressive pneumonia, bouhite, maedi, all referring to a respiratory syndrome or caprine arthritis and encephalitis, indicating that lesion targets are joints and brain of goats. However, MV can be widely spread in a flock or region before clinical cases would be observed. Usually, symptoms of the disease have an insidious onset and a slow progression. Since the main

Small ruminant lentiviruses can be propagated in vitro from peripheral blood leucocytes and target organs in a wide variety of primary cell cultures obtained from small ruminants, of which the most common are fibroblasts derived from goat synovial membrane and sheep choroid plexus cells. Also, several continuous cell lines, from various tissues, are permissive to small ruminant lentivirus infection and provide technical advantages over the former facilitating virus culture (Matsuura et al., 2011). Infection produces a characteristic cytopathic effect (Molitor et al., 1979) and different degrees of cell lysis, but involvement of small ruminant lentivirus has to be confirmed by other techniques, e.g. electron microscopy (Payne et al., 1986), immunolabelling or viral DNA amplification. Specific antibodies for viral antigens are highly valuable tools for diagnosis confirmation through performance of immunecytological or -histochemical techniques (Luján et al., 1994). In situ hybridisation and in situ PCR can also be of help to co-localise viral nucleic acids in lesions indicative of the disease. More sensitive than these is the reverse transcription polymerase chain reaction (PCR) amplification of viral nucleic acids in unfixed specimens. Sensitivity of PCRs designed to detect different regions of the virus or provirus has been comparatively studied and also with respect to the detection of antibodies through ELISA or AGID (de Andrés et al., 2005; Herrmann-Hoesing, 2010; Ramírez et al., 2013) with good results. However, factors like sensitivity of the chosen assays, different biological meanings of the assays or genetic variation of small ruminant lentivirus from various geographic areas, make these comparisons of limited diagnostic utility. In vivo detection of small ruminant lentivirus infection by molecular PCR-based techniques is carried out most commonly using peripheral blood leucocytes or mononuclear cells (de Andrés et al., 2005; Reina et al., 2009a), although frequently reduced levels of circulating infected cells limit test sensitivity (Grego et al., 2007). In general, differences in host genetic background and immune response, as well as viral load and genetic or biological properties of the virus, may explain differences in PCR test sensitivities (Cardinaux et al., 2013). Of interest is the association found between proviral load in peripheral blood monocytes by real-time qPCR and lesion severity in sheep (Herrmann-Hoesing et al., 2009). Use of alternative sample sources for PCR assays, e.g. blood clot, serum, plasma, whole blood, also results in different sensitivities and specificities. Use of milk samples in PCR have given variable results. In the semen, PCR sensitivity can be decreased by intermittent shedding of infected cells and is not necessarily related with that obtained on blood samples (Paula et al., 2009). Together with variable viral load in blood along infection, viral genetic heterogeneity, is considered to be the most common cause of decreased PCR sensitivity (Peterhans et al., 2004), pointing to a need to adapt PCR tests to diagnose local circulating viruses (Reina et al., 2006). Strategies like selecting the most conserved regions of the small ruminant lentivirus genome as diagnostic targets, designing primers with degenerate nucleotides at variable sites and multiplexing with several primers have been applied. qPCR techniques may be improved by using chemicals like fluorescence energy transfer (FRET), SYBR green intercalation or labelled probes. Recently, loop-mediated isothermal amplification (LAMP) has been considered more sensitive than conventional PCR for detection of small ruminant lentiviruses (Huang et al., 2012).

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PCR followed by sequencing and phylogenetic study has provided information on genetic divergence and is of special interest to characterise locally circulating virus strains, to optimise molecular diagnosis (Huang et al., 2012) and to reduce test escape (Brinkhof et al., 2010). Assays designed to distinguish small ruminant lentivirus strains include restriction enzyme analysis of PCR products (Rosati et al., 1995), multiplex real time PCR (Cardinaux et al., 2013), PCR combined with heteroduplex mobility (Valas et al., 1997) and single-strand conformation polymorphism assays (Olech et al., 2012). 9.3. Detection of anti-small ruminant lentivirus antibodies Serological diagnostic methods, detecting specific antibodies in infected animals, are considered the most convenient to detect small ruminant lentivirus infections (de Andrés et al., 2005). Small ruminant lentiviruses usually produce persistent infections that can elicit detectable immune responses beyond the first two weeks of infection (Simard and Briscoe, 1990). However, serological testing has several drawbacks that must be considered, e.g. false negative results due to the spectrum of antigen and antibody specificities involved in the test or delayed seroconversion. False positive results, that cannot be explained, can also be obtained in an animal’s life (Brinkhof and van Maanen, 2007), as well as diagnostic interference due to antibodies passively acquired with colostrum in lambs (Cutlip et al., 1988). Recently, vaccination against bluetongue with poorly purified inactivated vaccines has caused in several European countries false positive results in ELISA tests (Valas et al., 2011). Interestingly, genotype A encoded antigens tend to detect cross-reacting antibodies in type B infections better than the other way around (de Andrés et al., 2013). Additionally, there may be variation in diagnostic sensitivity according to disease status when assessing the production of antibodies against env TM (Bertoni et al., 1994; de Andrés et al., 2013) and env SU protein (Knowles et al., 1990) both in sheep and goats. Different techniques have been used to detect antibodies against small ruminant lentiviruses, but none can be considered to be ‘gold standard’ (de Andrés et al., 2005). AGID and ELISA are the prescribed tests for international trade, whereas western blot (WB), radioimmunoassay (RIA) and radioimmunoprecipitation assay (RIPA) are more complex and have been used only as confirmatory tests (de Andrés et al., 2005; Herrmann-Hoesing, 2010). In the AGID test, precipitating antibodies mainly against proteins SU and CA (Winward et al., 1979) are detected by the naked eye. AGID is considered highly specific, but less sensitive than ELISA (Synge and Ritchie, 2010) and, therefore, nowadays AGID is almost exclusively used to confirm ELISA results. Indirect ELISA assays are by far the most numerous in small ruminant lentivirus diagnosis. In contrast, few competitive ELISAs have been designed (reviewed by de Andrés et al., 2005); published data on four ELISAs, two of each type, showed sensitivity and specificity values over 95% (Herrmann-Hoesing et al., 2010). Some studies found whole virus or first generation ELISAs to be more sensitive, although less specific than recombinant proteinbased second generation ELISAs (Zanoni et al., 1994). gag CA and env TM antigens are conserved among small ruminant lentiviruses (Grego et al., 2002) The latter has been used in separate (Rosati et al., 1994) but more frequently in combination with CA antigens to develop second generation ELISAs (Saman et al., 1999). Some assays also included gag MA. Later ELISAs, based on recombinant or synthetic peptides or proteins of variable regions in gag CA, MA and NP (Grego et al., 2002; Lacerenza et al., 2008), env TM (de Andrés et al., 2013) or env SU (Glaria et al., 2012), have been found to be strain-specific and have been proposed to act tools for serotyping small ruminant lentivirus infections. Single broadly reactive

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monostrain commercial ELISAs have been useful in control programs of small ruminant lentiviruses. However, it might be necessary to develop new assays and to select the best combination of them, in order to detect local circulating strains and avoid misdiagnosis (Cardinaux et al., 2013). Milk/colostrum or bulk milk samples can provide advantages over blood for sample field collection in dairy breeds, and that is why they have been tested with ELISA methods for antibodies against small ruminant lentiviruses. Comparative studies have shown that kappa agreement index between serum and milk ELISA range between 0.60 and 1 (Keen et al., 1996; Plaza et al., 2009). Seminal fluid has been shown to be an appropriate sample to detect small ruminant lentivirus antibodies when sexual transmission is an issue (Ramírez et al., 2009). In general, ELISA tests have been found to be more sensitive than PCR techniques, except in juvenile animals (Alvarez et al., 2006; Muz et al., 2012), as well as in recent infections in general. In these cases, a combination of both techniques, even though making testing more expensive, can cover all cases and become very useful in control programs to avoid the risk of leaving infected individuals in the flock. 10. Transmission Lactogenic transmission small ruminant lentiviruses has been assumed to be the main route of transmission for many years, on the grounds of the demonstration of the presence of the virus in the mammary gland and the lacteal secretions (Bolea et al., 2006). However, lactation implies close contact between highly shedding infected female animals and their offspring (Houwers et al., 1989). This was countered by the low or even nil prevalence of infection in highly extensive sheep production systems, e.g. in Australia, Texas or Southern Spain ranch-type farms in arid environments, that points out to a bigger role of horizontal transmission than of lactogenic since both involve colostrum and milk intake, while only systems with daily or seasonal housing imply close contact between infected and susceptible individuals forced by indoors crowding. In fact, more recent research has shown that only up to 16% of lambs born to seropositive ewes have been found to be infected 24 h after start of sucking (Alvarez et al., 2005) and that during the first six months of life of kids, only 10–15% of infections can be accounted to transmission through colostrum (BroughtonNeiswanger et al., 2010). More support for the significance of horizontal transmission of the virus has become available since the epizootic in Iceland, where winter housing provided ideal conditions for horizontal transmission. Other evidences are increased seroprevalence with ageing, incorporation of new animals into flocks, long housing periods, increased infection pressure, lower ventilation and high stocking density in pens (Blacklaws et al., 2004; Peterhans et al., 2004; Reina et al., 2009a). Some data, e.g. increased sensitivity to VMV, presence of virus in alveolar fluid and transmission of the infection through infected alveolar macrophages in sheep (McNeilly et al., 2008) coupled to that flocks affected by sheep pulmonary adenocarcinoma showed increased seroprevalence (Gónzalez et al., 1993) more specifically support the hypothesis of airborne transmission. However, detection of provirus in air samples from pens and exhaled breath of infected sheep was not frequent and points to the need for close and continuous exposure for transmission (Villoria et al., 2013). This adds up to findings in small ruminant farms that denote importance of direct-contact exposure for transmission (Leginagoikoa et al., 2006; Pérez et al., 2010). Against this, it is important to minimise exposure of susceptible animals to high shedders and, as a consequence, periodic testing and early culling of infected animals is highly recommended (Pérez et al., 2010). If immediate culling is not possible, prophylactic measures, e.g. segregation with

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Table 1 Overview of control strategies for control of small ruminant lentivirus infections that have been described for application at small ruminant farms. Control strategy

Type of transmission prevented

Drawbacks

Benefits

Countries used

References

Culling and total replacement with uninfected animals

All

Useful for flocks of small size and/or high seroprevalence of infection Effective and rapid control of infection dissemination

Belgium, Finland, Iceland, Malta, Netherlands, Poland, Switzerland

de Boer et al. (1978),Pálsson (1978, 1983), Houwers et al. (1984, 1987), Houwers (1990), Luján et al. (1993), Pétursson (1994), Sihvonen et al. (2000)

Separation of seropositive and seronegative ewes into two different flocks

Horizontal

Very drastic with high financial impact Unviable in populations with high prevalence of the disease Loss of genetically interesting lines or animals Difficulties in finding seronegative replacement animals Requirements for a system to identify healthy animals Laborious management (double work for farmer) and high financial cost Need for suitable livestock facilities: if complete separation is not feasible, a physical separation of at least two metres in necessary

Artificial rearing of lambs [a: colostrum/milk from seronegative ewes, b: heat treated colostrum/milk; c: commercial milk replacers; d: bovine colostrum/milk]

Vertical and horizontal mainly ewe-lamb

Selective culling of infected animals and/or their progeny [a: compulsory, b: voluntary]

Vertical and horizontal

Vertical Replacement with seronegative and offspring: [a: periodical purchase of SRLV- horizontal free replacements, b: selection of offspring from old seronegative dams in the flock/ herd, c: replacement with

Laborious, time-consuming, expensive Offspring to be removed from dams immediately after birth. Problems associated with artificial feeding by lambs Little benefits in flocks/herds with moderate-to-increased seroprevalence, if contact with other animals in farm not avoided until adulthood [c, d] Lack of passive immunity of lambs [d] Possibly lamb anaemia, as a result of bovine colostrum/milk Loss of genetically interesting lines or animals Reduced efficacy in flocks/ herds with increased seroprevalence Possible reduction of flock/ herd size Requirement for accurate diagnosis by means of laboratory tests, to take account of subclinical infections [a] Price at slaughter may decrease suddenly [b] Limited participation of breeders (2)

[a, b] Difficult to find adequate replacements [a, b] Requirement for a system to accredit flock

Spain, USA Useful in flocks with moderate-to-high seroprevalence of infection Highly successful and rapid control if properly performed Drastic culling not necessary, with flock/ herd size not affected No need for external source of naïve animals Financial costs of control smaller than most other alternatives Genetically interesting animals are maintained

de Boer et al. (1978), Schipper et al., (1985), Houwers et al. (1989), Pérez et al. (2013)

Useful in flocks with increased seroprevalence Drastic culling not necessary, with flock/ herd size not affected Genetically interesting animals are maintained

Canada, Japan, Spain

de Boer and Houwers (1979), Houwers et al. (1983), (Bernadina and Franken 1985), Cutlip et al. (1986), Williams-Fulton and Simard (1989), Rowe et al. (1991), Berriatua et al. (2002), Alvarez et al. (2005), Juste et al. (2009), Leitner et al. (2010), Konishi et al. (2011)

Useful in flocks with reduced to moderate seroprevalence Practical approach for farmers Rapid reduced of seroprevalence, especially if sixmonthly testing applied Possible to reduce seroprevalence progressively, without increasing culling rate Elimination of progeny can accelerate control and acts on inherited susceptibility and vertical transmission

Australia, Belgium, Canada, Denmark, Finland, France, Japan, Ireland, Italy, UK, Netherlands, Norway, United Kingdom, USA

de Boer et al. (1978), Houwers et al. (1984, 1987), Guven (1985), Hoff-Jørgensen (1985), Cutlip et al. (1986), Williams-Fulton and Simard (1989); Houwers (1990), Greenwood et al. (1995), Remond et al. (1985), Schipper et al. (1985), Ferrer (1996), Sihvonen et al. (2000), Berriatua et al. (2002), Konishi et al. (2011), Gufler (2013)

Minimal disturbance in Finland, Netherlands, production Spain [b] Possible indirect genetic selection of resistant lineages [c] Dams at early stages of infection transmit

Sihvonen (1980), Houwers (1990), Ferrer (1996), Berriatua et al. (2002)

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Table 1 (Continued) Control strategy

Type of transmission prevented

offspring from younger seropositive dams

Breeding program focused on resistance to SRLV (marked assisted selection)

Vertical and horizontal

Drawbacks

Benefits

Countries used

infection to offspring at lower levels than animals at longstanding stage Little available information Elimination of progeny Not applied thusfar regarding possible can accelerate control resistance markers and acts on inherited Never applied clinically susceptibility and Increased cost for artificial vertical transmission insemination programs and Potential use as a for genotyping techniques method complementing Possible undesirable other ones and consequences (e.g., enhancing overall susceptibility to other efficacy of control diseases, negative impact on strategy production traits) SRLV strains must be taken into account. Success of program may be influenced by genetic background of animals and viral strain, affecting hostvirus interaction Viral strain may undergo mutation/recombination and adaptation

References

DeMartini et al. (1991), Blacklaws et al. (2004), Larruskain and Jugo (2013), Sider et al. (2013), White and Knowles (2013)

All methods described above require adequate identification of all animals in a farm and knowledge of seroprevalence of the flock/herd, by using techniques which allow early diagnosis; periodic testing should be performed in annual (at least) or, better, six-monthly intervals. SRLV, small ruminant lentivirus.

physical separation between infected and non-infected animals, should be adopted in the meantime. For instance, snatching progeny at birth, avoiding any contact with mothers and artificially rearing replacement lambs by feeding them with heated or uninfected colostrum and milk replacer, has been practiced in control programs with a reasonable success. However, the method by itself has little effect if replacement is not segregated from the rest of the flock (Leitner et al., 2010), which would act to prevent horizontal transmission. Actually, this may not hold true in the same measure for goats, where efficiency of transmission of small ruminant lentiviruses from dams to offspring is considered more significant than in sheep. Regarding the possibility of sexual transmission, presence of small ruminant lentiviruses in males’ genital system and viral shedding in semen have been shown. Additionally, goats can be experimentally infected through artificial insemination (de Souza et al., 2013), with an established association between presence of infected bucks and increased seroprevalence in herds (Kaba et al., 2013). The sexual route is not considered to be the most important, but requires further study. In any case, ideally to ensure safety, only certified small ruminant lentivirus-free males should be used as semen donors for artificial insemination in genetic selection programs to avoid horizontal and vertical transmission of the virus. Indirect-contact transmission through contaminated milking devices has been proposed to predispose dairy goats to an increased prevalence (Blacklaws et al., 2004; Peterhans et al., 2004). Also, a role for the intramammary route has been proposed in experimental infection studies. Hygienic measures and placing small ruminant lentivirus-free animals in the first positions of the milking chain help to avoid infection. In addition to colostrum/ milk, lung fluid and semen, small ruminant lentiviruses have been detected in nasal secretions, saliva and urine (Houwers, 1990). Although fomites, upon exposure of facilities and equipment, were once considered an unlikely (Houwers, 1990), but suspected

(Cardinaux et al., 2013), means of infection, they appear nowadays relevant, requiring further research. In line with this, some control programs avoid sharing equipment and require a period before introduction of animals free from small ruminant lentivirus in pastures previously grazed by infected animals. Of concern is also the role that wildlife contact may play, since these viruses may cross-infect particular wild ruminant species, e.g. wildlife goats (Oreamnos americanus) (Minardi da Cruz et al., 2013). Common-vehicle transmission like that generated by faecal contamination of water has been proven experimentally. Also, small ruminant lentiviruses have been detected in drinking troughs inside pens. Therefore, role of contaminated water and containers in natural transmission deserves further attention (Villoria et al., 2013). On the other hand, studies using a very low intravenous infectious dose indicate that iatrogenic transmission by means of contaminated reused needles/syringes and instruments can occur and should be avoided. In summary, there is a growing consensus that small ruminant lentivirus transmission occurs mainly through horizontal routes and that vertical lactogenic transmission, once considered the main transmission route, might be a complementary route that probably only takes real importance as a backup mechanism, when the horizontal route is slowed down by environmental or management factors. This implies that control strategies have to take into account both vertical and horizontal transmission, the latter likely being the cause of advanced situations, where infections become a clinical problem. 11. Control: costs and benefits Although significant advances have been accomplished in SRLV immunization, full protection has not been achieved because of a failure to fine-tune the balance between inflammatory responses driving to virus clearance and health and those leading to disease.

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Therefore, in the absence of effective vaccines (Reina et al., 2013), control programs remain the only approach to avoid infection by small ruminant lentivirus to spread in the small ruminant industry. These programs have been implemented for long periods in different countries, but often intermittently and only at local levels. An overview of the most important control strategies currently practiced is in Table 1. Small ruminant lentivirus infection is assumed to lead to decreased milk and meat production, clinical disease, early culling and trade restrictions in both, sheep and goats, but small ruminant lentivirus control programs are also costly, thus, cost-benefit analysis have to be done before their implementation. In this sense, effect of the infection in milk production is a controversial issue. Although many studies have repeatedly confirmed the significant negative effects of small ruminant lentivirus infection in milk production, there are also references which indicate that milk production has been found unaltered or even increased in small ruminant lentivirus-infected flocks. This is not the rule and can be explained by various reasons, e.g. decreased virulence of viral strains. This appears to apply at a relatively large scale in Spain, where the high milk-yield breed, Assaf, has almost fully replaced other indigenous breeds in some regions, even though prevalence of infection in ewes of that breed ranges between 44% and 96% among flocks and >80% in half of them (Leginagoikoa et al., 2006). Apart from managing factors, e.g. initial seroprevalence of the flock, density of animals, prolonged indoor period, differences in seroprevalence between breeds, have been interpreted as an expression of varying degrees of genetic susceptibility to small ruminant lentivirus infections (Houwers et al., 1989). This is consistent with the proposed strong inheritable component of resistance/susceptibility to small ruminant lentivirus infection (Berriatua et al., 2002; Leginagoikoa et al., 2006). Most control programs focus on elimination of infected animals and their progeny (Pérez et al., 2010). This strategy actually covers two risk factors: inherited susceptibility and vertical transmission. On the other hand, advances in identification of genetic markers for resistance/susceptibility to small ruminant lentivirus infections (Larruskain and Jugo, 2013) may allow selection of animals genetically resistant (White and Knowles, 2013) through marker-assisted selection (Table 1). Although future findings in this area may prove that genetic resistance does exist, implementation of selection programs still faces problems that deserve further evaluation, e.g. loss of genetic variability associated with selection, possible hindrance of genetic progress achieved in production traits, production/disease balance to be reached and efficiency in terms of cost/benefit, taking into account production losses, costs of infection diagnosis, costs of marker detection, costs of breeding and culling. Like in other production diseases, selection favouring genetic resistance may interfere with selection focused on production and scientists and breeders may adopt resilience rather than resistance as a more realistic goal. 12. Concluding remarks Small ruminant lentiviruses are included in the highly heterogeneous group of lentiviruses infecting sheep and goats and leading to different clinical manifestations, depending on factors such as virulence of strain and production/management system used. Additional genetic factors of virus and host may also be relevant. In order to control these infections and face their consequences, it is first necessary to perform diagnosis through periodically implemented and updated surveys, using reliable assays of suitable specificity spectrum to identify infected animals. Then, the control program to be implemented will depend on seroprevalence, management, financial constraints/opportunities at different levels – from the farmer to breeders associations and

governments – and expected cost/benefit balance in terms of economy, animal health and genetic objectives. Small ruminant lentiviruses are viruses retrotranscripting RNA to DNA that shows high rates of genetic variability. They can affect animals with clear preferences of strain for each host species (sheep or goats), where they cause a series of clinical manifestations depending on the virulence of the strain, the host genetic background and the farm production system. Then, in order to implement a control program as the currently only way to act against these infections, various factors, including local prevalence, farm production objectives and financial constraints, opportunities at various levels and expected cost/benefit balance in terms of economy, animal health and genetic objectives have to be carefully evaluated. Conflict of interest There is no conflict of interest with any financial organisation regarding the material discussed in the manuscript. 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