Current HIV Research, 2010, 8, 53-65
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Jembrana Disease Virus: Host Responses, Viral Dynamics and Disease Control Moira Desport* and Joshua Lewis School of Veterinary and Biomedical Science, Murdoch University, Perth, WA 6150, Australia Abstract: Jembrana disease virus (JDV) is the most recently discovered member of the lentivirus family and causes an acute clinical disease in Bali cattle with a fatality rate of approximately 15%. It is genetically related to bovine immunodeficiency virus (BIV) to the extent that infections cannot yet be differentially diagnosed using serological assays due to cross-reacting epitopes. Despite their close genetic relationship the pathogenesis of JDV infection in Bali cattle is very different to that of BIV in cattle and is unusual for a member of this virus family. The dynamics of JDV replication and clearance during the acute stage of Jembrana disease, the viral tropism, molecular analysis of the viral genome and mRNA transcripts, and the current status of vaccine development and diagnostic assays are all reviewed to provide a greater understanding of the factors that make JDV such an unusual lentivirus.
Keywords: Jembrana disease virus, tropism, viral load, lentivirus, tat, transcription. INTRODUCTION Jembrana disease first occurred on the Island of Bali in Indonesia in 1964 affecting buffaloes (Bubalis bubalis) and Bali cattle (Bos javanicus) and caused widespread mortalities. The initial outbreak occurred in the Jembrana district of Bali and the disease soon spread to surrounding districts with a Rinderpest-like agent suspected initially [1, 2]. A second outbreak occurred in 1971-72 in the adjacent Tabanan district with similar pathological and clinical signs but, unlike the initial outbreak, buffaloes were not affected [2]. The disease has now spread to other islands in Indonesia including Kalimantan (Indonesian Borneo), West Sumatra and Java and has become endemic in Bali [3-5]. In 1992 the aetiological agent of Jembrana disease was identified by membrane filtration as being between 50 and 100nm in diameter suggesting that a virus was responsible for the disease. Electron microscopic examination indicated that the virus matured by C-type budding [6] and replication was only detected in mononuclear cell cultures of peripheral blood origin but not in other cell cultures [7]. The characteristics of the virus were described as being consistent with viruses in the Retroviridae. Further nucleotide sequence and physicochemical analysis identified genetic and antigenic similarities with bovine immunodeficiency virus (BIV) and it was designated as a member of the lentivirus family and became known as Jembrana disease virus (JDV) in 1993 [6, 8]. Attempts to culture JDV in vitro have been mostly unsuccessful and this has hampered the research effort into this unusual lentivirus. Continuous and primary Bali cattle derived cells have been tested and, although uninfected mononuclear cell cultures do not display any cytopathic effect after inoculation with plasma from infected cattle, clinical signs of Jembrana disease are reproduced when *Address correspondence to this author at the Murdoch University, Department of Veterinary & Biomedical Sciences, Perth, WA 6150, Australia; Tel: (61) 8 93606714; Fax: (61) 8 9310 4144; E-mail
[email protected] 1570-162X/10 $55.00+.00
cultures maintained for 7-28 days are sub-inoculated into susceptible Bali cattle [7]. For many years titration of JDV in susceptible Bali cattle was the only available method to quantify viral load (VL) [9, 10] but indirect methods including capture ELISA, qRT-PCR and qPCR have been developed more recently which have facilitated a closer examination of viral dynamics during all stages of infection [11-13]. Most of the research that will be reviewed in the following sections has been performed using JDVTAB/87, a strain of JDV from the outbreak in the Tabanan region in 1987, although viruses from a more recent outbreak in the Pulukan region of Bali (JDVPUL/01) and in Kalimantan in Indonesian Borneo (JDVKAL/01) are also included. CLASSIFICATION AND VIRION CHARACTERISTICS JDV is a member of the of the lentivirinae genera of the orthoretrovirinae sub-family of the retrovirinae family [14]. The virus is morphologically similar to other lentiviruses with a virion size of 96 to 124 nm in diameter (average 98 nm) and a smooth bilaminar membrane with no obvious structures protruding from the envelope of the virus. Centrally and eccentrically located spherical nucleoids of 3044nm diameter are present in over 50% of viral particles and similar eccentric nucleoids have been observed in HIV-1 [15]. The bar shaped nucleoid that is described for BIV and other lentiviruses is not seen with JDV [6, 16]. Large numbers of nucleoid containing viruses of 75-130nm diameter were observed in sections of pelleted plasma by electron microscopy leading to the conclusion that JDV was not cell-associated [7]. High titres of infectious particles in the blood of cattle during the acute stage of Jembrana disease indicate that viral particles in plasma are of a mature form. However, the use of molecular techniques e.g. qRT-PCR to indirectly quantify viral loads suggests that, as in HIV, immature or defective particles are also present in plasma [11]. Extracellular viruses and particles in membrane-bound cytoplasmic vacuoles are both found in spleen and lymph nodes. Assembly and maturation of JDV occur via C-type budding through either intracytoplasmic membranes or the plasma membrane. Immature particles with relatively clear © 2010 Bentham Science Publishers Ltd.
54 Current HIV Research, 2010, Vol. 8, No. 1
Desport and Lewis
centres are formed which mature into virus particles with an electron dense core [6]. CLINICAL AND PATHOLOGICAL FEATURES OF JEMBRANA DISEASE The pathogenesis of Jembrana disease was originally investigated in 18-month-old Bali cattle after intravenous challenge with 10-fold dilutions of peripheral blood taken at intervals after experimental infection which resulted in the development of clinical signs of disease 5-12 days postinfection with a duration of approximately 7 days [9, 17]. A linear relationship was observed between the dilution of blood inoculated into the cattle and the incubation period before onset of clinical signs of disease [9]. The main clinical signs of infection are an acute inflammatory response, loss of condition, anorexia, lethargy, well defined large erosions of the oral mucous membranes on the ventral surface of the tongue and enlargement of superficial lymph nodes particularly the pre-scapular, pre-femoral and the parotid lymph nodes. The lesions in Bali cattle with Jembrana disease are dominated by the intense lymphoproliferative response, but once this acute stage of disease has resolved most cattle recover. Gross pathological changes include vascular damage such as mild exudates and haemorrhages, but the most striking changes are lymphadenopathy and splenomegaly. Lymphoid tissues of all organs, particularly the enlarged peripheral lymph nodes and spleen, contain proliferating lymphoblastic cells throughout the parafollicular T-cell areas, and B-cell follicles become atrophied. A proliferative lymphoid infiltrate is also found in the parenchyma of most organs, particularly the liver and kidneys and an infiltrate containing proliferative macrophage-like cells is found in the lungs [18]. Jembrana disease is characterized by marked haematological changes in affected Bali cattle which are summarized in Fig. (1) [17]. In the pre-febrile period there are alterations to the neutrophil to lymphocyte ratio due to a mild fluctuating neutrophilia and a progressive decrease in circulating lymphocytes. Typically during the febrile period there is a marked leucopenia, with reduction in the number of circulating lymphocytes and monocytes, and a Table 1.
thrombocytopenia. Other haematological changes include anaemia, increased blood urea concentrations, reduced erythrocytes and diminished total plasma protein concentration with the majority of these changes occurring principally during the febrile period [17]. Under experimental infection conditions the fatality rate for JDV infections ranges from 15-17% with the death of some cattle occurring during the febrile period whilst others succumb days or weeks after recovery often because they are unable to cope with secondary infections [13, 17]. In a recent series of experimental infections using JDVTAB/87 or JDVPUL/01 as challenge strains, 73% of Bali cattle developed clinical Jembrana disease after an incubation period of 5-12 days [13]. Febrile responses developed within 3-10 days of infection, coinciding with a leucopenia, both of which returned to normal levels between 13-17 days post-infection. Groups infected with JDVPUL/01 developed peak rectal temperatures on average 0.7 days before those infected with JDV TAB/87 (Table 1). Some cattle (15%) did not develop a typical febrile response but instead displayed only a transient mild fever for 1-2 days accompanied by lower levels of detectable circulating virus than the typical responders (Fig. 2 and Table 1). In addition, 3 cattle died after infection with JDVPUL/01 (Table 1). Failure to clear the virus was a common feature of these animals, since all had high plasma viral loads at death (Summarised in Fig. 2) [13]. JDV infected cattle develop delayed antibody responses 6-15 weeks after infection which may be indicative of a transient immunosuppression [13, 19, 20]. The severe acute disease and mortalities associated with JDV infection are unusual for lentiviruses and contrast sharply with BIV infections which are characterized by low viral titres and little if any signs of disease or mortalities [21, 22]. The association between lower peak VL (Table 1) and reduced or absent clinical signs seen in 15% of experimentally infected cattle has led to the hypothesis that, similar to equine infectious anaemia virus (EIAV) infection in horses [23], a threshold level of JDV is required for induction of acute disease in Bali cattle. Similarly, high levels of SIVsmmPBj14 in the plasma of pig-tailed macaques are associated with a virus threshold beyond which a synergistic cycle of lymphoid activation and
Summary of Observed Mean Data for Groups of Cattle Infected with JDVTAB/87, JDVPUL/01, Atypical Responders, Fatalities and Vaccinated with JDVacc Prior to Infection with JDVTAB/87 No. of Days Post Challenge
Cattle
Duration (Days)
Viral Load (Log10)
Peak VL
1 Day 39.30C
Peak oC
Last Day 39.30C
39.30C
AUC 10 Genome Copies/ml
1 day 39.30C
Peak
AUC 106 Genome Copies/ml
JDVTAB/87 (n=10)
11.1
7.1
11.6
14.8
7.2
12.6
9.8
11.0
11.5
JDVPUL/01 (n=9) (n=10)
11.0
9.0
10.9
14.0
6.0
9.6
8.7
10.0
10.4
Atypicals (n=4)
13.3
12.0
11.3
13.0
1.3
7.1
6.7
8.8
9.1
Fatalities (n=3)
11.7
9.7
11.3
N/A
8.0
9.9
8.7
10.7
11.2
Vaccinated (n=4)
13.3
11.3
13.8
17.0
4.3
6.8
7.8
9.9
10.2
st
6
st
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Fig. (1). Graphical representation of the typical changes in rectal temperature (oC) and white blood cell counts following infection with JDVTAB/87. The threshold value of febrile response at 39.3 oC is indicated (dashed line) together with differential cell counts which illustrate the leucopenia (white line), lymphopenia (), neutropenia () and monocytopenia () that develop during the acute stage of Jembrana disease.
Fig. (2). Graphical representation of the typical plasma viral loads (VL) following infection with JDVTAB/87 (n=10, ) or JDVPUL/01 (n=9, ), atypical responders (n=4, dashed line), fatalities (n=3, black line) and cattle vaccinated with JDVacc prior to challenge (n=4, white line). JDV genome copies/ml plasma were determined using qRT-PCR and transformed to log10 scale so that area under the curve (AUC) VL above the threshold value (dashed line) of 106 genome copies/ml plasma could be calculated.
viral replication accelerates uncontrollably resulting in an acutely lethal syndrome [24]. Cattle that recover from Jembrana disease develop immunity which protects against re-infection for up to 22 months post-infection in the majority of experimentally infected cattle [9]. This indicates that immunity is maintained over a long period of time and that a vaccine
which mimics this may be effective in providing long-term protection. TRANSMISSION Transmission of JDV has been reported to be similar to EIAV and is likely to occur via hematophagous arthropods
56 Current HIV Research, 2010, Vol. 8, No. 1
during the acute stage of disease when viral titres in blood are high [10, 25]. This is supported by epidemiological data which indicates that infection occurs after close contact between infected and susceptible cattle, and that the incidence of Jembrana disease is greater during the wet season in Bali, consistent with high numbers of biting arthropods. In experimentally infected cattle, transmission from infected to in-contact cattle has been clearly demonstrated [10]. Other modes of transmission, such as vertical transmission or via body fluids (milk, semen or saliva) have not been investigated fully, but there is evidence that during the acute phase of infection, JDV is shed into milk from infected cattle and intranasal, conjunctival and oral infection have been experimentally reproduced [10]. Understanding the mode of virus transmission is a critical part of controlling the spread of disease in an outbreak and VL data generated using qRT-PCR has recently been used to estimate a threshold above which the risk of virus transmission is increased [26]. Based on observations that bloodmeal residues on the mouthparts of tabanid flies of 4 10nl can been detected and a titre of EIAV of 106 ID50/ml in blood can be transmitted by a single fly, a plasma VL of 106 JDV genome copies/ml was estimated as a transmission threshold [27, 28]. This is approximately equivalent to an infectious titre of 104 ID50/ml [11] or 99.9% of the total VL during the acute stage of the disease is above this threshold (Fig. 2). The role of persistently viraemic recovered animals in virus transmission remains unclear as viral titres reduce quickly after the acute stage of disease to 100 ID50/ml at 32 days post-infection and drop further to 10 ID50/ml by 72 days [10] although cattle remain viraemic for at least 2 years after recovery [9]. In a recent field survey in Bali, proviral DNA levels in peripheral blood mononuclear cells (PBMC) were only detectable in 21% of seropositive cattle indicating that proviral loads are low in recovered cattle [12]. VIRAL REPLICATION JDV RNA can be detected in plasma as early as 2 days post-infection and peak VL of between 1010-1011 RNA copies/ml plasma occurs on average 11 days post challenge (Fig. 2 and Table 1). The febrile response (rectal temperature 39.3oC) develops as the VL increases and reaches a maximum within a day of the peak VL (Table 1). The mean VL, area under the curve calculation for VL 106 JDV genome copies/ml and febrile response values for experimental infections with JDVTAB/87 or JDVPUL/01 are summarised in Table 1 and were derived from a total of 19 Bali cattle. This analysis has provided evidence of varying replication dynamics between these two strains of virus [13]. Clinical disease followed a typical course in 19 of a total of 26 cattle with an incubation period of 5-12 days, a febrile period of 4-9 days and resolution of clinical signs 13-17 days post-infection. The mean plasma VL on the first day of the febrile response in the cattle infected with JDVPUL/01 was significantly lower than in cattle infected with JDVTAB/87. Similarly, the mean peak VL was significantly lower in JDVPUL/01 infected animals (Table 1). During the acute stage of disease JDVTAB/87 infected cattle are found to have a mean log10 plasma VL 106 genomes/ml of 11.5 versus 10.4 for
Desport and Lewis
JDVPUL/01 infected cattle. Plasma VL is above the threshold of 106 genome copies/ml for an average of 3 days longer in JDVTAB/87 infected cattle (Table 1) [13]. Atypical responses to infection with JDV were observed in 4 of the 26 cattle with development of little or no febrile response (mean 1.3 days where rectal temperatures were 39.30C). This was also accompanied by reduced viral replication with peak VL occurring approximately 2 days later than the normal responders. A reduction in the number of days where the plasma VL 106 genomes/ml was observed and the mean log10 peak VL of 8.8 genome copies/ml was significantly reduced compared to the mean peak VLs for JDVPUL/01 or JDVTAB/87 infected cattle (Table 1). Fatalities were only observed after infection with JDVPUL/01 in 3 cattle and were associated with failure to clear high plasma viral loads (Fig. 2) [13]. These may have been associated with group specific factors such as poor nutrition or secondary infections (unpublished observation). GENOME ORGANISATION TRANSCRIPTION
AND
VIRUS
JDV has the smallest genome of any of the lentiviruses at 7,732 nucleotides in length and encodes the typical lentiviral gag, pol and env genes. A complex transcription pattern including unspliced, singly and multiply spliced transcripts was recently described [29] with mRNA transcripts identified for gag/pol, env, vif, tat, rev and tmx indicating that at least 4 accessory gene products are transcribed in vivo (Fig. 3). Different types of retroviral Gag proteins may use distinct mechanisms for assembly which may be reflected by different core structures within the virus particles that are generated [30]. Uniquely among the lentiviruses, the BIV Gag precursor protein is cleaved into 6 major proteins in the order NH2-MA-p2L-CA-p3-NC-p2-COOH [31]. The first 8 residues of the p3 spacer sequence between CA and NC are important in the assembly of BIV Gag. This includes a pentapeptide motif (LVAAM) which appears to be conserved in EIAV (LAKAL), FIV (LAEAL), HIV-1 (LAEAM) and visna maedi virus (LAQAL). The motif also appears to be conserved in JDV, consisting of LAEAF, suggesting a similar mode of assembly to BIV Gag. However, only 2 of 5 cleavage sites in BIV gag are conserved in the JDV gag precursor indicating that it is only processed into matrix (MA), capsid (CA) and nucleocapsid (NC) proteins [8]. The JDV MA and CA proteins share several cross-reacting epitopes with BIV MA and CA proteins. The CA protein is the immuno-dominant protein in BIV and JDV and there are several cross-reacting epitopes in the CA proteins of the two bovine lentiviruses [6, 32] as well as more restricted cross-reactivity with other lentiviral CA proteins which all contain a highly conserved major homology region (MHR) [8, 33, 34]. The functional intravirion proteins (enzymes) of JDV are encoded by pol and are predicted to be expressed as a 1,027 amino acid and 118 kDa Pol precursor polyprotein, which is cleaved by the host cell proteases into an integrase (IN), a reverse transcriptase (RT) and viral protease (PR). In common with other lentivirus pol ORFs, JDV mRNA transcripts have been identified which indicate that Pol is produced by a -1 ribosomal frameshift and not from a single transcript (Fig. 3) [29]. Cis-acting sequences, including a
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Fig. (3). Schematic representation of the genome organisation of JDV indicating the major ORFS and predicted ORFs for the accessory proteins Vif, Tat, Rev and Tmx. Differently spliced mRNA transcripts identified from spleen tissue are represented by grey shaded boxes with non-coding exons indicated by patterned boxes and the splice acceptor (SA) and splice donor (SD) positions indicated.
heptanucleotide frameshift site identified for BIV which is perfectly conserved in JDV, are likely to be involved in this mechanism. The formation of pseudoknot structures has been reported to dramatically affect the efficiency of frameshifting in retroviral mRNAs [35] and the stable basepairing of a pseudoknot identified in the JDV genomic RNA indicates that the frameshifting mechanism for JDV may be more efficient than for BIV [36]. The Env polyprotein of JDV encoded by env ORF is 781 amino acids long (89 kDa) and undergoes further cleavage by the virus-encoded protease to produce SU and TM glycoproteins. The JDV SU is predicted to be 422 amino acids long (47 kDa) and is substantially smaller than that of BIV, a difference that is compounded by a lower number of potential N-linked glycosylation sites in the JDV env precursor. The TM protein is predicted to be 359 amino acids (41 kDa) and is more similar in size to that of BIV. Two different env mRNA transcripts were identified (Fig. 3)
which differed only in the presence or absence of a small non-coding exon encompassing nt 4014-4081 which was also observed in alternative rev and tat transcripts [29, 37]. This did not appear to be translated or influence the downstream splicing of env, tat or rev. An additional noncoding exon (nt 4663-4808) was also identified in a minority of tat mRNA transcripts from JDVPUL/01 and may contribute to the differences in the replication dynamics of this strain compared to JDVTAB/87 (Fig. 3) [37]. Small non-coding exons in HIV-1 transcripts have been associated with changes in the levels of gene expression [38] and the particular cell type from which the transcript is derived [39]. Non-coding exons have not been identified in BIV rev or env transcripts [40] leading to speculation that they may play a role in the high viral titres and acute pathogenicity of JDV compared to BIV [29]. The genomes of the bovine lentiviruses differ from other non-primate lentiviruses by lacking a functioning dUTPase
58 Current HIV Research, 2010, Vol. 8, No. 1
[36, 41] although a non-functioning dUTPase related segment has been identified recently [42]. Retroviral dUTPases have a central role in productive viral replication in nondividing cells, such as macrophages, where cellular dUTPases and the pool of available deoxynucleotides are at low levels [43-45]. The accumulation of G-to-A substitutions in CAEV has been shown to be prevented by the virally encoded dUTPase [46] and replication in macrophages without a mechanism for preventing these substitutions leads to a drift of the genome towards poly(A). The genomes of the bovine lentiviruses exhibit dramatic differences in their genome compositions in their 5’ compared to 3’ halves. Lentivirus genomes are characteristically A–rich along their entire length, but in a recent genome analysis both BIV and JDV were found to be A–rich only in their 5’ halves [47]. ROLE OF ACCESSORY PROTEINS AND LTRs The bovine lentiviruses differ from other members of the lentivirus family in the accessory proteins that they do or don’t encode. JDV encodes the most potent Tat of any of the lentiviruses which can functionally substitute for HIV and other lentivirus Tat proteins [48]. Differences in lentiviral replication dynamics have also been attributed, at least to some extent, to the occurrence of different splicing events at different stages of infection. Several different tat splice variants are found in PBMC during acute Jembrana disease and Tat is detected early in infection in PBMC lysates taken before the onset of fever [37]. Both exogenous and endogenous Tat induce apoptotic cell death in vitro and this is proposed to be mediated through the interaction of the cysteine rich region with both tubulin and microtubule dynamics. JDV Tat, like BIV Tat, is produced from a single exon tat-1 transcript which is highly conserved between even the most divergent strains of JDV and has an arginine-rich translocation motif which was found to be responsible for the internalization of extracellular Tat with both a nuclear and cytoplasmic distribution [37, 49]. This is proposed to be a mechanism whereby JDV can influence cellular gene expression in infected and neighbouring uninfected cells to make the cellular environment more amenable to viral infection and is potentially a key virulence determinant [50]. Apoptotic death induced by some viruses results in the formation of small membrane bound apoptotic bodies which can pinch off from the dying cell and be consumed by the phagocytic action of neighbouring cells. This is thought to facilitate the spread of virus without initiating a host response or the requirement of specific viral receptors on the neighbouring cell [51]. A striking absence in both BIV and JDV genomes is a nef ORF which is located in the 3’ region of env of the primate lentiviruses. However, both BIV and JDV encode a unique accessory protein, Tmx, in this region of the genome and although it is genetically unrelated to Nef, it is speculated that Tmx may fulfil similar functions to Nef. A putative polyclonal B-cell stimulatory epitope is present in the carboxyl end of the envelope glycoprotein of HIV-1 which is specifically associated with Nef [52, 53]. Although the function of Tmx is unknown, it is possibly involved in the proliferation of B cells that occurs during in vivo infections with these viruses [36, 54]. Alternatively or in addition, the lymphocytosis could be related to expression of exogenous
Desport and Lewis
Tat early in infection as HIV-1 Tat has been shown to cause B-cell hyperactivation in vitro [55]. The JDV LTR is 397bp in length and contains transcription factor binding sites including NF-B, AP-4 and Sp-1 and a perfectly conserved TATA box. It has a major deletion of 157bp compared to the BIV LTR which is 192bp longer in total. This results in the absence of motifs for several enhancer elements in the JDV LTR which are present in BIV, including the CCAAT/enhancer binding proteins (C/EBP) motif which is found in most eukaryotic and retroviral promoters. C/EBP proteins were found to be limiting for HIV-1 transcription but not infection, and primary macrophages did not support the replication of HIV1 harboring mutant C/EBP binding sites in the LTR [56]. However, primary CD4+ T cells supported replication of wild-type and mutant HIV-1 equally well indicating that this is a macrophage-specific regulatory mechanism for HIV-1 replication [57]. It is unclear whether JDV can productively infect macrophages and whilst it is tempting to link this with the unusual absence of this macrophage-specific motif in the JDV LTR, there are other transcription factor binding motifs which are present in the JDV LTR that have also been associated with lentivirus replication in macrophages. There are 3 potential PU.1 sites (consensus sequence GGAA) in the JDV LTR and these have been identified as being important for EIAV expression in macrophages although other elements within the enhancer region of the LTR are also required [58]. STRAIN VARIATION AND GENETIC STABILITY JDVTAB/87 is the only strain of JDV fully sequenced and characterised to date [8]. The genome of JDV is approximately 7732bp, 750bp smaller than BIV127, and is the smallest of the lentivirus genomes. It is unprecedented that 2 closely related lentiviruses should have genomes with so many insertions and deletions relative to each other and it may reflect a basic functional difference in the RTs encoded by these viruses compared to other lentiviruses [36]. In support of the hypothesis that JDV originated from BIV, potential recombination hot-spots have been identified by comparing the 2 genome sequences. A deletion in the SU region of strain JDVPUL/01 occurs at exactly the same position as a 468bp insertion in BIV127 SU. Similarly, an insertion of 7bp in the U3 region of JDV PUL/01 relative to JDV TAB/87 occurs at the same position in BIV127 U3 as an insertion of 157bp of unrelated sequence [59]. JDV strains from different regions of Bali over a period of nearly 20 years are genetically highly conserved with only 1% amino acid variation in pol compared to the JDV TAB/87 strain (Table 2) [59]. JDV KAL/01, identified from cattle in Kalimantan (Indonesian Borneo) in 2001 exhibited a greater level of variation in this region than the strains derived from Bali (Table 2). Analysis of the entire env of these strains revealed up to 5% amino acid variation between strains from Bali which was sufficient for JDV PUL/01 to cluster separately from other Bali derived strains following phylogenetic analysis (Fig. 4 and Table 3). A short region of highly conserved gag sequence from strains obtained from different Indonesian islands was analysed to help determine how the virus may have spread. In this region of the JDV genome, virus strains from Lampung province in Sumatra were highly
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Fig. (4). Phylogenetic analysis of the evolutionary relationship between the predicted env amino acid sequences from 8 strains of JDV, including JDVTAB/87. The amino acid substitution rate is shown as a bar and the percentage likelihood from 1000 bootstrap replicates, analysed by the neighbour-joining method, is indicated.
similar to Bali samples, displaying 100% amino acid homology with one strain from Badung district of Bali supporting the theory that the spread of JDV to Sumatra was most likely due to the illegal movement of cattle from Bali [3]. The origin of the disease in Kalimantan is unknown and occurred 2 decades later than the Sumatran outbreak. JDVKAL/01 is clearly divergent from the other sequences in the three regions analysed but, at least for the env phylogenetic analysis, clusters with JDVPUL/01 (Fig. 4). This suggests that the source of the virus in Borneo may not have resulted from movement of cattle from Sumatra but may have arisen from a related virus from Bali or perhaps was similar to the original source of JDV. Given the high levels of nucleotide homology between the samples from different regions of Bali, it appears that JDV strains in Bali may be a monophyletic cluster of geographically nearby isolates, similar to a phenomenon which has been observed for FIV [60]. Table 2.
Percentage Identities of Nucleotide (Above Diagonal) and Amino Acid (Below Diagonal) Sequences of 318bp of pol from JDV Strains from Different Regions of Bali (n=3) and Borneo (n=1)
Sample
JDVTAB/87
JDVPUL/01
JDVBAD/99
JDVKAL/01
JDVTAB/87
-
98
99
92
JDVPUL/01
100
-
98
91
JDVBAD/99
99
99
-
92
JDVKAL/01
94
94
95
-
There are several possible explanations for the stability of the JDV genome. All samples were collected during the acute stage of the disease and genetically homogenous populations of lentiviruses are commonly evident prior to seroconversion [61]. The conservation might be due to the fidelity of the JDV RT as this can be a major influence on the mutation rate [62]. During the acute phase of the disease there is no detectable antibody response to JDV and an
Table 3.
Sample
Percentage Identities of Nucleotide (Above Diagonal) and Amino Acid (Below Diagonal) Sequences of Entire env (2345 bp) from JDV Strains from Different Regions of Bali (n=3) and Borneo (n=1) JDVTAB/87
JDVPUL/01
JDVBAD/99
JDVKAL/01
JDVTAB/87
-
97
99
88
JDVPUL/01
97
-
96
88
JDVBAD/99
98
95
-
87
JDVKAL/01
87
87
85
-
apparent suppression of immune responses to other agents [20]. Suppression of the immune system during periods of maximum virus replication might be anticipated to result in neutral selection of JDV variants. The genetic stability could arise because transmission is most likely during the acute phase of the disease, before genetic drift or immune selection would have occurred. The absence of recurring cycles of disease is consistent with the genetic stability of the viral sequences and an analysis of the immune responses that occur post-infection is required to determine how infection is so tightly controlled. Despite the low sequence variation, experimental infection with different strains of JDV results in a broad spectrum of responses, ranging from an absence of any clinical signs of disease in 15% of cattle to fatalities in 11.5% of cattle [13]. The differences in the magnitude and duration of plasma VL generated after infection with JDVPUL/01 compared to JDVTAB/87 could be associated with the 3% difference in the predicted env sequences for these strains. Animals infected with JDVTAB/87 exhibit higher and longer plasma VL compared to those infected with JDVPUL/01 which could be due to both host and virus factors (Table 1). Differences in LTR sequences correlate with increased replication capacity of EIAV in vitro [63] and it is possible that a 7 nucleotide insertion in the U3 region of the LTR of
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JDVPUL/01 may account for at least some of the differences in the viral replication dynamics [13, 59]. CELL TROPISM AND IN VIVO PATHOGENESIS Initial studies into the pathogenesis of Jembrana disease revealed that in the first week after infection, a predominantly non-follicular lymphoproliferative response was observed in lymphoid organs with infiltrative processes in the kidney, liver and other non-lymphoid tissues. Responses in the spleen and lymph node were similar with the peri-arterial areas and the interfollicular red pulp showing active proliferation of large pleomorphic mononuclear cells [64]. Few CD4 and CD8 cells are found in the parafollicular areas of lymph nodes from necropsied animals during the acute stage of disease where a prominent lymphoproliferative response is observed. IgG positive cells in particular are prominent in the medullary cords of the lymph nodes and non-follicular compartments of the spleen where they are presumed to be undergoing maturation [18]. In situ hybridisation (ISH) studies revealed that the spleen is the first organ to be colonised during the early phase of infection and that this may act as a reservoir for further dissemination of virus as the disease progresses, so that infected cells are found in lymph node, lung, liver, kidneys, bone marrow etc. In lung sections, infected cells are predominantly located within alveolar septae and vessels. Bone marrow contains high levels of infected cells despite appearing normal in routine histopathology and is suggested to be an important source of infected cells in the circulation [8]. Infected cells have the appearance of large lymphocytes or haematopoetic precursor cells. Many infected cells are found within blood vessels suggesting that significant numbers of infected cells are present in circulation. From these initial tropism studies it was concluded that infected cells were most probably of lymphoid origin or of the monocyte/macrophage lineage. Pleomorphic cells were found to have variable amounts of intensely purple cytoplasm, marked nuclear pleomorphism and anisokaryosis with bizarre coarsely clumped chromatin, thus resembling centroblasts. Early investigators originally suggested that the phenotype of the lymphocytes proliferating during the acute stage of the disease was T-cells. It was assumed, although not proven, that the high level viraemia which occurs during the acute phase resulted from replication of virus in the population of proliferating cells. Follicular architecture was found to be obliterated by proliferating cells by 8 days after infection and marked follicular lymphoid reactions and plasma cell formation were only observed from the fifth week after infection [64]. The distribution of infected cells in post-mortem tissues taken at the acute stage of disease is predominantly in the parafollicular areas of the spleen and lymph node (Fig. 5) with little or no signal in the follicles [8]. The germinal centres are however depleted, and the remains of the mantle zone are surrounded by a wide zone of pleomorphic centroblast-like cells in densely packed sheets. A loss of IgG containing cells and a decrease in CD4: CD8 lymphocyte numbers during the first 2 weeks of infection was reported in earlier studies [18, 64]. A recent study using immunohistochemical techniques identified viral capsid
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antigen in the cytoplasm of some large pleomorphic centroblast-like cells that were scattered throughout the mantle zone and red pulp of the spleen, paracortex and medullary cords of lymph nodes as well as in the circulation [65]. A small proportion of JDV capsid containing cells were identified as B-lineage by fluorescent double immunolabelling with anti-JDV capsid and anti-CD79a MAbs. Many infected cells were identified as plasma cells by the presence of cytoplasmic IgG, indicating a tropism for IgG containing cells [65]. The distribution of monocyte/macrophage-lineage cells during the acute stage of Jembrana disease was investigated using 2 different MAbs on fixed bovine tissues. Recently blood-derived monocytes and neutrophils were identified using MAb MAC387 whilst MAb EBM11, which recognizes CD68, was used to identify mature tissue macrophages [66, 67]. The distribution of EBM11 positive cells compared to MAC387 positive cells in infected lymph nodes and lung is different, confirming that these antibodies identify different subsets of cells of the mononuclear phagocyte system. Despite similarities in the size, morphology and distribution of MAC387 positive cells and JDV-infected cells, no colocalization of staining of monocytes or neutrophils and JDV-infected cells was observed. Mature tissue macrophages were identified, using EBM11, in the medullary sinuses of the lymph node whereas the JDVpositive cells were localised to the medullary cords [65]. EBM11+ macrophages are present in the alveolar septae of the lungs and JDV capsid antigen was occasionally observed in large vacuolated macrophage-like cells. JDV capsidimmunopositive cells are scattered throughout the alveolar septae and, because double immunostaining is not possible with this combination of MAbs, it is unclear whether the positive staining in macrophage-like cells was due to productive infection or phagocytosis of infected cells. The role of macrophages in JDV infection of Bali cattle remains unclear. JDV is certainly present in the circulating PBMC population and yet monocytes identified using MAC387 are not infected and tissue macrophages identified using EBM11 do not share the same tissue location as the capsidcontaining cells. All of the other lentiviruses, including BIV, are able to infect macrophages and JDV would indeed be an exceptional lentivirus if it were found to lack this tropism. Whilst proliferation of CD3+ T-cells occurs during and after the acute stage of infections with JDV, they do not appear to be infected with JDV. This is supported by the absence of any positive ISH staining in mitotic cells [8]. The apparent tropism of JDV for cells of a non-T-cell lineage is perhaps not surprising as there are marked differences in the disease pathogenesis and genetic variability of JDV compared to most of the other lentiviruses, particularly those that are T-cell tropic [17, 59]. The detection of JDV capsid protein in a sub-population of B-cells and in terminally differentiated plasma cells indicates that JDV can replicate in cells of this lineage. The location of the infected cells in the mantle zone, outside the germinal centres (Fig. 5), suggests that productive infection occurs in mature rather than proliferating immature B-cells. Interestingly, B cells are infected at a low frequency by SIVsmmPBj14, an acutely lethal lentivirus infection in pigtail macaques with a similar pathogenesis to JDV [68]. In addition, B-cells, particularly
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Fig. (5). Large JDV capsid immunopositive cells are found scattered throughout the medullary cords of a lymph node taken on the second day of febrile response following experimental infection with JDVTAB/87. Fewer positive cells are found in the cortex and medullary sinuses and the lymphoid follicles (arrows) are largely spared.
IgG-containing cells, are a major reservoir for FIV in chronically infected cats [69]. HOST RANGE BIV is considered to have co-evolved over time with its bovine host and it was anticipated that an increase in pathogenicity might have occurred when different hosts e.g. sheep or goats were infected with BIV, as has occurred when other lentiviruses have crossed species boundaries. Whilst this was not observed in sheep under experimental conditions [70], or in calves infected with CAEV [71], the emergence of JDV in a different bovine species almost certainly represents such an occurrence. Clinical signs of Jembrana disease have only been described in Bali cattle, but a range of related bovine species and other ungulates have been successfully infected with the virus. Ongole cattle (Bos indicus), Friesian cattle (Bos taurus), buffaloes and pigs all respond to JDV infection by developing a transient febrile response, although no response is detected in sheep. Persistent infections have been detected in Ongole cattle for 3 months but not after 6 months, in Friesian cattle for 1 month but not after 4 months, in buffaloes for 9 months and in sheep for 4 months after inoculation. Buffalo are a common draft animal in Indonesia and may be capable of maintaining JDV in populations of animals in areas with few Bali cattle [9]. When cross-breeds of Bali cattle were experimentally infected with JDV, only 80% of Madura (Bos javanicus x Bos indicus) and 60% of Rambon (first generation Bos javanicus x Bos indicus) cattle developed clinical or haematological signs of disease; however, an
antibody response developed in all except one of the Rambon cattle [72]. The discovery of intracellular restriction factors, APOBEC3G and TRIM5 which are able to block retroviral replication at various stages, has provided new insights into the factors that influence cross-species transmission of lentiviruses [73]. The significance of recently identified bovine specific lentivirus restriction factors in the observed and experimentally induced host range and in the replication rates of JDV and BIV awaits investigation [74, 75]. VACCINATION AND IMMUNOLOGICAL CONTROL Quantification of the magnitude and duration of VL 106 genome copies/ml has revealed the benefits of using JDVacc, a whole virus inactivated vaccine that is currently used in Indonesia, and highlighted problems associated with using febrile responses as a correlate of vaccine efficacy [26]. The spread of Jembrana disease is currently controlled by ring vaccination of susceptible cattle in outbreak areas with 2 doses of JDVacc given with a 4 week interval. JDVacc is an inactivated tissue derived vaccine which is prepared by mixing spleen from an acutely infected animal with a mineral oil adjuvant. Initial vaccine efficacy trials indicated that the vaccine did not prevent Jembrana disease but was able to ameliorate the clinical signs of disease [76]. A more recent small trial with JDVacc in four cattle revealed that after challenge with JDVTAB/87 there was a reduction in total VL in the vaccinates compared to the controls [26]. By estimating a threshold of virus transmission at 106 genome
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copies/ml, it was calculated that the vaccine was able to reduce the average number of infectious days by 33% compared to the trial control group or 54% compared to JDVTAB/87 infected cattle (Table 1 and Fig. 2). Vaccinated animals exhibited lower peak VLs compared to the JDVTAB/87 infected cattle (Table 1), indicating that a low level of virus neutralization or reduction in early spread of virus may be due to the humoral immune responses generated after vaccination. The absence of detectable neutralizing antibodies after vaccination with JDVacc in the initial study combined with poor anti –Tm responses in the small trial indicates that the vaccine does not appear to stimulate strong responses to Env antigens. However, vaccinates were found to seroconvert to Env antigens within 3 weeks of infection compared to 8 weeks in the controls [26]. The most significant effects of JDVacc appear after the peak VL when vaccinates cleared circulating virus much faster than the control animals (Fig. 2). The elevated rectal temperatures at lower viral titres in the vaccinated group indicate that effective viral clearance is due to a primed CMI response and highlights the balance between effective immune activation and potentiation of viral replication. Neutralizing antibodies were not detected in pooled sera from JDVacc vaccinated animals that resisted challenge. In contrast, sera from recovered cattle was found to contain neutralizing activity but only if it was collected >4 months after recovery [76]. SEROPREVALENCE, EPIDEMIOLOGY AND DIAGNOSIS The seroprevalence of JDV was originally investigated in 1993 using cattle sera obtained from different districts on the islands of Bali, Sumatra, Kalimantan, Lombok, Sulawesi and Java [3]. A sucrose-purified whole virus antigen ELISA was developed and seropositive cattle were identified using this assay in 4 provinces in Indonesia: Bali, Lampung (in Sumatra), West Sumatra and East Java. The seroprevalence of antibody-positive cattle in Bali was higher in the Western districts (Jembrana, Tabanan and Buleleng) which correlated with the prevalence of clinical cases of Jembrana disease. Buffaloes in this district were also found to be seropositive (13/51 sampled). No seropositive cattle were detected in samples obtained from South Sulawesi, Lombok and Nusa Penida (a small island adjacent to Bali). Samples obtained from Bali in 2001 were tested using ELISAs with both JDV or BIV recombinant capsid proteins and Tm peptides. Differences were observed in the reactivities against JDV vs BIV antigens leading to the hypothesis that 2 bovine lentiviruses may be present in the cattle population in Bali [77]. Seropositive cattle were identified more recently in samples from Sulawesi, although no clinical signs or other evidence of Jembrana disease were reported, suggesting the presence of a non-pathogenic bovine lentivirus, possibly BIV [32]. The cross reactivity between the capsid proteins of BIV and JDV means that there are no specific serological tests to distinguish between infections with these viruses. A delayed seroconversion to viral antigens of 5-15 weeks after infection is observed and responses to capsid appear earliest and are maintained [6, 13]. Diagnostic methods for the detection of JDV infection in Bali were recently compared to determine which was the most sensitive and
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reliable method [12]. The preparation of plasma-derived whole virus antigen is increasingly difficult in Indonesia and a JDV p26-his antigen was found to be the most sensitive and reliable replacement for this antigen in ELISA. Improvements in the sensitivity of ELISA have been observed for detection of other lentiviral infections by the addition of a Tm peptide encompassing the principal immunodominant domain to make a fused p26/TM protein [78]. When coating antigens JDV p26/TM-his or p26-his were tested in ELISA with reference positive and negative sera close median values were obtained for both assays. However, when field sera were tested with both antigens the data obtained using p26/TM-his contained more false negatives and therefore was found to be much less sensitive. This data highlights differences that occur between samples obtained from controlled experimental conditions vs field conditions. A real-time PCR assay was found to detect JDV proviral DNA from samples of genomic DNA extracted from PBMC of experimentally infected recovered cattle. However, JDV proviral DNA could not be detected from 79% of seropositive field samples indicating that the proviral load is very low in cattle that have recovered from infection [12]. Immune system dysfunction is a consequence of many lentiviral infections and variable gag responses are observed after experimental infection with both BIV and JDV. Weak to undetectable CA antibody responses were recently observed in 15% of JDV experimentally infected cattle which also failed to develop the classical febrile response to infection. Interestingly, all except one of these animals developed strong TM responses detected using the JDV TMc peptide ELISA [13]. Capsid antibody responses are used as diagnostic indicators of bovine lentiviral infections [77, 79, 80] but the absence of detectable responses in some animals suggests that these diagnostic assays may be underestimating the prevalence of infections. Given the worldwide distribution of BIV seropositive cattle, including other regions of Asia, it is highly likely BIV is present in Indonesia. However, BIV proviral DNA was not detected in any PBMC DNA samples from Bali cattle that were seropositive in a JDV p26-his ELISA. Difficulties in amplifying BIV successfully from PBMC DNA samples have been reported [81] and BIV proviral DNA was found to be undetectable in PBMC taken 12 months after experimental infection [82]. It is therefore likely that failure to detect either JDV or BIV proviral DNA in most seropositive animals is largely due to low proviral loads. However, a combination of a JDV p26-his ELISA and realtime PCR is recommended as the most sensitive combination of assays to detect JDV infection in Indonesia. The delayed seroconversion would be expected to produce false-negative results in serological assays until 5-15 weeks after infection and cattle that have been recently infected would therefore be confirmed by the presence of proviral DNA [12]. The immune responses that develop in cattle that recover from Jembrana disease appear to control the infection as, although virus persists for at least 25 months, there is no progression of disease. In addition, when recovered cattle were rechallenged with JDV up to 22 months after the initial infection, no recurrence of disease was detected in 94% of cattle [9].
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FUTURE DIRECTION The bovine lentiviruses exhibit some characteristics that make them unique in the lentivirus family, whilst their genome organization, morphology and cross reactivity with other members of the group concur with this classification. JDV is often described as an atypical lentivirus because of the acute nature of Jembrana disease, the low level of viral variation, the delayed antibody response and the ensuing immunological control that develops post-infection which prevents subsequent heterologous infection and recurrence of disease. The obvious differences between the pathogenesis of HIV infection in humans and JDV infection in Bali cattle indicate that Jembrana disease is not a particularly relevant animal model for HIV. However, this difference is seen as advantageous in the development of a JDV transfer vector which is proposed to be more readily acceptable for human gene therapy than those from HIV [83, 84]. Replication defective gene transfer vectors derived from JDV can integrate into the host cell chromosome post-transduction and they offer potential as bovine vaccine vectors as well as vehicles for gene therapy.
[5]
Both JDV and BIV provide a unique opportunity to virologists to study virus-host interactions in simple animal models without confounding factors such as viral hypervariation. In addition, superinfection studies are underway with these viruses in Bali cattle which may provide further understanding of the virus and host specific factors that influence these potentially naturally occurring events. The rapid clearance of high titres of replicating virus and subsequent controlling immunity that develops following recovery from Jembrana disease in Bali cattle may provide valuable insights into the mechanisms that generate and maintain prolonged control of lentiviral replication.
[11]
Lentiviral infections continue to present challenges for development of effective vaccines and therapeutic drugs. The infection of cells of the immune system and the ensuing immune activation during the early acute disease undoubtedly contributes to the pathological changes that occur during clinical latency and to the development of clinical disease and death or recovery. An understanding of the precise tropism of JDV and immunological control during the acute disease and post-recovery may provide important clues as to how this control could be achieved in HIV infections. Substantial progress has been made towards understanding the pathogenesis of Jembrana disease and the dynamics of JDV replication in the last 10 years and continuing research into this unique lentivirus may reveal further information on lentiviral pathogenesis and host control of infection. REFERENCES [1] [2] [3]
[4]
Adiwinata RT. Some informative notes on a rinderpest-like disease on the island of Bali. Bull Off Int Epizoot 1968; 69(1): 7-14. Budiarso IT, Hardjosworo S. Jembrana disease in Bali cattle. Aust Vet J 1976; 52(2): 97. Hartaningsih N, Wilcox GE, Dharma DM, Soetrisno M. Distribution of Jembrana Disease in Cattle in Indonesia. Vet Microbiol 1993; 38(1-2): 23-9. Soeharsono S. Current Information on Jembrana Disease Distribution in Indonesia. In: Wilcox GE, Soeharsono S, Dharma DMN, Copland JW, Eds. Jembrana Disease and the Bovine
[6] [7]
[8]
[9]
[10]
[12]
[13]
[14]
[15] [16]
[17]
[18]
[19] [20]
[21] [22]
[23]
[24]
63
Lentivirus, Indonesia, Bali: Watson Ferguson and Co 1995; pp. 725. Soeharsono S, Temadja TIGN. The Occurence and History of Jembrana Disease in Indonesia. In: Wilcox GE, Soeharsono S, Dharma DMN, Copland JW, Eds. Jembrana Disease and the Bovine Lentivirus, Indonesia, Bali: Watson Ferguson and Co 1995; pp. 2-9. Kertayadnya G, Wilcox GE, Soeharsono S, et al. Characteristics of a retrovirus associated with Jembrana disease in Bali cattle. J Gen Virol 1993; 74 (Pt 9): 765-78. Wilcox GE, Kertayadnya G, Hartaningsih N, Dharma DM, Soeharsono S, Robertson T. Evidence for a viral aetiology of Jembrana disease in Bali cattle. Vet Microbiol 1992; 33(1-4): 36774. Chadwick BJ, Desport M, Brownlie J, Wilcox GE, Dharma DM. Detection of Jembrana disease virus in spleen, lymph nodes, bone marrow and other tissues by in situ hybridization of paraffinembedded sections. J Gen Virol 1998; 79(Pt 1): 101-6. Soeharsono S, Hartaningsih N, Soetrisno M, Kertayadnya G, Wilcox GE. Studies of experimental Jembrana disease in Bali cattle. I. Transmission and persistence of the infectious agent in ruminants and pigs, and resistance of recovered cattle to reinfection. J Comp Pathol 1990; 103(1): 49-59. Soeharsono S, Wilcox GE, Putra AA, Hartaningsih N, Sulistyana K, Tenaya M. The transmission of Jembrana disease, a lentivirus disease of Bos javanicus cattle. Epidemiol Infect 1995; 115(2): 367-74. Stewart M, Desport M, Hartaningsih N, Wilcox G. TaqMan realtime reverse transcription-PCR and JDVp26 antigen capture enzyme-linked immunosorbent assay to quantify Jembrana disease virus load during the acute phase of in vivo infection. J Clin Microbiol 2005; 43(11): 5574-80. Lewis JR, McNab TJ, Tenaya M, Hartaningsih N, Wilcox GE, Desport M. Comparison of Immunoassay and Real-Time PCR Methods for the Detection of Jembrana disease virus Infection in Bali Cattle J Virol Methods 2009; 159(1): 81-6. Desport M, Ditcham WG, Lewis JR, et al. Analysis of Jembrana disease virus replication dynamics in vivo reveals strain variation and atypical responses to infection. Virology 2009; 386(2): 310-6. Büchen-Osmond C. Index to ICTVdB virus descriptions In: Büchen-Osmond C, Ed. ICTVdB - The Universal Virus Database. version 4 ed: ICTVdB Management, Mailman School of Public Health, Columbia University, New York, NY, USA 2006. Palmer E, Sporborg C, Harrison A, Martin ML, Feorino P. Morphology and immunoelectron microscopy of AIDS virus. Arch Virol 1985; 85(3-4): 189-96. Gonda MA, Wong-Staal F, Gallo RC, Clements JE, Narayan O, Gilden RV. Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science 1985; 227(4683): 173-7. Soesanto M, Soeharsono S, Budiantono A, Sulistyana K, Tenaya M, Wilcox GE. Studies on experimental Jembrana disease in Bali cattle. II. Clinical signs and haematological changes. J Comp Pathol 1990; 103(1): 61-71. Dharma DM, Ladds PW, Wilcox GE, Campbell RS. Immunopathology of experimental Jembrana disease in Bali cattle. Vet Immunol Immunopathol 1994; 44(1): 31-44. Hartaningsih N, Wilcox GE, Kertayadnya G, Astawa M. Antibody response to Jembrana disease virus in Bali cattle. Vet Microbiol 1994; 39(1-2): 15-23. Wareing S, Hartaningsih N, Wilcox GE, Penhale WJ. Evidence for immunosuppression associated with Jembrana disease virus infection of cattle. Vet Microbiol 1999; 68(1-2): 179-85. Carpenter S, Miller LD, Alexandersen S, et al. Characterization of early pathogenic effects after experimental infection of calves with bovine immunodeficiency-like virus. J Virol 1992; 66(2): 1074-83. Snider TG 3rd, Hoyt PG, Coats KS, et al. Natural bovine lentiviral type 1 infection in Holstein dairy cattle. I. Clinical, serological, and pathological observations. Comp Immunol Microbiol Infect Dis 2003; 26(2): 89-101. Cook RF, Cook SJ, Berger SL, et al. Enhancement of equine infectious anemia virus virulence by identification and removal of suboptimal nucleotides. Virology 2003; 313(2): 588-603. Schwiebert R, Fultz PN. Immune activation and viral burden in acute disease induced by simian immunodeficiency virus
64 Current HIV Research, 2010, Vol. 8, No. 1
[25] [26]
[27]
[28]
[29]
[30] [31]
[32]
[33]
[34]
[35]
[36]
[37] [38]
[39]
[40]
[41]
[42] [43] [44]
SIVsmmPBj14: correlation between in vitro and in vivo events. J Virol 1994; 68(9): 5538-47. Issel CJ, Foil LD. Studies on equine infectious anemia virus transmission by insects. J Am Vet Med Assoc 1984; 184(3): 293-7. Ditcham WG, Lewis JR, Dobson RJ, Hartaningsih N, Wilcox GE, Desport M. Vaccination reduces the viral load and the risk of transmission of Jembrana disease virus in Bali cattle. Virology 2009; 386(2): 317-24. Foil LD, Adams WV, McManus JM, Issel CJ. Bloodmeal residues on mouthparts of Tabanus fuscicostatus (Diptera: Tabanidae) and the potential for mechanical transmission of pathogens. J Med Entomol 1987; 24(6): 613-6. Hawkins JA, Adams WV, Jr., Wilson BH, Issel CJ, Roth EE. Transmission of equine infectious anemia virus by Tabanus fuscicostatus. J Am Vet Med Assoc 1976; 168(1): 63-4. Stewart ME, Desport M, Setiyaningsih S, Hartaningsih N, Wilcox GE. Analysis of Jembrana disease virus mRNA transcripts produced during acute infection demonstrates a complex transcription pattern. Virus Res 2008; 135(2): 336-9. Guo X, Hu J, Whitney JB, Russell RS, Liang C. Important role for the CA-NC spacer region in the assembly of bovine immunodeficiency virus Gag protein. J Virol 2004; 78(2): 551-60. Tobin GJ, Sowder RC 2nd , Fabris D, et al. Amino acid sequence analysis of the proteolytic cleavage products of the bovine immunodeficiency virus Gag precursor polypeptide. J Virol 1994; 68(11): 7620-7. Desport M, Stewart ME, Sheridan CA, et al. Recombinant Jembrana disease virus gag proteins identify several different antigenic domains but do not facilitate serological differentiation of JDV and nonpathogenic bovine lentiviruses. J Virol Methods 2005; 124(1-2): 135-42. Cheevers WP, Knowles DP, McGuire TC, Cunningham DR, Adams DS, Gorham JR. Chronic Disease in Goats Orally Infected with Two Isolates of the Caprine Arthritis-Encephalitis Lentivirus. Lab Invest 1988; 58(5): 510-7. Rosati S, Profiti M, Lorenzetti R, et al. Development of recombinant capsid antigen/transmembrane epitope fusion proteins for serological diagnosis of animal lentivirus infections. J Virol Methods 2004; 121(1): 73-8. Chamorro M, Parkin N, Varmus HE. An RNA pseudoknot and an optimal heptameric shift site are required for highly efficient ribosomal frameshifting on a retroviral messenger RNA. Proc Natl Acad Sci USA 1992; 89(2): 713-7. Chadwick BJ, Coelen RJ, Wilcox GE, Sammels LM, Kertayadnya G. Nucleotide sequence analysis of Jembrana disease virus: a bovine lentivirus associated with an acute disease syndrome. J Gen Virol 1995; 76(Pt 7): 1637-50. Setiyaningsih S, Desport M, Stewart ME, Hartaningsih N, Wilcox GE. Sequence analysis of mRNA transcripts encoding Jembrana disease virus Tat-1 in vivo. Virus Res 2008; 132(1-2): 220-5. Krummheuer J, Lenz C, Kammler S, Scheid A, Schaal H. Influence of the small leader exons 2 and 3 on human immunodeficiency virus type 1 gene expression. Virology 2001; 286(2): 276-89. Robert-Guroff M, Popovic M, Gartner S, Markham P, Gallo RC, Reitz MS. Structure and expression of tat-, rev-, and nef-specific transcripts of human immunodeficiency virus type 1 in infected lymphocytes and macrophages. J Virol 1990; 64(7): 3391-8. Oberste MS, Greenwood JD, Gonda MA. Analysis of the transcription pattern and mapping of the putative rev and env splice junctions of bovine immunodeficiency-like virus. J Virol 1991; 65(7): 3932-7. McGeoch DJ. Protein sequence comparisons show that the 'pseudoproteases' encoded by poxviruses and certain retroviruses belong to the deoxyuridine triphosphatase family. Nucleic Acids Res 1990; 18(14): 4105-10. Avidan O, Hizi A. Expression and characterization of the integrase of bovine immunodeficiency virus. Virology 2008; 371(2): 309-21. Chen R, Wang H, Mansky LM. Roles of uracil-DNA glycosylase and dUTPase in virus replication. J Gen Virol. 2002; 83(Pt 10): 2339-45. Whetstone CA, Suarez DL, Miller JM, Pesch BA, Harp JA. Bovine lentivirus induces early transient B-cell proliferation in experimentally inoculated cattle and appears to be pantropic. J Virol 1997; 71(1): 640-4.
Desport and Lewis [45]
[46]
[47] [48]
[49]
[50] [51] [52] [53]
[54]
[55]
[56] [57]
[58]
[59]
[60] [61]
[62]
[63] [64]
[65] [66]
[67]
Terai C, Carson DA. Pyrimidine nucleotide and nucleic acid synthesis in human monocytes and macrophages. Exp Cell Res 1991; 193(2): 375-81. Turelli P, Guiguen F, Mornex JF, Vigne R, Querat G. dUTPaseminus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions. J Virol 1997; 71(6): 4522-30. Foley B. An overview of the molecular phylogeny of lentiviruses.: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 2000. Chen H, Wilcox G, Kertayadnya G, Wood C. Characterization of the Jembrana disease virus tat gene and the cis- and transregulatory elements in its long terminal repeats. J Virol 1999; 73(1): 658-66. Liu ZQ, Sheridan D, Wood C. Identification and characterization of the bovine immunodeficiency-like virus tat gene. J Virol 1992; 66(8): 5137-40. Deng G, Qiao W, Su Y, Sha R, Geng Y, Chen Q. Internalization of Jembrana disease virus Tat: possible pathway and implication. Virus Res 2006; 121(2): 122-33. Teodoro JG, Branton PE. Regulation of apoptosis by viral gene products. J Virol 1997; 71(3): 1739-46. Chirmule N, Oyaizu N, Saxinger C, Pahwa S. Nef protein of HIV-1 has B-cell stimulatory activity. AIDS 1994; 8(6): 733-4. Chirmule N, Kalyanaraman VS, Saxinger C, Wong-Staal F, Ghrayeb J, Pahwa S. Localization of B-cell stimulatory activity of HIV-1 to the carboxyl terminus of gp41. AIDS Res Hum Retroviruses 1990; 6(3): 299-305. Garvey KJ, Oberste MS, Elser JE, Braun MJ, Gonda MA. Nucleotide sequence and genome organization of biologically active proviruses of the bovine immunodeficiency-like virus. Virology 1990; 175(2): 391-409. Huang L, Li CJ, Pardee AB. Human immunodeficiency virus type 1 TAT protein activates B lymphocytes. Biochem Biophys Res Commun 1997; 237(2): 461-4. Henderson AJ, Connor RI, Calame KL. C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. Immunity 1996; 5(1): 91-101. Henderson AJ, Calame KL. CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4(+) T cells. Proc Natl Acad Sci USA 1997; 94(16): 8714-9. Hines R, Sorensen BR, Shea MA, Maury W. PU.1 binding to ets motifs within the equine infectious anemia virus long terminal repeat (LTR) enhancer: regulation of LTR activity and virus replication in macrophages. J Virol 2004; 78(7): 3407-18. Desport M, Stewart ME, Mikosza AS, et al. Sequence analysis of Jembrana disease virus strains reveals a genetically stable lentivirus. Virus Res 2007; 126(1-2): 233-44. Biek R, Rodrigo AG, Holley D, et al. Epidemiology, genetic diversity, and evolution of endemic feline immunodeficiency virus in a population of wild cougars. J Virol 2003; 77(17): 9578-89. Zhang LQ, MacKenzie P, Cleland A, Holmes EC, Brown AJ, Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol 1993; 67(6): 3345-56. Mansky LM, Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995; 69(8): 5087-94. Madden CR, Shih DS. Analysis of the long terminal repeat from a cytopathic strain of equine infectious anemia virus. Virology 1996; 225(2): 395-9. Dharma DM, Budiantono A, Campbell RS, Ladds PW. Studies on experimental Jembrana disease in Bali cattle. III. Pathology. J Comp Pathol 1991; 105(4): 397-414. Desport M, Tenaya IWM, McLachlan A, et al. In vivo Infection of IgG Containing Cells by Jembrana Disease Virus during Acute Infection. Virology 2009; 393: 221-7. Bielefeldt-Ohmann H, Sabara M, Lawman MJ, Griebel P, Babiuk LA. A monoclonal antibody detects macrophage maturation antigen which appears independently of class II antigen expression. Reactivity of monoclonal EBM11 with bovine macrophages. J Immunol 1988; 140(7): 2201-9. Greywoode GI, McCarthy SP, McGee JO. Labelling of cells of the mononuclear phagocyte system in routinely processed archival
Jembrana Disease Virus
[68]
[69] [70]
[71]
[72]
[73] [74]
[75]
Current HIV Research, 2010, Vol. 8, No. 1
biopsy specimens with monoclonal antibody EBM/11. J Clin Pathol 1990; 43(12): 992-6. O'Neil SP, Mossman SP, Maul DH, Hoover EA. In vivo cell and tissue tropism of SIVsmmPBj14-bcl.3. AIDS Res Hum Retroviruses 1999; 15(2): 203-15. English RV, Johnson CM, Gebhard DH, Tompkins MB. In vivo lymphocyte tropism of feline immunodeficiency virus. J Virol 1993; 67(9): 5175-86. Jacobs RM, Smith HE, Whetstone CA, Suarez DL, Jefferson B, Valli VE. Haematological and lymphocyte subset analyses in sheep inoculated with bovine immunodeficiency-like virus. Vet Res Commun 1994; 18(6): 471-82. Morin T, Guiguen F, Bouzar BA, et al. Clearance of a productive lentivirus infection in calves experimentally inoculated with caprine arthritis-encephalitis virus. J Virol 2003; 77(11): 6430-7. Soeharsono S, Wilcox GE, Dharma DM, Hartaningsih N, Kertayadnya G, Budiantono A. Species differences in the reaction of cattle to Jembrana disease virus infection. J Comp Pathol 1995; 112(4): 391-402. Anderson JL, Tachedijian G. Post-entry Restrictions to Lentiviral Replication. In: Desport M, Ed. Lentiviruses and Macrophages: Molecular and Cellular Interactions. Horizon Press 2010. Si Z, Vandegraaff N, O'Huigin C, et al. Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection. Proc Natl Acad Sci USA 2006; 103(19): 7454-9. Ylinen LM, Keckesova Z, Webb BL, Gifford RJ, Smith TP, Towers GJ. Isolation of an active Lv1 gene from cattle indicates that tripartite motif protein-mediated innate immunity to retroviral infection is widespread among mammals. J Virol 2006; 80(15): 7332-8.
Received: August 12, 2009
[76]
[77]
[78] [79]
[80] [81]
[82] [83]
[84]
65
Hartaningsih N, Dharma DM, Soeharsono S, Wilcox GE. The induction of a protective immunity against Jembrana disease in cattle by vaccination with inactivated tissue-derived virus antigens. Vet Immunol Immunopathol 2001; 78(2): 163-76. Barboni P, Thompson I, Brownlie J, Hartaningsih N, Collins ME. Evidence for the presence of two bovine lentiviruses in the cattle population of Bali. Vet Microbiol 2001; 80(4): 313-27. Celer V, Jr, Celer V. Detection of antibodies to ovine lentivirus using recombinant capsid and transmembrane proteins. J Vet Med B Infect Dis Vet Public Health 2001; 48(2): 89-95. Burkala EJ, Ellis TM, Voigt V, Wilcox GE. Serological evidence of an Australian bovine lentivirus. Vet Microbiol 1999; 68(1-2): 171-7. Meas S, Ohashi K, Tum S, C, et al. Seroprevalence of bovine immunodeficiency virus and bovine leukemia virus in draught animals in Cambodia. J Vet Med Sci 2000; 62(7): 779-81. Saman E, Van Eynde G, Lujan L, et al. A new sensitive serological assay for detection of lentivirus infections in small ruminants. Clin Diagn Lab Immunol 1999; 6(5): 734-40. Baron T, Betemps D, Mallet F, Cheynet V, Levy D, Belli P. Detection of bovine immunodeficiency-like virus infection in experimentally infected calves. Arch Virol 1998; 143(1): 181-9. Metharom P, Takyar S, Xia HQ, Ellem KA, Wilcox GE, Wei MQ. Development of disabled, replication-defective gene transfer vectors from the Jembrana disease virus, a new infectious agent of cattle. Vet Microbiol 2001; 80(1): 9-22. Metharom P, Takyar S, Xia HH, et al. Novel bovine lentiviral vectors based on Jembrana disease virus. J Gene Med 2000; 2(3): 176-85.
Revised: August 12, 2009
Accepted: August 12, 2009
