Dietary supplementation of Ascophylum nodosum improved kidney function of mink challenged with Aleutian mink disease virus.

BACKGROUND: Feed additives which can ease the negative effects of infection by the Aleutian mink disease virus (AMDV) are of interest to mink farmers. The effects of kelp meal (Ascophylum nodosum) supplementation on immune response, virus replication and blood parameters of mink inoculated with AMDV were assessed. AMDV-free black mink (n = 75) were intranasally inoculated with a local strain of AMDV and fed a commercial pellet supplemented with kelp meal at the rates of 1.5% or 0.75% of the feed or were kept as controls (no kelp) for 451 days. Blood was collected on days 0 (pre-inoculation), 31, 56, 99, 155, 366 and 451 post-inoculation (dpi). RESULTS: No significant difference was observed among the treatments for the proportion of animals positive for antibodies against the virus measured by the counter-immunoelectrophoresis (CIEP), viremia measured by PCR, antibody titer measured by quantitative ELISA, total serum protein measured by a refractometer or elevated levels of gamma globulin measured by iodine agglutination test at the sampling occasions. At the termination of the experiment on 451 dpi, there were no differences among treatments for antibody titer measured by CIEP, total serum protein, albumin, globulins, albumin:globulin ratio, alkaline phosphatase, gamma-glutamyl transferase, and proportions of PCR positive spleen, lymph node or bone marrow samples, but blood urea nitrogen and creatine levels were significantly lower in the 1.5% kelp supplemented group than in the controls. CONCLUSION: Kelp supplementation improved kidney function of mink infected with AMDV with no effect on liver function, immune response to infection by AMDV or virus replication.

Impact of viral features, host jumps and phylogeography on the rapid evolution of Aleutian mink disease virus (AMDV).

Aleutian mink disease virus (AMDV) is one the most relevant pathogens of domestic mink, where it can cause significant economic losses, and wild species, which are considered a threat to mink farms. Despite their relevance, many aspects of the origin, evolution, and geographic and host spreading patterns of AMDV have never been investigated on a global scale using a comprehensive biostatistical approach. The present study, benefitting from a large dataset of sequences collected worldwide and several phylodynamic-based approaches, demonstrates the ancient origin of AMDV and its broad, unconstrained circulation from the initial intercontinental spread to the massive among-country circulation, especially within Europe, combined with local persistence and evolution. Clear expansion of the viral population size occurred over time until more effective control measures started to be applied. The role of frequent changes in epidemiological niches, including different hosts, in driving the high nucleotide and amino acid evolutionary rates was also explored by comparing the strengths of selective pressures acting on different populations. The obtained results suggest that the viral passage among locations and between wild and domesticated animals poses a double threat to farm profitability and animal welfare and health, which is particularly relevant for endangered species. Therefore, further efforts must be made to limit viral circulation and to refine our knowledge of factors enhancing AMDV spread, particularly at the wild-domestic interface.

Aptamer-targeting of Aleutian mink disease virus (AMDV) can be an effective strategy to inhibit virus replication.

Aleutian mink disease (AMD), which is caused by Aleutian mink disease virus (AMDV), is an important contagious disease for which no effective vaccine is yet available. AMD causes major economic losses for mink farmers globally and threatens some carnivores such as skunks, genets, foxes and raccoons. Aptamers have exciting potential for the diagnosis and/or treatment of infectious viral diseases, including AMD. Using a magnetic beads-based systemic evolution of ligands by exponential enrichment (SELEX) approach, we have developed aptamers with activity against AMDV after 10 rounds of selection. After incubation with the ADVa012 aptamer (4 µM) for 48 h, the concentration of AMDV in the supernatant of infected cells was 47% lower than in the supernatant of untreated cells, whereas a random library of aptamers has no effect. The half-life of ADVa012 was ~ 32 h, which is significantly longer than that of other aptamers. Sequences and three dimensions structural modeling of selected aptamers indicated that they fold into similar stem-loop structures, which may be a preferred structure for binding to the target protein. The ADVa012 aptamer was shown to have an effective and long-lasting inhibitory effect on viral production in vitro.

A comparison between intraperitoneal injection and intranasal and oral inoculation of mink with Aleutian mink disease virus.

Intranasal, with (INS) and without (IN) sedation, and oral inoculation were compared with intraperitoneal (IP) injection for establishing infection with a local isolate of Aleutian mink disease virus (AMDV) in 35 American mink. Blood samples were collected on 0, 21, 36 and 56 day post-inoculation (dpi). Antiviral-antibodies and viral DNA in plasma and tissues were measured by counter-immunoelectrophoresis (CIEP) and PCR, respectively. The presence of AMDV DNA was tested by PCR in saliva, rectal and fecal samples collected on 0, 6, 10, 15, 21, 28, 36 and 56 dpi. Animals were killed at 56 dpi, samples of six organs were tested for antibody and AMDV DNA, and samples of the lungs, liver, kidneys and heart were subjected to histology. Viral DNA was detected in the spleen, lungs and lymph nodes of all inoculated mink on 56 dpi, indicating that all inoculation routes caused infection in mink. Viral DNA and antibodies were detected in plasma of all IP and INS inoculated mink by 36 dpi, but some animals which were inoculated orally or via IN remained seronegative by 56 dpi. It was concluded that INS route was the most effective method for establishing infection in mink without breaking the integrity of the animals' anatomical barriers. Viremia was short-lived in some mink, whereas antibody production persisted in seroconverted animals during the duration of the experiment. Saliva, rectal and fecal samples did not accurately detect infection. Histologic lesions of AD were observed on the four organs of most mink.

Reduced severity of histopathological lesions in mink selected for tolerance to Aleutian mink disease virus infection.

The objective of this study was to measure the effect of selection for tolerance on the severity of the Aleutian disease (AD) lesions in mink. Sensitivity and specificity of antibody detection in the blood by counter-immunoelectrophoresis (CIEP) relative to the presence of Aleutian mink disease virus (AMDV) in the spleen by PCR in naturally infected farmed mink were also estimated. Carcasses of 680 sero-positive (CIEP-P) black mink from 28 farms in Nova Scotia, Canada, and from 132 sero-negative (CIEP-N) mink from 14 of these farms were collected at pelting time. A total of 116 of the CIEP-P mink were from three farms where animals have been selected for tolerating AD for almost 20years. The severity of the AD lesions was assessed by histopathological examination of kidneys, lungs, heart, brain and liver on a scale of 0 to 4. Sensitivity and specificity of CIEP relative to PCR were 0.97 and 0.85, respectively, and 16.5% of CIEP-N mink were PCR positive, which could be one of the reasons for the failure of virus eradication by CIEP in Canada. The CIEP-N and tolerant CIEP-P animals had 9.39 and 6.23 greater odds of showing lower lesion severity, respectively, than the CIEP-P animals (P<0.01). The CIEP-N mink had a slightly higher chance (P=0.07) of showing lower lesion severity (odds ratio 1.51) compared with tolerant CIEP-P mink. The results suggested that tolerant mink had significantly reduced severity of AD lesions despite having anti-viral antibodies and carrying the virus.

Generation of an infectious clone of AMDV and identification of capsid residues essential for infectivity in cell culture.

Pathogenic strains of Aleutian mink disease virus (AMDV) such as Utah-1 do not replicate in cell culture (e.g., Crandell Rees feline kidney cells) while the in vitro-adapted AMDV strain ADV-Gorham (ADV-G) is not pathogenic. Here, we constructed a full-length infectious clone (pADV-G). Alignment of the VP2 gene of ADV-G with that of other AMDV strains revealed many amino acid (a.a.) residues conserved among pathogenic isolates that differed in ADV-G. Four virulence-associated, conserved residues of pADV-G VP2 were studied by site-directed mutagenesis (H92A, Q94S, Y115F, and I116L). Mutation of residue 92 or 94 decreased viral-transcription and viral-infectivity levels, whereas mutation of residue 115 or 116 did not affect viral-infectivity in CRFK cells. These results indicated that VP2 residues 92 and 94, both located on the surface of the viral capsid, are critical for AMDV infectivity in vitro.

Progression of experimental chronic Aleutian mink disease virus infection.

BACKGROUND: Aleutian mink disease virus (AMDV) is found world-wide and has a major impact on mink health and welfare by decreasing reproduction and fur quality. In the majority of mink, the infection is subclinical and the diagnosis must be confirmed by serology or polymerase chain reaction (PCR). Increased knowledge based on a systematically description of clinical signs, pathology and histopathology might be a tool to reduce the risk of infection from subclinically infected mink to AMDV free herds. The aim of this study was to give a histopathological description of the progression of a chronic experimental infection with a currently circulating Danish strain of AMDV, Saeby/DEN/799.1/05. These results were compared with the pathogenesis of previously published AMDV stains. RESULTS: This experimental AMDV infection resulted in only decreased appetite and soft or discolored feces, primarily within the first 8 weeks after AMDV inoculation. Gross pathology revealed few and inconsistent findings mainly associated with the liver, spleen and kidneys. The majority of the AMDV inoculated wild type mink (n = 41) developed various histopathological changes consistent with AMDV infection in one or more organs: infiltrations of mononuclear cells in liver, kidney and brain, reduced density of lymphocytes and increased numbers of plasma cells in lymph nodes and spleen. Natural infection, as occurred in the sentinel sapphire mink (four of six mink), progressed similar to the experimentally inoculated mink. CONCLUSIONS: Experimental AMDV inoculation mainly resulted in subclinical infection with unspecific clinical signs and gross pathology, and more consistent histopathology appearing at any time after AMDV inoculation during the 24 weeks of observation. Thus, the observed histopathology substantiates AMDV infection and no correlation to time of inoculation was found. This confirms that diagnosing AMDV infection requires serology and/or PCR and the Saeby/DEN/799.1/05 AMDV strain results in histopathology consistent with other AMDV strains.

A comparison between permissive and restricted infections with Aleutian mink disease parvovirus (ADV): characterization of the viral protein composition at nuclear sites of virus replication.

We used three-color fluorescent labeling and confocal microscopy to compare the permissive and the antibody-mediated, restricted replication of Aleutian mink disease parvovirus (ADV). In both permissive (CRFK cells) and restricted (K562 cells) situations, both ADV non-structural proteins (NS1 and NS2) concentrated at focal sites in the nucleus, which also contained viral DNA. Bromodeoxyuridine labeling demonstrated that these sites also supported active ADV single-strand DNA synthesis, indicating that they were replication compartments. ADV capsid proteins were located in intranuclear shells surrounding the replication compartments. At later time points, NS2 was readily detected in the cytoplasm of permissively infected CRFK cells, whereas the cytoplasmic presence of NS2 was much less pronounced in the K562 cells. These results showed that both permissive and restricted ADV replication are associated with a tight nuclear subcompartmentalization of viral products. Furthermore, differences between the permissive and restricted virus-cell interactions were noted, suggesting that there may be a morphological basis for examining the outcome of ADV infection.

Use of biotechnical methods in veterinary medicine.

Biotechnological methods offer promising approaches for improved diagnostic and prophylactic purposes. The following biotechnological techniques are used in the Institute of Virology at the Hanover Veterinary School:--Production of monoclonal antibodies directed against viral and bacteria-specific antigens such as bovine virus diarrhoea virus, classical swine fever (hog cholera) virus, feline leukaemia virus, animal parvoviruses, Alphavirus, Brucella and Francisella--Establishment of improved and sensitive diagnostic enzyme immunoassays (ELISA) using monoclonal antibodies--Molecular cloning and sequencing of classical swine fever virus RNA and parvovirus DNA--Development of diagnostic hybridisation techniques (dot, slot, Southern and Northern blot, in situ, oligonucleotides)--Detection of viral genomes in tissues of infected animals--Development of synthetic oligopeptides as diagnostic antigens and as potential immunogens for vaccines. Currently available techniques used in basic research (e.g. pathogenesis studies) will be tested for their application in routine diagnosis of viral diseases, e.g. by molecular hybridisation. Some techniques need to be simplified (e.g. RNA extraction procedures) and, particularly, alternative labelling schedules must be developed (e.g. biotin or sulfone labelling instead of radionuclides).

Effect of a valine residue at codon 352 of the VP2 capsid protein on in vivo replication and pathogenesis of Aleutian disease parvovirus in mink.

OBJECTIVE: To determine whether a group of 3 genetic differences in the nonstructural protein (NS1) or 1 genetic difference in the structural protein (VP2) of Aleutian disease parvovirus (ADV) is responsible for an increase in the in vivo replication and pathogenicity of G/U-8, a chimera of ADV-G (nonpathogenic) and ADV-Utah (pathogenic), compared with G/U-10. ANIMALS: 32 eight-month-old female sapphire mink (Mustela vison). PROCEDURE: Chimeric viruses were constructed, propagated in vitro, and used to inoculate mink. Antiviral antibody responses, presence of serum viral nucleic acid, and serum gamma globulin concentrations were monitored for 120 days following inoculation. Histologic examination of the liver, kidneys, spleen, and mesenteric lymph nodes was performed after necropsy. RESULTS: A chimera containing only the 3 amino acid substitutions in NS1 did not elicit measurable responses indicative of replication or pathogenicity in inoculated mink. Serum antiviral antibody responses, frequency of detection of viral nucleic acid in serum, gamma globulin response, and histologic changes in mink inoculated with chimeras containing a valine residue at codon 352 (352V) of VP2 capsid were increased, compared with values from mink inoculated with chimeric viruses that did not contain 352V. CONCLUSIONS AND CLINICAL RELEVANCE: A valine residue at codon 352 in the VP2 capsid protein of ADV affects in vivo viral replication and pathogenicity. This amino acid may be part of an incompletely defined pathogenic determinant of ADV. Further characterization of the pathogenic determinant may allow future development of focused preventive and therapeutic interventions for Aleutian disease of mink.

Mechanisms contributing to the virus persistence in Aleutian disease.

In this review published results and further studies concerning the persistence of Aleutian disease virus (ADV) isolate SL3 are presented. By Southern blot and in situ hybridization with strand-specific RNA probes focal replication of ADV-DNA was demonstrated in spleen, mesenteric lymph nodes, sporadically in mononuclear cells of the peripheral blood and bone marrow cells. These findings further support the concept of the lymphotropism of ADV. All cell culture-adapted ADV strains appear to have a ts-defect. Our in vitro studies indicate that the ADV isolate G(orham) induced the synthesis of comparable amounts of viral replicative DNA and viral proteins VP1 and VP2 at the non-permissive temperature of 37 degrees C. However, the viral progeny DNA synthesis was about threefold less at 37 degrees C compared to the permissive temperature of 32 degrees C. These findings suggest that the reduced level of viral progeny DNA at 37 degrees C accounts for the reduced production of infectious ADV. Finally, we provided experimental evidence that the apparent lack of neutralizing antibodies in AD is due to the masking of critical viral epitopes by cellular phospholipids.

Inactivation of Aleutian mink disease virus through high temperature exposure in vitro and under field-based composting conditions.

Disposal of manure contaminated with Aleutian mink disease virus (AMDV) is a significant concern to the mink industry. Inactivation of AMDV under field conditions has received limited attention in the scientific literature. We evaluated the thermal inactivation of AMDV in vitro and during composting of mink manure. Spleen homogenate containing AMDV was heated under controlled conditions at 45°C, 55°C, and 65°C for 3 days. Results of the in vitro study identified complete absence of viral replication in mink at 65°C only. Next, manure-mixed AMDV packed in polyester pouches was inserted in different layers of three replicate mink manure compost piles. The virus was retrieved after the compost piles had undergone a heating period and subsequently returned to ambient temperatures. Temperature regimes in the compost piles were categorized as ≥65°C, ≥60-64°C, and ≥55-59°C. Initially, layer-wise composite virus samples were assayed for virus replication in mink. Twenty-one-day post-inoculation (p.i.) plasma tested for AMDV and antibodies indicated infection in 40%, 80%, and 100% of mink inoculated from samples originating from the top, center and bottom layers of the piles, respectively. Subsequently, the virus was extracted from individual pouches in compost layers achieving thermal activity ≥65°C and was tested in mink. No antibodies or virus was detected in plasma taken weekly up to day 21 p.i. PCR data of bone marrow and lymph nodes collected on day 21 p.i. also showed no AMDV. However, mink that received virus from positive control manure indicated infection in their plasma as early as 1 week p.i.

Molecular characterization of the small nonstructural proteins of parvovirus Aleutian mink disease virus (AMDV) during infection.

Aleutian mink disease virus (AMDV) is the only member in genus Amdovirus of the family Parvoviridae. During AMDV infection, six species of viral transcripts are generated from one precursor mRNA through alternative splicing and alternative polyadenylation. In addition to the large non-structural protein NS1, two small non-structural proteins, NS2 and NS3, are putatively encoded (Qiu J, et al., 2006. J. Virol. 80 654-662). However, these two proteins have not been experimentally demonstrated during virus infection, and nothing is known about their function. Here, we studied the nonstructural protein expression profile of AMDV, and for the first time, confirmed expression of NS2 and NS3 during infection, and identified their intracellular localization. More importantly, we provided evidence that both NS2 and NS3 are necessary for AMDV replication.

Internal polyadenylation of parvoviral precursor mRNA limits progeny virus production.

Aleutian Mink Disease Virus (AMDV) is the only virus in the genus Amdovirus of family Parvoviridae. In adult mink, AMDV causes a persistent infection associated with severe dysfunction of the immune system. Cleavage of AMDV capsid proteins has been previously shown to play a role in regulating progeny virus production (Fang Cheng et al., J. Virol. 84:2687-2696, 2010). The present study shows that AMDV has evolved a second strategy to limit expression of capsid proteins by preventing processing of the full-length capsid protein-encoding mRNA transcripts. Characterization of the cis-elements of the proximal polyadenylation site [(pA)p] in the infectious clone of AMDV revealed that polyadenylation at the (pA)p site is controlled by an upstream element (USE) of 200 nts in length, the AAUAAA signal, and a downstream element (DSE) of 40 nts. A decrease in polyadenylation at the (pA)p site, either by mutating the AAUAAA signal or the DSE, which does not affect the encoding of amino acids in the infectious clone, increased the expression of capsid protein VP1/VP2 and thereby increased progeny virus production approximately 2-3-fold. This increase was accompanied by enhanced replication of the AMDV genome. Thus, this study reveals correlations among internal polyadenylation, capsid production, viral DNA replication and progeny virus production of AMDV, indicating that internal polyadenylation is a limiting step for parvovirus replication and progeny virus production.

Pathogenesis of aleutian mink disease parvovirus and similarities to b19 infection.

Aleutian mink disease parvovirus (ADV) is an unusual member of the autonomous parvoviruses in both its replication and pathogenesis. Infection of newborn mink kits results in an acute disease typified by virus replication in type II pneumocytes in the lung. This replication is permissive and cytopathic, characterized by the production of high levels of viral replicative intermediates and infectious progeny. However, infection of adult Aleutian mink leads to a chronic form of the disease termed Aleutian disease (AD). In this case, virus replication occurs predominantly in lymph node macrophages and is restricted, with viral DNA replication, RNA transcription, protein expression and production of infectious progeny occurring at low levels. B19 is the only autonomous parvovirus known to infect humans. The primary site of virus replication in both children and adults is in erythrocyte precursors in the blood and bone marrow, although viral genomes have been detected in various other tissues. B19 infection often causes a self-limiting disease although persistent infection of B19 can occur in both immuno-compromised and -competent people. Perhaps the most striking similarity between infection with ADV or with B19 is the important role the humoral immune response to infection has in pathogenesis. It can be both protective and pathogenic. Due to of the central role of antibody in the disease caused by either virus, understanding the specific roles of antibody production in protection, antibody-mediated enhancement of infection, the establishment of persistent infection and immune-mediated pathology will provide insight into the pathogenesis of these infections. A second similarity between the two viruses is the ability to establish persistent infection. Persistence of ADV is associated with restricted replication. Although many cellular factors may contribute to restricted virus replication, the interactions between the major non-structural protein, NS1, and the cells are likely to be critical. Parallels exist between the expression and post-translational modification of ADV and B19 NS1 proteins that may contribute to restriction of virus replication. Thus, a study of the regulation of NS1 expression and its interactions with cell signalling pathways may lead to increased understanding of the restricted replication of these two viruses, and perhaps of persistent infection.

Two mink parvoviruses use different cellular receptors for entry into CRFK cells.

Mink enteritis virus (MEV) and Aleutian mink disease parvovirus (ADV) are two mink parvoviruses that replicate permissively in Crandell feline kidney (CRFK) cells. We have used this cell model to examine if these two mink parvoviruses use the same cellular receptor. Whereas the cellular receptor for MEV is expected to be the transferrin receptor (TfR), the cellular receptor for ADV has not been clearly identified. We used short hairpin RNAs (shRNAs) produced from plasmids to trigger RNA interference (RNAi), specifically and effectively reducing TfR expression in CRFK cells. TfR expression was reduced to levels undetectable by immunofluorescence in the majority of cells. In viral infection assays, we show that TfR expression was necessary for MEV infection but was not required for ADV infection. Thus, our results demonstrate that TfR is the cellular receptor for MEV, but not the cellular receptor for ADV. The use of two different receptors by MEV and ADV to infect the same cell line is yet another difference between these two parvoviruses that may contribute to their unique pathogenesis in mink.

The monomer covalently closed linear replicative form DNA of Aleutian disease parvovirus is infectious after transfection into permissive cells.

The recently described monomer covalently closed linear replicative form DNA (Mccl RF DNA) of Aleutian disease parvovirus (ADV) is an infectious intermediate of the viral DNA replication cycle. Transfection of highly purified Mccl RF DNA into susceptible feline kidney cells (CCC clone 81 cells) resulted in viral DNA replication, expression of viral proteins and synthesis of infectious progeny virus. Mccl RF DNAs generated under permissive (32 degrees C) or non-permissive (37 degrees C) conditions were shown to be biologically indistinguishable. The accumulation of the Mccl RF DNA form at the non-permissive temperature in vitro strongly resembles that in bone marrow cells of naturally infected mink and may reflect one mechanism contributing to virus persistence of ADV in vivo.

Violet mink develop an acute disease after experimental infection with Aleutian disease virus (ADV) isolate ADV SL3.

Six-Aleutian (aa)-genotype violet mink were infected intraperitoneally with the Aleutian Disease Virus (ADV) bone marrow derived isolate ADV SL3. All animals developed virus-specific antibodies and hypergammaglobulinaemia. Mortality during the fourteen week duration of the infection was 50%. The virus induced (histo)pathological lesions typical for Aleutian Disease. By immunohistochemical examination using a virus capsid-specific monoclonal antibody viral antigen was detected in lymph nodes, spleen, kidneys and once in hepatic Kupffer cells. By Southern blot and in situ hybridization studies with strand-specific RNA probes able to distinguish viral replicative forms from merely sequestered genomic DNA, ADV replication was detected in mesenteric lymph nodes and spleen. In one mink DNA replicative forms were also found in bone marrow cells or mononuclear cells of the peripheral blood, respectively. Only single-stranded viral DNA was detected in liver, kidney, gut and lung of infected animals. From Southern blot hybridization results a different, possibly organ-specific permissiveness of ADV in vivo is suggested.

S-phase-dependent cell cycle disturbances caused by Aleutian mink disease parvovirus.

We examined replication of the autonomous parvovirus Aleutian mink disease parvovirus (ADV) in relation to cell cycle progression of permissive Crandell feline kidney (CRFK) cells. Flow cytometric analysis showed that ADV caused a composite, binary pattern of cell cycle arrest. ADV-induced cell cycle arrest occurred exclusively in cells containing de novo-synthesized viral nonstructural (NS) proteins. Production of ADV NS proteins, indicative of ADV replication, was triggered during S-phase traverse. The NS+ cells that were generated during later parts of S phase did not undergo cytokinesis and formed a distinct population, termed population A. Formation of population A was not prevented by VM-26, indicating that these cells were arrested in late S or G2 phase. Cells in population A continued to support high-level ADV DNA replication and production of infectious virus after the normal S phase had ceased. A second, postmitotic, NS+ population (termed population B) arose in G0/G1, downstream of population A. Population B cells were unable to traverse S phase but did exhibit low-level DNA synthesis. Since the nature of this DNA synthesis was not examined, we cannot at present differentiate between G1 and early S arrest in population B. Cells that became NS+ during S phase entered population A, whereas population B cells apparently remained NS- during S phase and expressed high NS levels postmitosis in G0/G1. This suggested that population B resulted from leakage of cells with subthreshold levels of ADV products through the late S/G2 block and, consequently, that the binary pattern of ADV-induced cell cycle arrest may be governed merely by viral replication levels within a single S phase. Flow cytometric analysis of propidium iodide fluorescence and bromodeoxyuridine uptake showed that population A cells sustained significantly higher levels of DNA replication than population B cells during the ADV-induced cell cycle arrest. Therefore, the type of ADV-induced cell cycle arrest was not trivial and could have implications for subsequent viral replication in the target cell.

Aleutian mink disease: puzzles and paradigms.

Aleutian mink disease (AD) is a naturally occurring persistent virus infection of mink caused by the Aleutian mink disease parvovirus (ADV). The classical form of AD, which occurs in adult mink, is notable for high titers of antiviral antibodies, hypergammaglobulinemia, plasmacytosis, and immune complex disease. In addition, there is a progressive renal disease characterized by mesangial proliferative glomerulonephritis and severe interstitial nephritis. Development of AD depends on both host and viral factors, and mink of certain genotypes fail to develop progressive disease when inoculated with low-virulence strains of virus. In newborn mink kits, ADV causes a fatal, acute interstitial pneumonitis associated with permissive viral replication in alveolar type 2 cells, but treatment of newborn kits with anti-viral antibody aborts the acute disease and converts into one resembling the persistent infection observed in adults. In infected adult mink, ADV is sequestered as immune complexes in lymphoid organs, but actual viral replication is restricted at the level of the individual cell and can be detected in only a small population of macrophages and follicular dendritic cells. ADV infection of mink primary macrophages and the human macrophage cell line U937 is antibody dependent and leads to the production of the cytokine interleukin-6. Furthermore, levels of interleukin-6 are increased in lymph node culture supernatants from infected mink. Chronic production of interleukin-6 may promote development of the immune disorder characteristic of AD.