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PubMed1996

Molecular biology and pathogenesis of animal lentivirus infections.

Lentiviruses are a subfamily of retroviruses that are characterized by long incubation periods between infection of the host and the manifestation of clinical disease. Human immunodeficiency virus type 1, the causative agent of AIDS, is the most widely studied lentivirus. However, the lentiviruses that infect sheep, goats, and horses were identified and studied prior to the emergence of human immunodeficiency virus type 1. These and other animal lentiviruses provide important systems in which to investigate the molecular pathogenesis of this family of viruses. This review will focus on two animal lentivirus models: the ovine lentivirus visna virus; and the simian lentivirus, simian immunodeficiency virus. These animal lentiviruses have been used to examine, in particular, the pathogenesis of lentivirus-induced central nervous system disease as models for humans with AIDS as well as other chronic diseases.

Animals↗
PubMed2004

Development of recombinant capsid antigen/transmembrane epitope fusion proteins for serological diagnosis of animal lentivirus infections.

Among animal lentiviruses, Feline immunodeficiency virus (FIV), Equine infectious anaemia virus (EIAV) and Small ruminant lentiviruses (SRLV) are important pathogens associated with a variety of clinical pictures including immunodeficiency, anaemia, arthritis, pneumonia. The detection of viral antibody response represents a practical diagnostic approach in all lentivirus infections since they remain detectable long life. Capsid antigen (CA) is the major viral core protein and specific antibodies against this antigen are usually first recognised in infected sheep, goat and horse, remaining detectable for long period. Transmembrane (TM) domain of envelope glycoprotein contains a well conserved motif known to form an immunodominant epitope in several lentiviruses. In this study a simple strategy was developed to express the entire CA and the TM epitope in a single fusion protein from equine, feline and small ruminant lentiviruses in prokaryotic system and evaluated the diagnostic utility of a purified preparation in an indirect ELISA for each of the three infections. Results demonstrate that, for FIV and SRLV infections, the combination of CA and TM fractions increases the sensitivity of diagnostic tests based only on CA. The corresponding CA/TM antigen from EIAV showed excellent agreement with Coggins test.

Amino Acid Motifs↗
PubMed2006

Neurologic disease in captive lions (Panthera leo) with low-titer lion lentivirus infection.

Lion lentivirus (LLV; also known as feline immunodeficiency virus of lion, Panthera leo [FIVPle]) is present in free-ranging and captive lion populations at a seroprevalence of up to 100%; however, clinical signs are rarely reported. LLV displays up to 25% interclade sequence diversity, suggesting that it has been in the lion population for some time and may be significantly host adapted. Three captive lions diagnosed with LLV infection displayed lymphocyte subset alterations and progressive behavioral, locomotor, and neuroanatomic abnormalities. No evidence of infection with other potential neuropathogens was found. Antemortem electrodiagnostics and radiologic imaging indicated a diagnosis consistent with lentiviral neuropathy. PCR was used to determine a partial lentiviral genomic sequence and to quantify the proviral burden in eight postmortem tissue specimens. Phylogenetic analysis demonstrated that the virus was consistent with the LLV detected in other captive and free-ranging lions. Despite progressive neurologic signs, the proviral load in tissues, including several regions of the brain, was low; furthermore, gross and histopathologic changes in the brain were minimal. These findings suggest that the symptoms in these animals resulted from nonspecific encephalopathy, similar to human immunodeficiency virus, FIV, and simian immunodeficiency virus (SIV) neuropathies, rather than a direct effect of active viral replication. The association of neuropathy and lymphocyte subset alterations with chronic LLV infection suggests that long-term LLV infection can have detrimental effects for the host, including death. This is similar to reports of aged sootey mangabeys dying from diseases typically associated with end-stage SIV infection and indicates areas for further research of lentiviral infections of seemingly adapted natural hosts, including mechanisms of host control and viral adaptation.

Animals↗
PubMed1999

A new sensitive serological assay for detection of lentivirus infections in small ruminants.

Lentivirus infections in small ruminants represent an economic problem affecting several European countries with important sheep-breeding industries. Programs for control and eradication of these infections are being initiated and require reliable screening assays. This communication describes the construction and evaluation of a new serological screening enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to maedi-visna virus (MVV) in sheep and to caprine arthritis encephalitis virus (CAEV) in goats. The solid phase is sensitized with a combination of the major core protein p25 of MVV produced in Escherichia coli and a peptide derived from the immunodominant region of the viral transmembrane protein gp46. The peptide carries an N-terminal biotin residue and is complexed with streptavidin prior to being coated. The new assay was evaluated with 2,336 sheep serum samples from different European countries with large differences in the levels of prevalence of MVV infections, and the results have been compared to those of the standard agar gel immunodiffusion test. Discrepant samples were analyzed by Western blotting with viral lysate, and most sera could be classified unambiguously. The estimated overall sensitivity of the new ELISA was 99.4% (95% confidence interval [CI], 98.4 to 99. 8%) and the specificity was 99.3% (95% CI, 98.7 to 99.6%). A limited set of goat sera (n = 212) was also analyzed, with similar results. These data indicate that the new assay is a reliable tool that can be used in control and eradication programs for small ruminant lentivirus infections.

Amino Acid Sequence↗
PubMed1993

Pathogenesis of lymphoid interstitial pneumonia in natural and experimental ovine lentivirus infection.

Ovine lentivirus (OvLV), as a member of the lentivirinae subfamily of Retroviridae, shares morphological, genomic, and cytopathic features with human immunodeficiency virus (HIV). Although OvLV infection does not induce profound immune deficiency in sheep, it has many similarities with HIV infection, such as the capacity to infect macrophages, undergo antigenic variation in vivo, and induce slow progressive diseases involving the pulmonary, lymphoid, and central nervous systems. Studies of the pathogenesis of disease in sheep naturally or experimentally infected by OvLV are providing clues to the pathogenesis of HIV infection, including the significance of viral load, the emergence of cytopathic variants, the mechanisms and significance of viral antigenic variation, and viral neutralization, and mechanisms of lymphoproliferation and tissue destruction induced by the virus. Preliminary evidence suggests that infection by other microbial agents, including Mycoplasma species, may play a cofactor role in the pathogenesis of lentivirus-associated lymphoid interstitial pneumonia in sheep, but further studies are required to address this issue.

Animals↗
PubMed1997

Serologic reactivity using conserved envelope epitopes in feline lentivirus-infected felids.

An enzyme-linked immunosorbent assay (ELISA) based on synthetic peptides identical to lentivirus envelope protein amino acid sequences was used to study serologic reactivity of lentivirus-infected domestic cats and nondomestic felids. One feline immunodeficiency virus (FIV) peptide, P237, was consistently recognized by antibodies from FIV-infected cats, but 2 other FIV peptide antigens were not. The molecular basis for this serologic reactivity was examined. Lentivirus-infected nondomestic Felis species reacted intensely with a puma lentivirus (PLV) peptide corresponding to the conserved FIV peptide. However, lentivirus-infected Panthera species, from which a different lentivirus has been isolated, did not react with the PLV. FIV-infected domestic felids also did not have significant reactivity with the PLV peptide. The peptide ELISA is comparable in sensitivity and specificity to western blot analysis and a commercial enzyme immunoassay. Unlike the other assays, however, the peptide ELISA is inexpensive, requires a small amount of serum, enables the study of specific isotype reactivity, and discriminates between antibodies to FIV and those to PLV. Antibody tests based upon the FIV and the PLV peptides should be useful for detecting the possible introduction of FIV into exotic felids or of lentiviruses from nondomestic felids into the domestic cat population.

Amino Acid Sequence↗
PubMed2003

In vivo impairment of neutrophil recruitment during lentivirus infection.

Evidence indicates that the lentivirus, HIV, infection affects neutrophil response to bacteria and bacterial products in vitro. We used a novel model of rapid onset immunosuppression following infection with a similar lentivirus, feline immunodeficiency virus (FIV), in cats to examine neutrophil function within the microvasculature in vivo and to determine the steps that are impaired in the neutrophil recruitment cascade. In uninfected cats and cats infected neonatally with FIV, the mesentery was exteriorized, but remained autoperfused during intravital microscopy for 4 h. When the tissue was superfused with 10 micro g/ml of LPS for 4 h, intravital microscopy displayed a profound increase in neutrophil rolling at both 8 and 12 wk of age in uninfected cats. At 12 wk of age, FIV-infected animals showed a profound decrease in the number of rolling neutrophils. In vitro studies revealed that neutrophils from infected and uninfected animals rolled equally well on surrogate selectin substrata. In addition, in vivo neutrophil adhesion and emigration out of the vasculature were severely reduced, and in vitro neutrophil chemotaxis from FIV-infected animals was significantly impaired in response to fMLP or IL-8. However, FIV infection of neutrophils could not be detected. In summary, in vivo lentivirus infection with immunosuppression leads to a severe impairment in neutrophil rolling, adhesion, and emigration in response to bacterial stimulants potentially involving both endothelial and neutrophil dysfunction. These in vivo studies also indicate that neutrophil dysfunction should be taken into account when treating infections and tissue injury.

Aging↗
PubMed1994

Lentivirus infection of macrophages.

The ovine and caprine lentiviruses infect monocytes, and the viral DNA is integrated into the cellular DNA. The provirus remains silent until the monocyte matures into a macrophage. Intrinsic to this maturation is the induction of a class of immediate early genes in the monocyte that includes the transcription factors JUN and FOS. These transcription factors are thought to couple short-term signals in the cell to long-term cellular differentiation by regulation of specific cellular genes. Thus, JUN and FOS bind to the AP-1 site in the promoters of cellular genes and activate their transcription, resulting in maturation of the monocyte into a macrophage. In addition, these cellular factors activate the same AP-1 sequence in the visna virus LTR, leading to transcriptional activation, full viral gene expression, and production of progeny virus. The expression of viral antigens in the context of MHC class II on the macrophage leads to the production of cytokines and a lymphoproliferative response that causes the lesions in specific target organs in an infected animal. We still understand only the framework of these events. The specific mechanisms by which viral genes alter macrophage gene expression and the molecular basis of different viral tropism for specific tissue macrophages, i.e. microglia, remain to be determined.

Animals↗
PubMedDate not supplied

Increased expression of tissue factor mRNA and procoagulant activity in ovine lentivirus-infected alveolar macrophages.

To link ovine lentivirus infection to lung tissue damage, we studied the procoagulant response in alveolar macrophages from experimentally infected lambs and in in vitro infected alveolar macrophages. We cloned ovine tissue factor cDNA and analysed its in vitro expression by Northern blotting. Visna-maedi virus induced tissue factor mRNA. In order to correlate this mRNA induction with its cellular function, we analysed macrophage procoagulant activity after in vitro and in vivo infection. The procoagulant activity was increased by interaction with the virus in both cases. Thus, visna-maedi virus-induced expression of tissue factor mRNA was associated with enhanced macrophage procoagulant activity. These findings indicate an active role of alveolar macrophages in the pathogenesis of these inflammatory lung lesions.

Animals↗
PubMed1995

Virologic and serologic characteristics of a natural chimpanzee lentivirus infection.

This study set out to characterize the unique features of natural lentivirus infection in chimpanzees over time. The virologic and serologic characteristics of this infection were followed longitudinally in a naturally infected chimpanzee together with a small cohort of experimentally HIV-1-infected chimpanzees. The subsequent isolates from the naturally infected chimpanzee were all non-syncytium forming (NSI) versus syncytium forming in the experimentally infected animals. In contrast to HIV-1-infected chimpanzees virus load was higher and plasma viremia occurred but in a cyclic pattern. Serologic follow-up suggested the development of neutralizing antibodies with subsequent escape of new isolates. Interestingly, the sequence of the principal neutralizing (V3 loop) domain (of HIV-1) remained constant over time. Antibodies to peptides from the V3 loop were type specific. The occurrence of persistent, fluctuating plasma viremia and NSI-type virus variants of this natural lentivirus infection are unique characteristics not previously reported in experimentally infected chimpanzees.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Characteristics of ovine and caprine lentivirus infections.

A majority of ovine lentivirus (OvLv) infections seen on farms develop after long incubation and a slow progression of disease to death but in nature they may also have short latency and cause acute leukoencephalitis and/or acute arthritis and pneumonia in young kids or lambs with exceptionally high mortality. Histopathologically, OvLv diseases may be characterized by lymphoid infiltration, lymphoid hyperplasia with germinal centers and plasmocytosis in the lungs and/or in the CNS, joints and udder. Lymphoid hyperplasia in lymph nodes and spleen, as well as lymphoid infiltration in the kidneys, are almost always seen in advanced cases. In some cases, it shows similarities to lymphoproliferative diseases that are considered malignant. Alveolar epithelial hyperplasia in the lungs is generally also seen, especially in older goats with caprine arthritis encephalitis virus (CAEV), and proliferation of these epithelial cells may form acine and papillary structures and in some cases are histopathologically indistinguishable from tumor nodules seen in sheep pulmonary adenomatosis. Because of complexities in the host-lentovirus interaction, cell-associated transmission and extensive antigenic and genomic variation among infecting isolates, control of infection or prevention of spread are problematic by traditional methods and exploration of alternative control strategies employing selection and expansion of animals genetically resistant to OvLv or transgenic for certain viral genes, merits consideration. Interestingly, the pure Awassi sheep breed are susceptible to infection but do not develop the disease, as do European breeds or cross-breeds in Israel, ie they are infected but not diseased. It seems that the local Bedouin black goat breed is resistant to infection of CAEV under natural conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Peripheral neuropathy in lentivirus infection: evidence of inflammation and axonal injury.

OBJECTIVE: As distal sensory polyneuropathy (DSP) is a major neurological complication of HIV-1 infection, we investigated the extent of peripheral nervous system disease in animals infected with the lentivirus, feline immunodeficiency virus (FIV), because it causes neurological disease and immunosuppression in cats similar to HIV-1 in humans. METHODS: After infection with a neurovirulent FIV molecular clone, neurobehavioral testing, nerve morphology, viral detection and load measurements were performed. RESULTS: Neurobehavioral studies showed delayed withdrawal in response to a noxious stimulus among FIV-infected animals compared with sham-infected controls (P < 0.05). Dorsal root ganglia and sciatic nerves from FIV-infected ammals showed activated macrophages that were increased in number and size compared with controls. In addition, TNF-alpha messenger RNA was detectable in most nerves and spinal cords from the FIV-infected group, but was infrequently detected in controls. Viral RNA copy numbers in plasma and sciatic nerves were detectable in all FIV-infected animals at high levels. Studies of sural nerves identified myelinated fiber atrophy in 12-week FIV-infected animals compared with age-matched control animals, which was accompanied by reduced myelin sheath thickness (P < 0.05). The footpads of FIV-infected animals displayed reduced intraepidermal fiber density compared with control animals (P < 0.01). CONCLUSION: FIV infection results in the rapid onset of peripheral neuropathy, defined by axonal injury and macrophage activation, together with abundant virus within the nerve, indicating that it may serve as a model of HIV-related DSP.

Animals↗
PubMed1998

Structural responses of pulmonary intravascular macrophages in lentivirus-infected and/or recombinant ovine interferon-tau-treated lambs.

Ovine lentivirus (OvLV), a retrovirus, infects and disseminates to various tissue organs via monocytes. The differentiation of infected monocytes into macrophages is a prerequisite for viral replication, and the presence of infected macrophages in tissue organs induces chronic immunopathology such as lymphoid interstitial pneumonia. The pulmonary intravascular macrophage (PIM) is a recently identified mononuclear phagocyte in domestic animal species, including sheep. Recombinant ovine interferon-tau (roIFN-tau), a type I IFN originally named as the ovine trophoblast protein, has potent antiviral activity against OvLV and human immunodeficiency virus and prevents the development of OvLV-associated lung pathology. We investigated and compared the structural features of PIMs in OvLV-infected and/or roIFN-tau-treated 1-month-old lambs using transmission electron microscopy. The PIMs' numerical counts were performed in toluidine blue-stained sections of Epoxy-embedded lung tissues. A reduction in the number of PIMs was observed with OvLV infection and/or roIFN-tau treatment of lambs as compared to the control group (P < or = 0.05). The majority of the PIMs in OvLV-infected and/or roIFN-tau-treated groups were devoid of their surface coat. The PIMs of OvLV-infected lambs exhibited signs of biosynthetic activation such as expanded rough endoplasmic reticulum, prominent Golgi complexes, and accumulation of secretory vesicles. A few PIMs contained OvLV-like structures. In roIFN-tau-treated OvLV-infected lambs, the lymphocytes had ruffled plasma membranes and were in intimate contact with the PIMs, as is observed during cytotoxic cell-mediated killing of target cells. Most of the PIMs in roIFN-tau-treated OvLV-infected lambs appeared smaller in size. Ovine lentivirus and roIFN-tau, individually or in combination, alter the integrity of the surface coat of PIMs and cause their disappearance from the lungs. Ovine lentivirus infection induces morphological changes that correlate with cytotoxic cell behavior between lymphocytes and PIMs in roIFN-tau-treated or placebo-treated lambs. The loss of PIMs, probably infected with OvLV, either through direct killing by roIFN-tau or indirectly by roIFN-tau-activated cytotoxic T lymphocytes may represent different aspects of therapeutic actions of this cytokine.

Animals↗
PubMed1999

The effects of ovine lentivirus infection on some productive aspects in a Sardinian sheep flock from Italy.

The effects of ovine lentivirus infection on the fat, protein and lactose concentrations on the somatic cell counts in ewes' milk, on milk production and on the birth weight and growth of lambs were studied in a flock of Sardinian sheep from central Italy. Data on 61 lactations of ewes positive to both the agargel immunodiffusion test and an enzyme-linked immunosorbent assay were compared with those on 46 lactations of seronegative ewes. Confounders such as parity, age, lactation length, litter size, and the sex of the lambs were considered. None of these traits seemed to be negatively influenced by the infection.

Animals↗
PubMed1997

Type 1 and type 2 cytokine gene expression by viral gp135 surface protein-activated T lymphocytes in caprine arthritis-encephalitis lentivirus infection.

Peripheral blood mononuclear cells (PBMC) from Saanen goats experimentally infected with the lentivirus caprine arthritis-encephalitis virus (CAEV) were evaluated by semiquantitative reverse transcriptase PCR for gamma interferon (IFN-gamma), interleukin-4 (IL-4), and IL-2 gene expression following in vitro stimulation with purified CAEV gp135 surface protein (SU). Studies examined three goats with chronic arthritis and four clinically asymptomatic goats at 5 years postinfection. SU-responsive IFN-gamma mRNA-positive cells and IL-4 mRNA-positive cells in PBMC from infected goats reflected differences in lymphokine balance associated with disease status. IFN-gamma mRNA-positive cells were dominant in PBMC from asymptomatic goats, whereas SU-responsive IL-4 mRNA-positive cells were dominant in PBMC from goats with arthritis. IL-2 gene expression was not responsive to SU stimulation of PBMC from either asymptomatic or arthritic goats. Lymphokine mRNA profiles in SU-stimulated PBMC were dependent on the presence of CD4+ T lymphocytes. The results indicate that asymptomatic goats have a dominant population of CAEV SU-reactive T-helper 1 (Th1)-like lymphocytes in PBMC whereas goats with clinical arthritis have a dominant population of SU-reactive Th2-like lymphocytes.

Animals↗
PubMed1998

Dynamics of cell-associated viremia and antibody response during the early phase of lentivirus infection in sheep.

OBJECTIVE: To determine patterns of cell-associated viremia and antibody responses during the early phase of ovine lentivirus (OvLV) infection in sheep. ANIMALS: 18 neonatal lambs. PROCEDURES: 12 lambs were inoculated intratracheally with OvLV within 24 hours after birth; 6 lambs were inoculated with noninfected cell culture supernatant. Degree of cell-associated viremia was measured every other week for 16 weeks by use of a limited dilution assay. Antibody responses to OvLV transmembrane (TM) and p25 proteins were determined weekly by use of recombinant ELISA. Neutralizing antibody responses were measured before and 8 and 16 weeks after inoculation. RESULTS: Degree of cell-associated viremia peaked between 2 and 6 weeks after inoculation and then decreased. For inoculated lambs, mean anti-p25 titer peaked 5 weeks after inoculation then slowly declined, whereas mean anti-TM and neutralizing antibody titers increased steadily. Over time, mean degree of cell-associated viremia was negatively correlated with mean anti-TM titer. Maximum individual degree of cell-associated viremia was positively correlated with maximum individual anti-TM titer. CONCLUSIONS: Results suggest that after experimental inoculation, OvLV replicates actively for several weeks and that an increase in anti-TM titer coincides with a decrease in degree of cell-associated viremia. Although the role antibodies play in protecting against lentivirus infection remains uncertain, understanding the dynamics of the antibody response may have important implications for diagnosis of OvLV infection, and antibodies may prove to be valuable markers for prediction of infection and disease.

Animals↗
PubMed1995

Feline lentivirus infection in nondomestic felids.

Human immunodeficiency virus and feline immunodeficiency virus are both lentiviruses that cause immunosuppressive disease. Similarities between these diseases have promoted the study of feline immunodeficiency virus as a model for human immunodeficiency virus. Not only have lentiviruses been found in domestic cats but they have been found in nondomestic felids as well. Florida panthers, African lions, and other nondomestic felids have been found to have antibodies directed against lentiviruses and each nondomestic cat has antibodies to a virus that is specific for that species. The phylogenetic relationships of these lentiviruses have been studied and mapped using nucleic acid sequencing technology. Phylogenetic mapping has been an important step for future development of vaccines and antiviral therapy.

Animals↗