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Biomedical subjects

O Narayan

Publications and source records attributed to O Narayan.

At least 145 records · Page 8Linked to original sources
PubMed1989

Modulation of lentivirus replication by antibodies. Non-neutralizing antibodies to caprine arthritis-encephalitis virus enhance early stages of infection in macrophages, but do not cause increased production of virions.

Non-neutralizing antibodies to caprine arthritis-encephalitis virus (CAEV) enhance the early stages of the virus life cycle but do not potentiate enhanced production of virus particles by macrophages. In primary macrophages used for these studies, there was enhancement in binding, internalization and uncoating of virus pretreated with non-neutralizing sera in comparison to virus pretreated with a non-immune serum. However, this did not lead to enhanced production of virus particles. Failure of non-neutralizing sera to inactivate CAEV may be due in part to low avidity of the antibodies for the virus particles which contain sialic acids on their envelopes, because desialylation of the particles made them neutralizable. The non-neutralizing antibodies probably bound to most of the native virus particles which were then internalized via Fc receptor-mediated endocytosis and degraded. Sialylated particles that failed to bind antibodies probably caused the infection. Thus there was no true enhancement of infection. The previously reported increase in severity of lesions in animals immunized with inactivated CAEV particles prior to challenge with live virus suggested enhancement of infection but in the light of our finding this may have been caused by factors other than an increase in production in the number of infectious virus particles.

Animals↗
PubMed1989

Evidence for interference, coinfections, and intertypic virus enhancement of infection by ovine-caprine lentiviruses.

The ovine-caprine lentiviruses share nucleotide homology and serological properties in their gag-pol genes and gene products but constitute two distinct biological groups represented by ovine visna virus of Icelandic origin and by caprine arthritis-encephalitis and ovine progressive pneumonia viruses of U.S. origin. Two members of each group, visna 1514 and its antigenic variant LV1-1 in the first group and CAEV/CO and S93, a field isolate virus from a local arthritic sheep, in the second group, were examined in the present study in competitive-binding studies in fibroblast and macrophage cell cultures. The cultures were preinoculated with each of the four viruses and then reinoculated with either 1514 virus or CAEV/CO, labeled with [35S]methionine. Both 1514 and CAEV/CO caused homologous interference. LV1-1 and S93 viruses shared the interference patterns of 1514 and CAEV/CO, respectively. 1514 and LV1-1 did not interfere with binding of CAEV/CO. Similarly, CAEV/CO and S93 did not interfere with binding of 1514. Remarkably, certain combinations, such as S93 plus 1514, resulted in enhanced binding of the second virus. Other experiments showed that the enhancement in binding extended to enhancement in replication of the second virus. These latter data suggested that individual cells supported replication of both viruses. Further testing of this phenomenon showed that goats could be doubly infected with two noninterfering viruses, 1514 and CAEV/CO. The ability of noninterfering related lentiviruses to infect the same cell and also the same host animal may be important in the natural history of these viruses in providing ideal conditions for the development of new recombinant viruses.

Animals↗
PubMed1989

Modulation of lentivirus replication by antibodies: Fc portion of immunoglobulin molecule is essential for enhancement of binding, internalization, and neutralization of visna virus in macrophages.

Antibodies to visna virus neutralized the virus in fibroblasts and macrophages but specifically enhanced the binding, penetration, and uncoating of the virus in the latter cells. F(ab')2 fragments of the immune antibody neutralized the virus in fibroblasts but did not enhance the early stages of the virus life cycle in macrophages. Furthermore, these fragments did not neutralize infectivity in macrophages but delayed the appearance of infectious virus in cells after the inoculation of preincubated virus-F(ab')2 complexes.

Animals↗
PubMed1989

Lentivirus-induced interferon inhibits maturation and proliferation of monocytes and restricts the replication of caprine arthritis-encephalitis virus.

In this study, we investigated the effect of a lentivirus-induced interferon (LV-IFN) on the interaction of caprine arthritis-encephalitis virus and its host cell, the monocyte-macrophage. LV-IFN was produced in culture supernatant 48 h after adding fresh goat lymphocytes to caprine arthritis-encephalitis virus-infected goat macrophages. The culture supernatant contained IFN activity at a titer of 1:360 as assayed by inhibition of vesicular stomatitis virus-induced lysis of fibroblasts. LV-IFN inhibited in vitro monocyte proliferation and maturation of monocytes to macrophages. Nevertheless, treated monocytes produced prostaglandin E2, a cytokine generally produced by activated macrophages. By inhibiting the maturation of monocytes to the more permissive macrophage, LV-IFN indirectly downregulated virus replication. The cytokine also had a direct inhibitory effect on virus gene expression in already mature macrophages. In these cells, LV-IFN blocked the viral life cycle at the level of transcription. Finally, LV-IFN blocked fusion between infected macrophages and highly permissive goat synovial membrane cells. By restricting macrophage maturation, viral replication, and cell fusion, LV-IFN may downregulate the net rate of virus replication in vivo. These functions may contribute to the persistence of the virus in the host by reducing the expression of the viral genome.

Animals↗
PubMed1988

Neurotransmitter abnormalities in Borna disease.

Borna disease (BD) agent is an infectious pathogen that causes progressive central nervous system (CNS) dysfunction in a wide range of vertebrate hosts. The course of BD in adult rats is biphasic. The acute phase is characterized by aggressive behavior and inflammatory cell infiltrates in brain. With chronic infection animals become listless and inflammation resolves. BD antigens are similarly distributed in neurons in hippocampus, neocortex, cerebellum and brainstem in acutely and chronically infected animals. We have recently examined brain levels of neuronal transcripts in rats with acute and chronic BD. Levels for 3 of these mRNAs, cholecystokinin, glutamic acid decarboxylase and somatostatin, were decreased in acutely infected rats and increased toward control values in chronically infected rats. A fourth transcript, MuBr8, correlated in distribution with BD antigen, was persistently decreased throughout the course of infection. These data may have implications for understanding the pathogenesis of neurologic disturbances in BD and other inflammatory CNS diseases.

Actins↗
PubMed1988

Lentivirus-host interactions: lessons from visna and caprine arthritis-encephalitis viruses.

The biological properties of the ruminant animal lentiviruses, visna and caprine arthritis-encephalitis viruses, closely resemble those of their human counterparts, the human immunodeficiency viruses (HIV). All of these viruses are morphologically identical and are disseminated from host to host in nature during exchange of body fluids. Artificial conditions that favor excess exchange of such fluids precipitate epidemics by these viruses. The strategy of replication of the animal viruses in tissue culture and in vivo are very similar to that of the human virus. Virus replication is highly productive in tissue culture and leads to cytopathic effects characterized by fusion. In vivo, the rate of virus replication is restricted and lesions, suggestive of an immunopathological origin, develop after prolonged periods of subclinical infection. Similar to the animal viruses, the human viruses have a tropism for macrophages in vivo, and this leads somehow to a loss of T helper lymphocytes and proliferation of cytotoxic lymphocytes. In addition, the viruses are highly neurotropic and this results in acute fulminating disease in neonatal hosts and chronic encephalopathy in adults. Both animal and human viruses cause persistent infections and have similar strategies for eluding host immune responses. These include sequestration of neutralizing epitopes, induction of low titers of neutralizing antibodies, and antigenic drift during persistent infection. Despite close homology between genetic sequences of HIV-I and -II, these two viruses seem to have as much biological disparity from each other as does visna virus from caprine arthritis-encephalitis virus. The latter two viruses induce neutralizing antibodies that are highly strain specific and show no cross protection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Diseases↗
PubMed1988

Hyaluronidase enhances cell fusion and synthesis of viral DNA during infection with caprine arthritis encephalitis virus.

Caprine arthritis encephalitis virus (CAEV) is a lentivirus which infects goats and causes chronic progressive arthritis after a prolonged incubation period. CAEV replicates productively in cultures of goat synovial membrane cells and causes cytopathic effects characterized by multinucleated giant cell formation. The enzyme hyaluronidase was found to accelerate this virus induced fusion of GSM cells. Hyaluronidase treatment also resulted in synthesis of increased levels of unintegrated viral DNA early after infection. However, there was no significant increase in viral RNA in the infected cells or in the amount of virus produced. These studies suggest that hyaluronidase facilitates the interaction of CAEV with the target cells. Further it suggests that only a few copies of viral DNA are required to achieve maximal levels of virus replication. Additional copies of viral DNA appear to be redundant not contributing to viral specific transcription or increased production of virus.

Animal Diseases↗
PubMed1988

The neurobiology of human immunodeficiency virus infections.

A variety of diseases of the central and peripheral nervous systems evolves during the course of human immunodeficiency virus (HIV) infections. Most are not related to documented opportunistic infections and may be the direct result of HIV infections, as large proportions of healthy and ill HIV-infected persons show evidence of nervous system infection. These diseases occur at different times during the infection and have diverse inflammatory, demyelinating, or degenerative pathological features that suggest different pathogenetic mechanisms. The route and determinants of HIV invasion of the nervous system are unknown. Within the brain, viral antigen and RNA are found predominantly in macrophages, but the reason why profound dementia and cortical atrophy result from this infection remains a mystery. By analogy to other lentivirus infections, particularly visna virus in sheep, neuropathological changes may be mediated by cytokines. Other possible pathogenetic mechanisms include toxicity of viral polypeptides, transactivation of viral or cellular genes, autoimmunity, or other opportunistic infections. Clarification of the pathogenesis of HIV-related diseases is critical to the design of rational therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Sialic acids on the surface of caprine arthritis-encephalitis virus define the biological properties of the virus.

The lentivirus caprine arthritis-encephalitis virus (CAEV) is a pathogen of goats. It is transmitted in milk and causes a persistent infection in goats, which often fail to produce neutralizing antibodies to the virus. Native CAEV particles are remarkably resistant to digestion with proteinase K and are neutralized extremely slowly by immune sera. Our studies showed that the virus particles are heavily sialylated. Studies with highly specific sialyltransferase enzymes identified penultimate carbohydrate linkages typical of O- and N-linked oligosaccharides on the virus and suggested that the virus may be more heavily sialylated on O-linked than on N-linked oligosaccharides. Removal of sialic acids from the virus by neuraminidase treatment did not reduce infectivity of the particles. However, desialylation rendered the virus more susceptible to proteolysis by proteinase K. Desialylation also enhanced the kinetics of neutralization of the virus by goat antibodies. These results suggest that the carbohydrates on the viral surface are important both in protecting viral proteins from digestion by proteases and in protecting the virus from rapid neutralization by antibodies.

Endopeptidase K↗
PubMed1988

Separate epitopes in the envelope of visna virus are responsible for fusion and neutralization: biological implications for anti-fusion antibodies in limiting virus replication.

Visna virus is a lentivirus which causes fusion of infected cells in vitro. Two types of fusion occur. Fusion from without requires no viral replication and a relatively high multiplicity of infection; fusion from within results from the replication of virus in cells. By using fusion from without as an assay, the mechanism of fusion by visna virus was investigated. Immune sera which contained both anti-fusion and neutralizing antibodies interacted with the virus with rapid kinetics in blocking fusion but relatively slow kinetics in the virus neutralization assay. By using visna virus and an antigenic variant, the epitopes responsible for fusion and virus neutralization were shown to be different. Antigenic variation of visna virus resulted in alteration of the neutralization epitope and conservation of the fusion epitope. This suggested that there were two populations of antibodies and that the viral epitopes for fusion and neutralization were separate. These data suggest that visna virus is capable of infecting cells via two pathways: one via the fusion site and the other via the viral epitope which mediates neutralization.

Antigens, Viral↗
PubMed1987

Pathogenesis of visna/maedi and caprine arthritis-encephalitis: new leads on the mechanism of restricted virus replication and persistent inflammation.

Lentiviruses are unique retroviruses which cause diseases with long incubation periods and prolonged clinical courses. The prototype lentiviruses, visna/maedi of sheep and arthritis-encephalitis virus of goats (CAEV), infect cells of the monocyte-macrophage system and replicate at a restricted level in these cells. The virus life cycle is closely associated with maturational factors in the cells; monocytes support the early stages of the replication cycle which goes to completion only when the cells mature to macrophages. Virus replication in the monocyte-macrophage results in lesions characterized by mononuclear cell infiltration of the central nervous system (CNS), lungs, synovium and mammary gland and their draining lymph nodes. Co-cultivation of sheep or goat lymphocytes with macrophages infected with visna or CAE viruses results in production of a unique interferon (LV-IFN). LV-IFN is a non-glycosylated protein of 54,000 to 64,000 daltons and has biological properties which have several implications for pathogenesis. Firstly, it retards the rate of maturation of monocytes and thus indirectly slows the rate of virus replication. Second, it restricts the rate of virus replication in mature macrophages by preventing virus maturation. Third, it induces expression of class II (Ia) antigens of the major histocompatibility complex on cells of macrophage lineage. Thus, by curtailing virus replication and enhancing expression of MHC class II antigens, LV-IFN may contribute to the induction and augmentation of the host's lymphoproliferative response to the virus.

Animals↗
PubMed1987

Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation.

Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.

Animals↗
PubMed1987

Topographical rearrangements of visna virus envelope glycoprotein during antigenic drift.

Visna virus undergoes antigenic drift during persistent infection in sheep and thus eludes neutralizing antibodies directed against its major envelope glycoprotein, gp135. Antigenic variants contain point mutations in the 3' end of the genome, presumably within the envelope glycoprotein gene. To localize the changes in the viral proteins of antigenic mutants, we isolated 35 monoclonal antibodies (MAbs) against the envelope glycoprotein gp135 or the major core protein p27 of visna virus. The MAbs defined five partially overlapping epitopes on gp135. We used the MAbs and polyclonal immune sera directed against visna virus, gp135, or p27 in enzyme-linked immunosorbent assays to compare visna virus (strain 1514) with antigenic mutants (LV1-1 to LV1-6) previously isolated from a single sheep persistently infected with plaque-purified strain 1514. Polyclonal immune sera and anti-core p27 MAbs failed to distinguish antigenic differences among the viruses. By contrast, the anti-gp135 MAbs detected changes in all five epitopes of the envelope glycoprotein. Three gp135 epitopes, prominently exposed on strain 1514, were lost or obscured on the mutants; two covert gp135 epitopes, poorly exposed on strain 1514, were reciprocally revealed on the mutants. Even virus LV1-2, which is indistinguishable from parental strain 1514 by serum neutralization tests and which differs from it by only two unique oligonucleotides on RNase-T1 fingerprinting, displayed global changes in gp135. Our data suggest that visna virus variants may emerge more frequently during persistent infection than can be detected by serological tests involving the use of polyclonal immune sera, and the extent of phenotypic changes in their envelope glycoproteins may be greater than predicted by the small number of genetic changes previously observed. We suggest that topographical rearrangements in the three-dimensional structure of gp135 may magnify the primary amino acid sequence changes caused by point mutations in the env gene. This may complicate strategies to construct lentiviral vaccines by using the envelope glycoprotein.

Animals↗