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PubMed1985

Restricted replication of lentiviruses. Visna viruses induce a unique interferon during interaction between lymphocytes and infected macrophages.

Lentivirus infections are characterized by a persistent, restricted type of virus replication in tissues. Using sheep and goat lentiviruses, whose target cells in vivo are macrophages, we explored virus-host cell interactions to determine whether an interferon (IFN) is produced during virus replication in vivo which causes restricted replication. We show that the lentiviruses were incapable of inducing IFN directly in any infected cell, including macrophages and lymphocytes. However, after infection with these viruses, sheep and goat macrophages acquired a factor that triggered IFN production by T lymphocytes. Only sheep/goat lentiviruses were capable of inducing the factor and, although these viruses replicated productively in various cell cultures of the natural host animal, only infected macrophages developed the IFN-inducing factor. The factor was produced continuously and was strictly cell associated, requiring direct contact with lymphocytes. The lymphocytes responded with a single, sudden release of IFN beginning 7 h after cocultivation and reaching peak values at 48 h, after which they ceased production and became refractory. IFN production was not immunologically specific and did not require histocompatibility between donors of the two cell types. The IFN is a nonglycosylated protein of molecular weight 54,000-64,000, and is stable to heat and acid treatments. These findings identify a unique IFN and a new method for virus induction of IFN. The novel two-stage process of induction provides a mechanism for local amplification and continuity of production of IFN in vivo. This is compatible with infection in the animal whose lentivirus-induced pathologic lesions consist of accumulations of lymphocytes and infected macrophages in target tissues.

Animals↗
PubMed2025

Defective but tumorigenic: the evolutionary and functional roles of mutated oncoviruses.

Human oncogenic viruses contribute significantly to the global health burden and include seven types: Epstein-Barr virus, hepatitis B virus, human T-cell leukemia virus type 1, human papillomavirus, hepatitis C virus, Kaposi's sarcoma-associated herpesvirus, and Merkel cell polyomavirus. While the roles of latent or integrated viral genomes in cancer have been documented, emerging evidence highlights the contribution of defective viruses-those carrying intragenic deletions or loss-of-function mutations-in promoting viral oncogenesis. These altered genomes often lack genes essential for lytic replication or immune recognition, which enhances their persistence and immune evasion. In virus-associated diseases, specific patterns of gene retention and deletion suggest that host-driven selective pressures drive the emergence of these altered genomes. This review examines the generation, prevalence, and functional impact of these viruses, reframing them as active participants in disease development and progression. Recognizing their role offers new insights into viral tumor evolution and creates opportunities for applications in viral diagnostics and targeted intervention strategies.

Humans↗
PubMed1992

The different interactions of a gIII mutant of pseudorabies virus with several different cell types.

Glycoprotein gIII of pseudorabies virus (PrV) is multifunctional. It plays a role in the stable adsorption of the virus to its host cells by interacting with a cellular heparin-like substance. It also affects both release of mature virus from infected cell types and virulence. Thus, although non-essential for growth in vitro, gIII plays a central role in the biology of the virus. The primary attachment of a mutant, PrV2, which has an in-frame internal deletion and expresses a shortened version of gIII, and of wild-type (wt) virus, to MDBK cells has been shown to occur similarly. To ascertain whether different domains of gIII control the expression of the different biological functions of the gIII protein, we have compared several aspects of virus-host cell interactions of PrV2, of a gIII-null virus, and of wt virus. Our results showed that the deletion of the internal segment of the gIII glycoprotein affects adsorption and virus release differently, i.e. that these two functions of gIII appear to be independent of each other. Furthermore, we observed that although the primary adsorption of PrV2 and wt virus to MDBK cells is similar, PrV2 behaved like a gIII-null mutant with respect to virulence. The apparent contradiction between these two findings was resolved when it was found that although PrV2 binds as well as does wt to some cell types, it binds poorly to other cell types. The functional importance of different domains of gIII in virus adsorption thus differs, depending on the cell type with which the virus interacts.

Animals↗
PubMed1975

Temperature-sensitive host range mutants of herpes simplex virus type 2.

Herpesviruses are capable of several types of infection of a host cell. To investigate the early events which ultimately determine the nature of the virus-host cell interaction, a system was established utilizing temperature-sensitive mutants of herpes simplex virus type 2. Four mutants have been isolated which fail to induce cytopathic effects and do not replicate at 39 C in hamster embryo fibroblast cells. At least one mutant is virus DNA negative. Since intracellular complementation is detectable between pairs of mutants, a virus function is known to be temperature sensitive. However, all four mutants induce cytopathic effects and replicate to parental virus levels in rabbit kidney cells at 39 C. This suggests that a host cell function, lacking or nonfunctional in HEF cells but present in rabbit kidney cells at 39 C, is required for the replication of these mutants in hamster embryo fibroblasts cells at 39 C. Therefore, we conclude that these mutants are both temperature sensitive and exhibit host range properties.

Animals↗
PubMed1990

The adenovirus EII early promoter has multiple EIA-sensitive elements, two of which function cooperatively in basal and virus-induced transcription.

The mechanism by which the adenovirus-encoded nuclear oncogene EIA activates transcription of several viral and host promoters is an important issue in the regulation of eucaryotic gene expression and virus-host cell interactions. Identification of cis-acting elements of the promoters and the cognate host transcription factors that are targets for EIA action is crucial for our understanding of the EIA-mediated control of coordinately regulated genes. The adenovirus EII early promoter has a complex architecture and contains two overlapping promoters with start sites at +1 (major promoter) and -26 (minor promoter). The major promoter responds strongly to virus-encoded trans activators EIA and EIV and contains four elements: a TAGA motif analogous to the TATA box, two EIIF sites present in an inverted orientation, and an ATF/CREB site. To determine precisely the roles played by these cis-acting elements in both basal and virus-induced transcription when the promoter is situated in its natural context, we investigated the phenotype of a series of linker scan promoter substitution mutants inserted into the viral chromosome. Promoter constructs harboring linker scan mutations in each element were rebuilt into a novel EIA- adenovirus vector, and transcriptional activity was monitored in virus-infected cells. In the absence of virus-encoded trans activators, basal activity in vivo was dependent on all four cis-acting elements. Surprisingly, a promoter mutant with only one of the two EIIF sites intact could not promote transcription in vivo, suggesting that the two EIIF sites function cooperatively even in basal transcription. Promoters harboring mutations in either of these two EIIF sites also failed to bind to an infection-specific form of EIIF in gel shift assays and competed only very weakly for EIIF binding with the wild-type promoter fragment. The dramatic cooperativity shown by the two inverted EIIF sites of the EII promoter both in vivo and in vitro could reflect simultaneous contact of both sites by the transcription factor EIIF. Furthermore, promoter mutants with mutations in the TAGA motif, the two EIIF sites, and the single ATF site all failed to respond to virus-encoded trans activators. Whereas recent results demonstrate that EIIF activity can be modulated independently by EIV, leading to transactivation of this promoter, our results and those published previously strongly indicate that the three different transcription factors that bind to TAGA, EIIF, and ATF motifs of the EII early promoter are all targets for EIA regulation in vivo. Thus, strong transactivation of the EII early promoter through these multiple EIA-sensitive elements and independently by the recently discovered EIV pathway suggests that the EII early promoter is stringently regulated in virus-infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenovirus Early Proteins↗
PubMed1990

Infection of the human monocytic cell line Mono Mac6 with human immunodeficiency virus types 1 and 2 results in long-term production of virus variants with increased cytopathogenicity for CD4+ T cells.

The recently established human monocytic cell line Mono Mac6 expressing distinct characteristics of mature monocytes/macrophages was tested for its susceptibility to infection with human immunodeficiency virus. Inoculation of the cells with the T-cell-tropic human immunodeficiency virus strains human T-lymphotropic virus type IIIB and lymphadenopathy-associated virus type 2 led to a noncytopathic productive infection becoming apparent only after a latency period of up to 56 days. The infectibility of the Mono Mac6 cells was dependent on low levels of CD4 expression, as demonstrated by blocking experiments with various CD4-specific antibodies. Increasing with time after infection (greater than 200 days), the cultured Mono Mac6 cells released virus variants which showed shortened latency periods when passaged onto uninfected Mono Mac6 cells. Also, cytopathogenicity for several CD4+ T cells of the Mono Mac6-derived virus was drastically increased; thus, the infection of the H9 cell line with low doses of virus (less than 0.1 50% tissue culture infective dose per cell) led to giant syncytium formation within 1 day and subsequent death of all fused cells. We propose Mono Mac6 cells as a new model for the study of human immunodeficiency virus infecting the monocyte/macrophage lineage, particularly with regard to virus-host cell interaction and the influence of cell differentiation and activation on latency and development of virulence. The human immunodeficiency virus-infected Mono Mac6 cell may also serve as a valuable tool for in vitro testing of antiviral therapies.

CD4 Antigens↗
PubMed1991

Replication of an acutely lethal simian immunodeficiency virus activates and induces proliferation of lymphocytes.

A variant of simian immunodeficiency virus from sooty mangabey monkeys (SIVsmm), termed SIVsmmPBj14, was previously identified and shown to induce acute disease and death within 1 to 2 weeks of inoculation of pig-tailed macaques and mangabey monkeys (P. N. Fultz, H. M. McClure, D. C. Anderson, and W. M. Switzer, AIDS Res. Hum. Retroviruses 5:397-409, 1989). SIVsmmPBj14 differed from its parent virus, SIVsmm9, not only in pathogenicity but also in multiple in vitro properties. As a first approach to understanding the biological and molecular mechanisms responsible for the acute disease and death induced by this variant, virus-host cell interactions of SIVsmmPBj14 and SIVsmm9 were studied. Initial rates of replication of the two viruses were identical in primary peripheral blood mononuclear cells (PBMC) from normal pig-tailed macaques and mangabey monkeys, but SIVsmmPBj14 infection always resulted in higher yields of virus than did SIVsmm9 infection, as assessed by levels of reverse transcriptase activity in culture supernatants. Surprisingly, despite its cytopathicity for macaque and mangabey CD4+ cells, replication of SIVsmmPBj14 was accompanied by up to 10-fold increases in number of viable cells compared with cell numbers in uninfected or SIVsmm9-infected cultures. Furthermore, SIVsmmPBj14 was shown to infect and replicate in resting PBMC just as efficiently as in mitogen-stimulated PBMC, irrespective of whether exogenous interleukin-2 (IL-2) or antibodies that neutralized IL-2 were added to culture media. Accumulation of virus in culture supernatants of resting PBMC preceded by several days the appearance of activated cells which expressed the IL-2 receptor alpha subunit (CD25), suggesting that activation of cells was not essential for replication. The ability to activate and to induce simian PBMC to proliferate appeared specific for the acutely lethal variant because incorporation of [3H]thymidine by PBMC from naive animals was observed only upon incubation with concentrated, heat-inactivated SIVsmmPBj14 and not with other viruses. Both CD4(+)- and CD8(+)-enriched cell populations proliferated in response to SIVsmmPBj14. These results are consistent with in vivo observations and suggest that the abilities both to replicate in resting cells and to induce lymphocytes to proliferate may contribute to the extreme virulence of SIVsmmPBj14.

Animals↗
PubMed1992

Non-isotopic in situ hybridisation and immunophenotyping of infected cells in the investigation of human fetal parvovirus infection.

AIMS: To compare the use of biotinylated and digoxigenin labelled probes for diagnosis of human fetal parvovirus B19 infection in formalin fixed, paraffin wax embedded tissues; and to assess the cellular distribution of the virus in positive cases. METHODS: Sections of lung tissue from 23 cases of anatomically normal non-immune fetal hydrops presenting between 1984 and 1989, and from 13 control cases of hydrops due to chromosomal abnormality were probed for B19 DNA by in situ hybridisation using both biotinylated and digoxigenin labelled probes. The distribution of the virus was then investigated in all cases of fetal B19 infection confirmed in this laboratory to date (n = 11) by combining in situ hybridisation for viral DNA (using the digoxigenin system) with immunohistological labelling for a range of cellular antigens. RESULTS: Five unequivocal cases of B19 infection were identified among the 23 fetuses with unexplained hydrops using both probe labels. When combined with data from previous studies of the period 1974-1983, the results indicate that B19 infection was responsible for 27% of cases of anatomically normal non-immune hydrops and 8% of all cases, of non-immune hydrops presenting to this hospital over 15 years. False positive signal was seen in an additional three cases, using biotinylated probes. Digoxigenin labelled probes gave greater specificity and permitted detailed investigation of tissues high in endogenous biotin. Though most cells containing B19 DNA colabelled as erythroid precursors, viral DNA was frequently detected within mononuclear-phagocytic cells. In three cases viral signal was also found within occasional myocardial cells labelled by antibody to desmin. CONCLUSIONS: A relatively high proportion of cases of anatomically normal, non-immune hydrops are caused by B19 infection. Digoxigenin is a more reliable probe label than biotin for in situ hybridisation in archival fetal tissues. Double labelling for cellular antigens and viral nucleic acid is a powerful technique for investigating virus-host cell interactions, and provides evidence that cell types other than those of erythroid lineage may have a role in human fetal parvovirus infection.

DNA Probes↗
PubMed1989

Ultrastructural localization of herpes simplex virus RNA by in situ hybridization.

We studied the subcellular localization of virally encoded RNA by pre-embedding in situ hybridization, using colloidal gold as an electron-dense marker. Fibroblasts infected with Herpes simplex virus (HSV) were fixed, permeabilized, then hybridized with a biotinylated HSV DNA probe under conditions favoring DNA-RNA hybrid formation. HSV probe was localized with 5-nm streptavidin-gold conjugates. Transmission electron microscopy revealed 5-nm gold in clusters and singlets within HSV-infected cells. Formalin-fixed cells contained a mean of 4.6 clusters per cytoplasmic profile and 13.2 clusters per nuclear profile. Combined formalin-glutaraldehyde fixation increased the mean number of clusters per cytoplasmic and nuclear profile to 7.2 (57% increase) and 17.5 (33% increase), respectively. Gold clusters were frequently located in regions adjacent to the nuclear envelope but were not bound to viral nucleocapsids or endoplasmic reticulum. Labeling was unaffected by pre-hybridization DNAse treatment of cells. RNAse eliminated 87% of cytoplasmic and 97% of nuclear clusters. These findings indicate that clustered gold particles labeled viral RNA, with probable binding of multiple DNA probe molecules and/or gold particles to RNA strands. This novel pre-embedding technique may be a useful tool for ultrastructural evaluation of virus-host cell interactions.

Cell Nucleus↗
PubMed2026

The role of Epstein-Barr virus in NK/T cell lymphoproliferative disorders: molecular mechanisms and potential therapeutic strategies.

Epstein-Barr virus (EBV) is a widely prevalent lymphotropic γ-herpesvirus, with approximately 95% of the population showing evidence of infection at some point during their lifetime. While most infections are asymptomatic or follow a self-limiting clinical course, in certain populations, EBV can lead to a range of lymphoproliferative disorders (LPDs), particularly subtypes originating from T cells and natural killer (NK) cells, which are often characterized by highly aggressive disease progression. This review aims to systematically discuss the molecular basis of EBV infection, covering its viral biological properties, regulation of the latent and lytic cycles, key viral protein functions (e.g., LMP1, LMP2A, EBNA1), miRNA regulatory mechanisms, and the activation of various host signaling pathways (such as NF-κB, PI3K-AKT, JAK-STAT) that contribute to the maintenance of latent infection, cell transformation, and immune evasion. Additionally, the review focuses on the pathogenic contributions of these mechanisms in EBV-related T/NK cell lymphoproliferative diseases. Research highlights include the in-depth analysis of virus-host genome interaction mechanisms, the identification of novel molecular biomarkers, and the development of targeted therapeutic strategies (e.g., PD-1/PD-L1 immune checkpoint inhibitors, EBV-specific T cell therapy). Through this comprehensive review, it is hoped that personalized medicine and artificial intelligence-assisted multimodal decision-making will be applied to the precise prevention and treatment of EBV-related diseases.

Humans↗
PubMed2022

Flavivirus-Host Interaction Landscape Visualized through Genome-Wide CRISPR Screens.

Flaviviruses comprise several important human pathogens which cause significant morbidity and mortality worldwide. Like any other virus, they are obligate intracellular parasites. Therefore, studying the host cellular factors that promote or restrict their replication and pathogenesis becomes vital. Since inhibiting the host dependency factors or activating the host restriction factors can suppress the viral replication and propagation in the cell, identifying them reveals potential targets for antiviral therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has provided an effective means of producing customizable genetic modifications and performing forward genetic screens in a broad spectrum of cell types and organisms. The ease, rapidity, and high reproducibility of CRISPR technology have made it an excellent tool for carrying out genome-wide screens to identify and characterize viral host dependency factors systematically. Here, we review the insights from various Genome-wide CRISPR screens that have advanced our understanding of Flavivirus-Host interactions.

Humans↗
PubMed1991

HIV-1 propagates in human neuroblastoma cells.

A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directly infects cells of the central nervous system (CNS). The propagation of HIV was attempted in six cell lines: three related and three unrelated to the nervous system. HIV was able to propagate in two human neuroblastoma cell lines and a lymphocytic cell line control but did not result in infections of African green monkey kidney cells, human cervix carcinoma cells, and one human brain astrocytoma cell line. Neuroblastoma cell lines infected with HIV showed peaks of reverse transcriptase activity at 10-14 days postinfection. After prolonged growth in cell cultures, one of the neuroblastoma cell lines showed multiphasic virus production, additional high peaks of reverse transcriptase activity, 20-fold greater than the first, lasting from 36 to 74 days and 110 to 140 days postinfection. The presence of HIV was confirmed by p24 antigen capture. The neuroblastoma cell lines had weak but detectable levels of CD4 immunoreactivity by immunoperoxidase and flow immunocytometric analysis. Although no T4-specific RNA sequences were detected by hybridization of Northern blots of total and poly A-selected RNA extracted from the two neuroblastoma cell lines by using a T4 specific complimentary DNA probe, monoclonal antibodies to the CD4 receptor blocked HIV infection in both neuroblastoma cell lines. Thus, the infection of neuroblastoma cells by HIV occurs in part by a CD4-dependent mechanism. Passaging the neuroblastoma cell lines weekly and bimonthly resulted in similar cell cycle-DNA content patterns for the more permissive cell line and with significant numbers of cells in the S phase. HIV-infected neuroblastoma cell lines provide an in vitro model for the evaluation of virus-host cell interactions and may be useful in addressing the issue of the persistence of HIV in the human CNS.

Animals↗
PubMed1976

Herpesvirus type 2-related antigens and their relevance to humoral and cell-mediated immunity in patients with cervical cancer.

The central theme of this communication is the interaction of herpes simplex virus type 2 with its host. In addition to the productive infection, we are confronted by latency and, as suggested by recent studies, by cancer. The possible mechanisms of latency and the role it may play as a precursor of carcinogenesis are discussed. If virus is to coexist with its host, a defined level of molecular interaction between host and viral gene products must exist. The association of AG-4 with active tumor growth and its identification as a minor virion protein, also exposed on the surface of the infected cell, open new vistas in the understanding of the role virus-host cell interactions may play in tumor growth. The modulation of the host immune response by the results of this interaction may play a significant role in cancer control. In these terms, the observation that antibody to AG-4 is a macroglobulin and that, therefore, immunity to AG-4 may be T-cell independent, should be given further consideration.

Antibody Formation↗
PubMed1976

Diseases associated with herpesviruses.

Human herpesviruses have been associated with numerous diseases throughout history (Table 3), but their ability to induce latent and recurrent infections, alongwith their oncogenic capabilities, is only beginning to be understood. Accordingly, our ability to deal with the diseases induced by herpesviruses is severely limited by our lack of information concerning the basic processes of virus-host cell interactions and systemic host factors; especially immune factors that are involved in the disease process.

Antiviral Agents↗
PubMedDate not supplied

Microfluorometric quantitation of size, deoxyribonucleic acid and viral antigenic determinants in cells productively infected with HSV-2.

The interaction of herpes simplex virus type 2 (HSV-2) with the eukaryotic human cell line (HEp-2) was investigated by flow microfluorometric analysis. The three parameters that were quantitated include cell size, deoxyribonucleic acid content and the expression of virus-specific antigens. Productively infected cells are always smaller than uninfected ones, and they resolve into two populations with respect to viral antigenic content. Consistent with viral replication, one of these two populations, displaying a higher viral antigenic content, shows morphologic features characteristic of cell degeneration. On the other hand, the second population, with a relatively lower content of viral antigens, displays morphologic features consistent with increased cell growth. Indeed, microfluorometric measurements of the HSV-2-infected cells with respect to DNA content and expression of viral antigenic determinants resolves four cell populations. Of them, one displays the lowest level of viral antigens with the highest (equivalent to 8N) DNA content, features consistent with transformation. The results demonstrate the great potential of this technique for the detection, separation and quantitation of statistically significant cell populations not otherwise identified and for the analysis of virus-host cell interactions resulting in different pathologic outcomes.

Antigens, Viral↗
PubMed1975

Electron-microscopic study of a Mycoplasmatales virus, strain MV-Lg-pS2-L 172.

Morphology and adsorption of a globular virus, lysing Acholeplasma laidlawii were studied in ultrathin sections of plaques in a lawn of the host strain. The virus was globular, about 50 to 90 nm in diameter, with a clearly defined membrane, 6.5 to 8 nm thick. A protuberance about 25 to 35 nm long and 12 to 20 nm thick was observed on numerous virus particles. The evenly granulated, electron-optically dense content of the cells became clearer in cells affected by the viruses. Fibrillar structures of different thickness and small dense areas appeared in cells assumed to be in the preliminary stages of lysis. The interactions in the virus-host system and possible development stages of the virsu are discussed.

Acholeplasma laidlawii↗
PubMed1988

Transformation of C127 mouse fibroblasts by human papillomavirus 16.

We have compared the ability of cloned DNAs of HPV16, a human papillomavirus associated with cervical carcinoma, and BPV1, a papillomavirus inducing skin lesions in cattle, to transform murine C127 cells. Unlike BPV1, HPV16 DNA failed to induce foci when C127 cells were transfected and maintained as monolayers; HPV16-transformed C127 cells could only be detected after cotransfection with HPV16 and pSV2neo DNA, selection for resistance to G418, and assay of pooled selectants for colony growth in agar. HPV16 and BPV1 C127 cells differed in terms of the size and morphology of their colonies in agar, but not in their colony-forming efficiencies. In addition, the tumors they induced in nude mice were clearly histologically distinct, with the HPV16 C127 tumors considerably more anaplastic. The HPV16 C127 cells contained viral DNA at high copy numbers integrated at random sites in the C127 genome, while the BPV1 C127, as expected, contained episomal BPV1 DNA molecules. The high complexity of the integrated HPV16 DNA was maintained in the pooled cells grown through extended passage in vitro, in clonal lines derived from single agar colonies, in nude mouse tumors induced by the cells, and in a nude mouse tumor-derived cell line, indicating the stability of the HPV16 sequences in the cells. HPV16 transcripts in the transformed C127 cells were present in three size classes (1.5, 2, and 4 kilobases) on Northern blots. The different transformed phenotypes in the same cell line induced by two structurally similar, yet distinct viruses imply differences in the underlying transforming mechanisms and possible different virus-host cell molecular interactions.

Animals↗
PubMed1975

Defense mechanisms against bovine herpesvirus: relationship of virus-host cell events to susceptibility to antibody-complement cell lysis.

The interaction of infectious bovine rhinotracheitis virus and susceptible host cells was examined to determine whether an infected cell could be destroyed by humoral immune mechanisms before or after the transmission of virus to susceptible adjacent cells. Viral antigens were detectable on cell membranes at 6 h postinfection, but cells were not susceptible to antibody-complement lysis until 10 h postinfection. Intracellular infectious virus was also detectable at 10 h postinfection, and transmission to adjacent cells by the intracellular route began at this time. Extracellular virus was not detectable until 12 to 13 h postinfection. By the continual addition of antibody and complement, virus dissemination could be reduced more than 50-fold. These results support the hypothesis that the humoral immune mechanism may be involved in the recovery from herpesvirus infections.

Animals↗