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Biomedical subjects

F J Ferdinand

Publications and source records attributed to F J Ferdinand.

At least 19 recordsLinked to original sources
PubMed1990

Strategies in therapy and immunoprophylaxis of human immunodeficiency virus infection.

In designing antiviral drugs and therapeutic schemes some basic considerations should be taken into account: 1. RNA viruses and especially HIV (Human Immunodeficiency Virus) respond to environmental changes with evading mutations, hence, the high degree of variability of these viruses. All drugs interfering with viral functions will presumably give rise to resistant variants. 2. Approaches using cytotoxic peptides may induce adverse immune responses. Vaccines may elicit neutralizing antibodies, cellular cytotoxic responses, or both. The limitations of subunit vaccines or oligopeptides in eliciting cell mediated cytotoxicity in all vaccinees are outlined. Recent developments and the suitability of the SIV mac/rhesus monkey model are reviewed. The importance of adjuvants is indicated.

Adjuvants, Immunologic↗
PubMed1989

Inhibition of SV40 DNA replication by Rous sarcoma virus LTR enhancer.

Simian virus 40 (SV40) late region recombinant constructs containing the Rous sarcoma virus (RSV) src gene along with RSV enhancer stimulated expression but completely abolished SV40 DNA replication. Constructs, in which the heterologous enhancer sequences were omitted, did replicate normally in African green monkey kidney cells and, in the presence of helper virus, gave rise to infectious progeny. Inhibition of SV40 DNA replication follows a cis-acting mechanism and is most likely due to a conformational change of the SV40 chromatin structure.

Avian Sarcoma Viruses↗
PubMed1989

Isolation of human immunodeficiency virus-related simian immunodeficiency viruses from African green monkeys.

We have isolated lentivirus strains that are related to the human immunodeficiency virus (HIV) from African green monkeys (Cercopithecus aethiops; AGM). Although immunologically related, these SIVagm are clearly distinct from other simian immunodeficiency virus (SIV) isolates, including isolates from Macaca mulatta (SIVmac) or even from other AGM. The SIVagm strains described in this communication grow well in a limited number of human T-lymphoma lines. Virus density, morphology, and reverse transcriptase activity are characteristic of the lentivirus group. SIVagm exhibits the following pattern of major virus proteins: p18, p28, gp45, p64, gp140. They appear to bind to the target cell via the CD4 or its primate analogue. Four virus isolates have already been molecularly cloned for detailed genomic analysis and within this SIV agm group they exhibit the genomic variability that is typical of lentiviruses. AGMs infected with this virus apparently remain healthy and therefore SIVagm not only provides a virus model for vaccine studies but also allows investigation of the defense mechanisms (immunological and others) that keep the AGMs healthy. Furthermore, precise genomic analysis of these and other SIV strains will lead to a better understanding of the evolution and pathogenicity of human lentiviruses like HIV.

Animals↗
PubMed1989

Molecularly cloned simian immunodeficiency virus SIVagm3 is highly divergent from other SIVagm isolates and is biologically active in vitro and in vivo.

Simian immunodeficiency viruses have been isolated from African green monkeys originating from Ethiopia. A molecular clone, termed SIVagm3, was found to be highly divergent from SIVagmTYO-1 in terms of its restriction map and partial nucleotide sequence. A premature stop codon present in the transmembrane protein of SIVagm TYO-1 was absent in SIVagm3. SIVagm3 was biologically active in vitro and in vivo and displayed characteristics reminiscent of the wild-type virus. Biological activity was demonstrated by seroconversion of juvenile African green monkeys and Macaca nemestrina after inoculation. In contrast to antibody reactivity mainly directed against env proteins in naturally infected African green monkeys. African green monkeys and M. nemestrina infected with the cloned virus showed antibody reactivity directed against all major proteins as demonstrated by immunoblot analysis. The availability of a biologically fully competent molecular clone of SIVagm allows us now to address various pertinent questions in an animal model system which should help to understand features of human immunodeficiency virus infection in human beings.

Amino Acid Sequence↗
PubMed1989

Mechanisms of tumor induction by human retroviruses.

Oncogenesis can be induced by chronic and acute RNA tumor viruses through a promoter/enhancer insertion mechanism and through a transforming protein coded by a viral oncogene (v-onc), respectively. A hypothetical trans-activating mechanism is invoked by retroviruses with trans-activating regulatory proteins. So far, in humans only HTLV-I has been firmly linked to a malignancy. The same virus is also implicated in slowly progressing neurological disorders. Except for transformation by viral oncogenes, these mechanisms give rise to monoclonal tumors.

HTLV-I Infections↗
PubMed1987

Perspectives of HIV vaccine developments.

Human immunodeficiency virus type 1 (HIV-1) may enter the blood stream as free virus or via infected lymphocytes, which poses problems for vaccine development. The classical vaccine designs, attenuated, inactivated, or subunit vaccine will be discussed with regard to HIV. Development of a recombinant subunit vaccine appears to be the most promising approach. Forthcoming results from experiments involving inoculation of chimpanzees should allow evaluation of the feasibility of using a subunit vaccine based on the env-glycoprotein. Also the use of live recombinant vaccinia merits further investigation.

Animals↗
PubMed1985

Developmental and molecular aspects of nephroblastomas induced by avian myeloblastosis-associated virus 2-O.

Avian myeloblastosis-associated virus-induced nephroblastomas are tumors consisting mainly of mesenchymal and epithelial renal elements with variable degrees of differentiation. The spatial distribution of developmental stages reflects a gradient of differentiation from less differential structures in the periphery towards more differentiated structures in the center of the lobules formed in the nephroblastomas. These heterogenic tumors contain discrete virus-cell DNA junction fragments and are therefore clonal outgrowths of a single transformed cell. These findings support the hypothesis that a mesenchymal, nephrogenic cell residual in the postembryonic kidney is the origin of the tumor, which grows by proliferation and differentiation of this target cell. All the tumors expressed higher levels of viral genomic and env messages than nontransformed tissue from the same kidney. A screening of oncogene expression with 13 different oncogenes revealed enhanced myc levels. There was, however, no rearrangement of c-myc or of the other oncogenes detected with EcoRI-digested tumor DNAs. This suggests that there is no insertion of viral elements adjacent to a c-myc. The levels of myc expression in embryonic kidneys were as high as in the tumors. Therefore, the enhanced myc expression in nephroblastomas is a reflection of the embryonic status of the tumor rather than a newly acquired function. This finding, plus the similarity of development and morphology of nephroblastomas and embryonic kidneys, suggests that the tumors arise as a result of a deficiency in a function which turns the embryonic status off.

Animals↗
PubMed1984

Biological and biochemical characterization of a new isolate of feline sarcoma virus: Theilen-Pedersen (TP1-FeSV).

A new feline sarcoma virus designated Theilen-Pedersen (TP1-FeSV) has been isolated from a spontaneous, slowly growing fibrosarcoma of a domestic short-haired 4-year-old castrated cat. The virus codes for a gag-onc fusion protein of 83,000 molecular weight phosphorylated in vivo at serine, threonine, and tyrosine residues. Cells transformed in vitro with TP1-FeSV exhibit five- to 10-fold elevated levels of phosphotyrosine over FeLV-infected cells. The gag-onc polyprotein has associated with it a tyrosyl protein kinase activity which in vitro results in autophosphorylation of the molecule at tyrosine residues. The fusion protein cannot be labeled metabolically with [3H]glucosamine and tunicamycin has no effect on the electrophoretic mobility of the in vivo [32P]orthophosphate-labeled fusion protein. The fusion protein, in common with the gag precursor Pr65gag, can be metabolically labeled with palmitic acid.

Acylation↗
PubMed1984

Drastic rise of intracellular adenosine(5')tetraphospho(5')adenosine correlates with onset of DNA synthesis in eukaryotic cells.

An assay of adenosine(5')tetraphospho(5')adenosine (Ap4A), based on the luciferin/luciferase method for ATP measurement, was developed, which allows one to determine picomolar amounts of unlabeled Ap4A in cellular extracts. In eukaryotic cells this method yielded levels of Ap4A varying from 0.01 microM to 13 microM depending on the growth, cell cycle, transformation, and differentiation state of cells. After mitogenic stimulation of G1-arrested mouse 3T3 and baby hamster kidney fibroblasts the Ap4A pools gradually increased 1000-fold during progression through the G1 phase reaching maximum Ap4A concentrations of about 10 microM in the S phase. Quiescent 3T3 cells reach a high level of Ap4A (1 microM) in a 'committed' but prereplicative state if exposed to an external mitogenic stimulant (excess of serum) and simultaneously to a synchronizer which inhibits entry into the S phase (hydroxyurea). When the block for DNA replication was removed at varying times after removal of the stimulant decay of commitment to DNA synthesis was found correlated with a shrinkage of the Ap4A pool. Cells lacking a defined G1 phase (V79 lung fibroblasts, Physarum) possess a constitutively high base level of Ap4A (about 0.3 microM) even during mitosis. From this high level, Ap4A concentration increases only about tenfold during the S phase. Temperature-down-shift experiments, using chick embryo cells infected with transformation-defective temperature-sensitive viral mutants(td-ts), have shown that the expression of the transformed state at 35 degrees C is accompanied by a tenfold increase of the cellular Ap4A pool. Treatment of exponentially growing human cells with interferon leads, concomitantly with an inhibition of DNA syntheses, to a tenfold decrease in intracellular Ap4A levels within 20 h. The possibility of Ap4A being a 'second messenger' of cell cycle and proliferation control is discussed in the light of these results and those reported previously demonstrating that Ap4A is a ligand of mammalian DNA polymerase alpha, triggers DNA replication in quiescent mammalian cells and is active in priming DNA synthesis.

Adenine Nucleotides↗
PubMed1983

Inhibition of Rous sarcoma virus assembly by treatment with 2',5' adenosine nucleotides.

We have investigated the influence of 2',5' adenosine nucleotides on the replication and transformation of cells by Rous sarcoma virus (RSV). Treatment with the nucleotides ppp2',5'A4 and 2',5'A4 causes a striking reduction (50-fold) in the yield of infectious progeny virus, while ppp2',5A2 and 2',5'A3 had virtually no effect. The reduction in infectivity seen with 2',5'A4 nucleotides is paralleled by a smaller but significant (three- to four-fold) reduction in the amount of particles released as measured by reverse transcriptase activity and levels of viral structural proteins. The reduced infectivity of released particles is not due to viral RNA being missing since the amount of genomic RNA in particles from 2',5'A4-treated cultures was likewise only reduced by a factor of 2-3. Pulse-chase radioactive label experiments showed that processing of both viral group-specific antigens (gag) and viral envelope glycoprotein (env) gene products was completely normal in nucleotide-treated cultures, but that the rate of appearance of viral proteins in mature virus in the culture supernatants was reduced by a factor of about 3-4. Taken together, the data show that assembly of viral structural proteins into virions which can be released into the medium is slowed, and that assembly of virus particles with reduced infectivity follows upon nucleotide treatment. This inhibition of infectious virus production takes place without significant toxic effects on the cell; host protein synthesis is only 20% inhibited. There is also no significant effect on the secretory ability of the cells as measured by total protein release into the medium or release of fibronectin. The transformed cell phenotype was also subtly affected by 2',5'A4, but not by other oligomers. Plasminogen activator protease activity was sharply reduced upon treatment, while other typical features of RSV-transformed cells such as elevated hexose transport, and pp60src-associated protein phosphokinase activity, were little affected.

Adenine Nucleotides↗
PubMed1978

Transcription of host-substituted simian virus 40 DNA in whole cells and extracts.

Viral transcriptional complexes were extracted from the nuclei of monkey kidney cells infected with wild-type simian virus 40 (SV40) or a variant strain containing a high proportion of host-substituted DNA molecules. The RNAs synthesized by these complexes in an in vitro system were analyzed for their content of SV40 and host sequences by a technique of sequential hybridization to plaque-purified and substituted viral DNAs. The relative labeling of the two types of sequences was commensurate with their proportion in the viral DNA (about 20% host). The substituted virus contains both reiterated and unique types of cellular sequences, and both kinds appeared to be transcribed. Transcripts of the substituted sequences formed a much smaller proportion of the virus related RNA recovered from intact infected cells, suggesting that host sequence transcripts are synthesized but rapidly degraded in the whole cell. The alternative, that transcription of these sequences is artificially enhanced in the in vitro system, cannot be rigorously excluded. We compared the self-annealing of viral RNAs from nuclear extracts of cells infected with wild-type and substituted viruses; transcripts labeled both in vivo and in vitro showed a two- to threefold-higher level of self-annealing in the case of the variant than in the case of wild type SV40.

Base Sequence↗
PubMed1977

Characterization of early simian virus 40 transcriptional complexes: late transcription in the absence of detectable DNA replication.

Isolation of early viral transcriptional complexes and incorporation in vitro of radiolabeled precursors into nascent RNA has permitted an analysis of early simian virus 40 (SV40) transcription. Under conditions such that viral DNA replication was undetectable, both early and late SV40 RNA were synthesized. This finding provides evidence that viral DNA replication is not an absolute requirement for late transcription and supports earlier observations that late viral RNA is synthesized in SV40-infected nonpermissive mouse cells. The majority of the early viral transcriptional activity can be solubilized, indicating that a substantial portion of this RNA is transcribed from free rather than integrated templates. Sedimentation analysis of the transcriptional complexes resulted in the detection of two separate peaks of activity, suggesting the possibility of two distinct types of early SV40 templates.

Chromosome Mapping↗
PubMed1976

Genome localization of simian virus 40 RNA species.

The topographical locations on the simian virus 40 (SV40) genome of the templates for virus-specific RNA species present late in the lytic infection were determined by RNA-DNA hybridization experiments with the Hind restriction enzyme fragments. Two classes of late virus-specific cytoplasmic mRNA's can be separated on the basis of either sedimentation properties in neutral sucrose or electrophoretic mobility in polyacrylamide gels. In the 16S class, two species of RNA were identified by hybridization experiments. One of these species was complementary to sequences of the early template on the minus (E) strand (0.175 to 0.655 map units), and the other more abundant species was complementary to sequences present in the late template on the plus (L) strand (0.655 to 0.175 map units). In addition two species were detected in the 16S class of late cytoplasmic virus-specific mRNA. One of these species was the major late RNA detected and consisted of a polyadenylated transcript complementary to the plus (L) DNA strands of Hind fragments K, F, J, and G (0.945 to 0.175 map units). This species appears to specify the major capsid protein (VP1). A less abundant nonpolyadenylated 16S RNA species complementary to the plus (L) strands of Hind fragments C, D, and E (0.655 to 0.945 map units) may result from post-transcriptional processing or nonspecific degradation of the 19S viral RNA complementary to the plus (L) strand.

Base Sequence↗