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Journal Highlights
Recombinant Poliovirus Takes China By Storm
Liu A recombinant poliovirus spread 2,200 km from the point of origin within 2.5 years. Evolutionary and epidemiologic analyses suggest that the recombinant derives from coinfection in 1991 of one individual with wild type 1 poliovirus and the Sabin type 1 oral poliovirus vaccine strain, says first author Hong-Mei Liu, of the U.S. Centers for Disease Control and Prevention and the National Vaccine and Serum Institute, Beijing. All recombinants "had a homologous 367-nucleotide block of sequences, spanning the VP1/2A junction, that was derived from the Sabin type 1 OPV strain (LSc 2ab)," the authors write. The overall synonymous substitution rate per synonymous site per year for the complete VP1 and 2A genetic interval was (3.73 ± 0.52) X 10-2.
"We have found many other natural poliovirus recombinants in China and other countries, and we would like to learn more about the frequency, mechanisms, and biological significance of these recombination events," says Liu.
(H.-M. Liu, D.-P. Zheng, L.-B. Zhang, M. Steven Oberste, M. A. Pallansch, and O. M. Kew. 2000. Molecular evolution of a type 1 wild-vaccine poliovirus recombinant during widespread circulation in China. J. Virol. 74:11153-11161.) Abstract | Full Text
Antibiotic Suppresses Surgically Induced Inflammation Absent Infection
Yuen Kwok-Yung Yuen of the University of Hong Kong Queen Mary Hospital and colleagues have shown that clarithromycin, a macrolide antibiotic, markedly reduced inflammation induced by surgical trauma. In this study, 54 mastectomy patients were randomly divided into two groups, one of which received 500 mg of clarithromycin from the day before to three days after mastectomy.
Treatment was associated with attenuation of febrile response, tachycardia, tachypnea, and an increase in monocyte counts (P <0.0001, <0.01, <0.05, and <0.01, respectively), and with a significant reduction in postoperative pain and increased range of shoulder motion.
"This is not unexpected because the chemical structure of macrolides is quite similar to cyclosporin, which is used to prevent rejection in transplantation," says Yuen. "However, macrolides do not have the side effects associated with immunosuppression." Yuen plans further research into antibiotic immunomodulation under both infectious and noninfectious conditions.
(L. W. C. Chow, K.-Y. Yuen, P. C. Y. Woo, and W. I. Wei. 2000. Clarythromycin attenuates mastectomy-induced acute inflammatory response. Clin. Diagn. Lab. Immunol. 7:925-931.) Abstract | Full Text
Sensitive Genetic Screen for Protease Activity
Site-specific proteases play a key role in signal transduction, apoptosis, and many other biological processes. The human immunodeficiency virus (HIV) protease is essential for infectivity, but HIV's rapid evolution limits efficiency of protease inhibitors.
Daniel Ladant of the Institut Pasteur, Paris, and colleagues have developed a genetic screen that makes functional characterization of proteases easy. They engineer into the middle of the Bordetella pertussis adenylate cyclase (AC) polypeptide a sequence corresponding to a specific cleavage site of the HIV protease. Expressed in AC-deficient Escherichia coli, it restores the normal phenotype. Adding HIV protease into the cells inactivates the AC. HIV protease inhibitors such as saquinavir can then restore the normal phenotype.
"We further showed that HIV protease variants resistant to particular inhibitors can easily be distinguished from the wild-type protease," says Ladant. "Given its exquisite sensitivity, this screening system could be applied more generally, either to screen libraries for proteases that could cleave a precise peptide sequence, or conversely to determine the target site of a given protease," says Ladant.
(N. Dautin, G. Karimova, A. Ullmann, and D. Ladant. 2000. A sensitive genetic screen for protease activity based on a cyclic AMP signaling cascade in Escherichia coli. J. Bacteriol. 182:7060-7066.) Abstract | Full Text
Antiretrovirals Suppress Replication of Pig Retrovirus In Vitro
Pig organs are physiologically suitable for use as human transplants. However, they have been found to contain porcine endogenous retroviruses (PERV), which have been shown to infect human cells in vitro, raising the possibility of transmission.
Ed Otto of Genetic Therapy, Inc., Gaithersburg, Md., and colleagues have shown in vitro that "AZT is a potent inhibitor of PERV replication in 293 cells, with a 50% inhibitory concentration (IC50) of approximately 0.25 m M. DdI also inhibited PERV, with an IC50 of approximately 1 m M," according to this report. "These concentrations are similar to IC50s reported in in vitro studies of human immunodeficiency virus type 1 . . . 3TC, d4T, and indinavir were not effective inhibitors of PERV replication."
"These results demonstrate that PERV replication can be controlled using standard antiretroviral therapies but that, like MLV, the virus is inherently resistant to some commonly used therapies," the authors conclude.
(S. K. Powell, M. E. Gates, G. Langford, M.-L. Gu, C. Lockey, Z. Long, and E. Otto. 2000. Antiretroviral agents inhibit infection of human cells by porcine endogenous retroviruses. Antimicrob. Agents Chemother. 44:3432-3433.) Abstract | Full Text
Novel Pathway Converts Human Fibrosarcoma to Aggressive Phenotype
Recent in vivo studies by Eric Stanbridge of the University of California, Irvine, and others showed that deleting an endogenous mutant ras allele from the HT1080 human fibrosarcoma cell line converted the tumorigenic phenotype from aggressive to weak.
Stanbridge and coworkers now examine multiple signaling pathways, showing that when downregulated, none affect the aggressive tumorigenic phenotype of HT1080 cells. "Conversely, overexpression of activated MEK in the cells that lack a mutant ras allele converts them from weak to aggressively tumorigenic," says Stanbridge. "Comparison of the various dominant-negative and constitutively active transfectants indicates that overexpression of activated MEK is critical and activates target(s) that convert(s) the cells to an aggressive phenotype."
Stanbridge seeks to identify these targets in order to determine the ultimate trigger for aggressive tumor growth. That, he says, "may provide further pharmacologic opportunities for therapeutic intervention."
(S. Gupta, R. Plattner, C. J. Der and E. J. Stanbridge. 2000. Dissection of ras-dependent signaling pathways controlling aggressive tumor growth of human fibrosarcoma cells: evidence for a potential novel pathway. Mol. Cell Biol. 20:9294-9306.) Abstract | Full Text
Macrophages Infected with C. trachomatis Induce T Cell Apoptosis: Mechanism May Cause Persistent Arthritis
Recent research has shown that live, metabolically active Chlamydia trachomatis (CT) in the inflamed joint are responsible for the persistence of CT-induced arthritis, an untreatable condition.
Michael C. Jendro and colleagues of the Medical School Hannover, Germany, have shown that CT-infected macrophages can induce T cell apoptosis. That, says Jendro, "may explain how persistently infected macrophages escape T cell surveillance and why the Chlamydia-specific T cell response is diminished during persistent chlamydial infection. By modulating this mechanism with anti-apoptotic antibodies or reagents we can possibly prevent T cell apoptosis. This might lead to a better anti-chlamydial T cell response, and hopefully to eradication of these bacteria."
"We are investigating the molecular mechanism by which the CT-infected macrophages execute T cells; whether CT-induced apoptosis occurs in vivo, and whether different chlamydial species share this capability," says Jendro.
(M. C. Jendro, T. Deutsch, B. Korber, L. Kohler, J. G. Kuipers, B. Krausse-Opatz, J. Westermann, E. Raum, and H. Zeidler. 2000. Infection of human monocyte-derived macrophages with Chlamydia trachomatis induces apoptosis of T cells: a potential mechanism for persistent infection. Infect. Immun. 68:6704-6711.) Abstract | Full Text
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