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Biomedical subjects

B R Murphy

Publications and source records attributed to B R Murphy.

297 records · Page 17Linked to original sources
PubMed1968

Factors modifying host resistance to viral infection. 3. Effect of whole body x-irradiation on experimental encephalomyocarditis virus infection in mice.

The resistance of mice to encephalomyocarditis (EMC) virus was markedly decreased by prior exposure to whole body X-irradiation. In contrast to non-irradiated controls, the course of EMC virus infection in X-irradiated animals was characterized by (a) an enhanced mortality, (b) shortening of the incubation period, (c) higher levels of virus in the blood during the viremic phase and persistence of the viremia until death, (d) failure to develop detectable serum levels of neutralizing antibody, and (e) the earlier appearance and higher levels of virus in brain and heart tissue. The level of interferon in the serum during the course of infection was similar in both groups. The administration of relatively small quantities of anti-EMC virus neutralizing antibody to X-irradiated mice during the early phases of the infection with EMC virus restored their resistance to levels comparable to nonirradiated animals. An alteration of local organ defense mechanisms in the central nervous system could not be demonstrated. It is proposed that (a) the inability of the X-irradiated animal to elaborate specific neutralizing antibody was a critical determinant in their failure to clear the viremia, (b) this increase in the level and duration of the viremic phase resulted in the exposure of target organs to a greater inoculum of virus, and (c) the enhanced mortality observed in irradiated mice reflected this greater target organ involvement. The experimental model presented, therefore, suggests that the immunologic response is a critical determinant of host resistance during this primary systemic virus infection.

Animals↗
PubMedDate not supplied

An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters.

The purpose of the present study was to produce an influenza A H2N2 donor virus from which an attenuating PB2 gene bearing three discrete temperature sensitive (ts) mutations could be readily transferred to currently epidemic influenza A H1N1 and H3N2 viruses via genetic reassortment. An influenza A transfectant virus was first produced that contained site-directed ts mutations at amino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability independent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/LA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replication in the lungs of immunocompetent hamsters. This indicated that the A/AA/60-A/LA/87 gene constellation contributed significantly to the overall level of temperature-sensitivity, attenuation, and stability of the A/LA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.

Animals↗
PubMedDate not supplied

The association of the temperature-sensitive phenotype with viral attenuation in animals and humans: implications for the development and use of live virus vaccines.

Viruses that possess temperature-sensitive mutations are consistently attenuated in vivo compared with the wild-type parental strains. Such temperature-sensitive (ts) mutants are currently used in several live attenuated virus vaccines and have been proposed for use against several additional viral diseases, including influenza. This paper reviews the following: (1) the evidence that the ts mutation itself is responsible for attenuation; (2) experimental infection of animals and humans with ts mutant viruses; (3) the experience of humans with naturally occurring ts mutants; and (4) the rationale for the use of ts mutants in live virus vaccines. In addition, the potential of ts mutants to produce altered patterns of disease is considered. After the known and potential benefits and possible risks involved in the use of ts mutant viruses are weighed, the continuing use and development of vaccines using live attenuated ts virus seems warranted.

Animals↗
PubMedDate not supplied

Use of temperature-sensitive and cold-adapted mutant viruses in immunoprophylaxis of acute respiratory tract disease.

Efforts currently are underway to develop mutations in the influenza A viral genome that will bring about a satisfactory level of attenuation and that can be identified by simple in vitro techniques. Two types of donor viruses that bear such mutations are being evaluated. One donor virus possesses temperature-sensitive (ts) mutations on the P1 and P3 genes, while the other donor bears both ts and cold-adaptation (ca) mutations. The mutant genes from these donors were transferred by gene reassortment to recombinant viruses bearing the surface antigens of new epidemic or pandemic viruses, and in every instance a satisfactory level of attenuation was achieved. However, genetic instability remains a formidable problem. Temperature-sensitive mutants of respiratory syncytial virus also have been evaluated for their usefulness in immunoprophylaxis of respiratory tract disease. Although the desired mutant has not been identified, some progress has been made.

Acute Disease↗
PubMedDate not supplied

The pharmacokinetics of albumin conjugates of D-penicillamine in humans.

D-penicillamine (D-PEN) is incompletely recovered during short-term balance studies, despite rapid elimination of D-PEN and its low molecular weight metabolites. Urinary excretion of metabolites of D-PEN also persists long after cessation of chronic therapy. A study was performed to determine whether the formation and later breakdown of a stable disulfide between D-PEN and plasma albumin could explain these aspects of D-PEN pharmacokinetics. Five human volunteers received D-penicillamine, 250 mg orally, daily for 21 days. Plasma concentration-time profiles for D-PEN and D-PEN-albumin disulfide (D-PEN-albumin) were determined during the first day and pre-dose concentrations were measured on five further occasions. The pharmacokinetics of D-PEN on the first day were similar to those reported previously. No D-PEN was found in any of the pre-dose specimens. The concentration of D-PEN-albumin rose rapidly during the first day, with an estimated 8.6% of the bioavailable D-PEN being transformed to D-PEN-albumin. Pseudo-steady-state concentrations of D-PEN-albumin were achieved in three subjects at between 14 and 21 days. The mean trough concentration of D-PEN-albumin at 21 days (19.5 microM) exceeded the peak concentration of D-PEN (during the first day) by 5.7-fold. The terminal elimination half-life of D-PEN-albumin was 1.65 +/- 0.29 days, which compared with an elimination half-life of 59 +/- 8.4 min for D-PEN.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Biological, genetic and biochemical characterization of a cold-adapted recombinant A/Victoria/3/75 virus and its evaluation in volunteers.

A recombinant virus AA-CR19 was produced that contains RNA segments coding for one polymerase protein, the nucleoprotein and the matrix protein of cold-adapted A/Ann Arbor/6/60, but HA, NA and two other genes coding for polymerase proteins from A/Victoria/3/75. The nonstructural protein gene is probably derived from A/Ann Arbor/6/60, but may contain a spontaneous mutation. Biological characterization of AA-CR19 showed that it possesses the gene(s) responsible for cold-adaptation and temperature-sensitivity of the A/Ann Arbor/6/60 parent. At a dose of 10(7.2) TCID/50. AA-CR19 was found to be immunogenic and attenuated for seronegative volunteers.

Adult↗