P. De Somer

ADMINISTRATION OF HUMAN FIBROBLAST INTERFERON IN CHRONIC HEPATITIS-B INFECTION

One patient with hepatitis-B surface antigen (HBsAg)-positive chronic aggressive hepatitis, and two chimpanzee carriers of HBsAg, were each given seven doses of 10(7) I.U. of human fibroblast interferon over two weeks. The main differnce observed after treatment was a depression of the nucleocapsid hepatitis-0 core antigen in the liver, indicating that hepatitis-B virus infection is sensitive to interferon. Except for a short febrile reaction, no undesirable effects were seen after the administration of human fibroblast interferon which has not been previously given to man.

Mechanism of action of interferon: I. Relationship with viral ribonucleic acid

Abstract The mechanism of action of interferon has been investigated in two different cell systems, with concordant results. Interferon is able to suppress the one-cycle synthesis of poliovirus in embryonated eggs inoculated with infectious polio ribonucleic acid (RNA). This observation represents the basis of a sensitive method for quantitative bioassay of interferon activity. Interferon-treated chick embryo cells infected with Western equine encephalitis (WEE) virus do not yield detectable infectious viral RNA, as shown by extraction with cold phenol. It appears that interferon action occurs within the cell, after penetration of virus and before formation of mature virus particles. A close relationship with viral RNA metabolism is suggested.

Mass production of human interferon in diploid cells stimulated by poly-I:C.

Summary The production of interferon by human diploid cells stimulated by poly-I:C can be increased by pretreatment of the cells with interferon (priming effect). Large amounts of interferon (30000 units/ml) can be obtained by combining priming with a superinduction schedule adapted from that described for rabbit kidney cultures (Tan et al. 1970; Vilcek & Ng, 1971). Human plasma protein could replace bovine serum albumin in the production medium.

Tissue distribution of human interferons after exogenous administration in rabbits, monkeys, and mice

SummaryPreparations of human leukocyte (α) and fibroblast (β) interferon were given intramuscularly to rabbits and monkeys, and circulating interferon was measured. In rabbits, but not in monkeys, a marked difference between the two interferons was noted in that higher titers of circulating antiviral activity were obtained with leukocyte than with fibroblast interferon. In mice, injected interperitoneally, a similar difference could be noted. However, levels of antiviral activity in homogenates of spleens and lungs did not differ between mice injected with either interferon.Fibroblast interferon that was injected intrathecally in monkeys was found to diffuse throughout the cerebrospinal canal and to reach the serum compartment. Some interferon could also be recovered from the pia mater surrounding the brain hemispheres, but none was found in the deeper layers of the brain.

Antiviral Activity of Polyribocytidylic Acid in Cells Primed with Polyriboinosinic Acid

Separate administration of polyribocytidylic acid [poly(rC)] and polyriboinosinic acid [poly(rI)] to cell cultures in vitro resulted in an antiviral activity identical to or greater than that resulting from addition of the poly(rI) • poly(rC) complex. Priming of cells with poly(rI), followed by treatment with poly(rC), gave a consistently greater antiviral activity than poly(rI) • poly(rC) itself. This priming effect was obtained in several cell cultures challenged with different viruses. In vivo, the antiviral activity of poly(rI) • poly(rC) was only partially restored if poly(rI) and poly(rC) were injected separately; prior injection of poly(rI) proved superior in restoring this antiviral activity as compared to prior injection of poly(rC).

Interferon production by the spleen of rats after intravenous injection of Sindbis virus or heat-killed Escherichia coli.

1. Large amounts of interferon were obtained in the spleen of rats intravenously injected with Sindbis virus or heat-killed E. coli. Peak values occurred 2 hours after E. coli and 6 to 12 hours after Sindbis administration. 2. It was demonstrated that fragmented spleen tissue derived from rats injected with Sindbis virus or heat-killed E. coli, produce an interferon-like substance when incubated in vitro in tissue culture medium. 3. Splenectomy reduced 7 times the serum interferon response to E. coli but did not affect that to Sindbis virus. 4. Under proper experimental conditions combined injections of E. coli and Sindbis virus acted synergistically on the interferon response. 5. Germfree reared rats responded equally well to endotoxin treatment as did conventional animals. 6. The injection of E. coli resulted in a “hypareactive” state which lasted several days and during which the spleen interferon yield after Sindbis challenge was decreased. Conversely, Sindbis virus also rendered the animals resistant to the interferon inducing effect of E. coli. Large amounts of interferon were obtained in the spleen of rats intravenously injected with Sindbis virus or heat-killed E. coli. Peak values occurred 2 hours after E. coli and 6 to 12 hours after Sindbis administration. It was demonstrated that fragmented spleen tissue derived from rats injected with Sindbis virus or heat-killed E. coli, produce an interferon-like substance when incubated in vitro in tissue culture medium. Splenectomy reduced 7 times the serum interferon response to E. coli but did not affect that to Sindbis virus. Under proper experimental conditions combined injections of E. coli and Sindbis virus acted synergistically on the interferon response. Germfree reared rats responded equally well to endotoxin treatment as did conventional animals. The injection of E. coli resulted in a “hypareactive” state which lasted several days and during which the spleen interferon yield after Sindbis challenge was decreased. Conversely, Sindbis virus also rendered the animals resistant to the interferon inducing effect of E. coli.

Protective effect of interferon and polyacrylic acid in newborn mice infected with a lethal dose of vesicular stomatitis virus

Abstract Repeated intraperitoneal doses of preformed interferon and a single intraperitoneal injection of polyacrylic acid were shown to protect newborn mice from lethal infection with vesicular stomatitis virus. Both survival time and number of surviving mice were considerably increased by the injections. The antiviral activity of interferon and polyacrylic acid was inversely proportional to the dose of challenge virus. Nearly 100% of the mice treated with interferon survived a nearly 100% lethal infection (16 LD50). Polyacrylic acid diminished the mortality rate by 50 %. It is concluded that polyacrylic acid induces good host resistance to viruses and may be suitable in the prophylaxis of virus infections in vivo.

Pharmacokinetics of E-5-(2-Bromovinyl)-2′-Deoxyuridine in Mice

The pharmacokinetics of the newly developed anti-herpes agent, E-5-(2-bromovinyl)-2′-deoxyuridine, was compared with that of the standard anti-herpes drug 5-iodo-2′-deoxyuridine. Both compounds were administered to mice at 100 mg/kg by either the intraperitoneal, subcutaneous, or oral route. The active blood drug levels achieved by E-5-(2-bromovinyl)-2′-deoxyuridine were considerably higher than those attained by 5-iodo-2′-deoxyuridine (serum peak concentrations: 40 to 100 and 4 to 10 μg/ml, respectively). Active blood drug levels could still be found 320 min after oral administration of E-5-(2-bromovinyl)-2′-deoxyuridine.

Stabilisation of mouse and human interferons by acid pH against inactivation due to shaking and guanidine hydrochloride.

Summary The inactivation of poly(I)·poly(C)-induced and virus-induced human fibroblast interferon, virus-induced human leukocyte interferon, poly(I)·poly (C)-induced and virus-induced mouse tissue culture interferon and virus-induced mouse serum interferon by shaking and by guani-dine hydrochloride was studied. Only human leukocyte interferon was completely resistant to these treatments. All other interferons examined were largely inactivated, but a small amount of each preparation was resistant to inactivation. The residual activity from either treatment was completely resistant to the other. Inactivation by both shaking and guani-dine hydrochloride was prevented in acid (pH 2 and 3.5) conditions. Possible explanations for these observations are considered.

In vitro andin vivo inhibition of virus multiplication by microwave hyperthermia

SummaryThe effects of microwave hyperthermia (41° and 43° C) on virus multiplication have been exploredin vitro (HSV-1 infected primary rabbit kidney cultures) andin vivo (mice infected with HSV-1 or vaccinia). In vitro the cells were inoculated with HSV-1 and heated to 41° or 43° C either before or after infection. Virus yields were significantly decreased when the cells were exposed to hyperthermia within the first few hours after infection, while hyperthermia was without effect when applied before infection or with several hours delay after infection.In mice inoculated intranasally with HSV-1, mortality due to herpes encephalitis was significantly reduced upon daily exposure to microwave hyperthermia from the day of infection onward.In mice inoculated intravenously with vaccinia, a significant decrease in the number of specific tail lesions was observed if the animals were exposed to microwave hyperthermia within the first three days after infection, while irradiation prior to infection or delayed until several days after infection did not exhibit an appreciable effect.Our data suggest that microwave hyperthermia interferes directly with the virus multiplication cycle bothin vitro andin vivo.