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The effects of monoclonal antibody used in combination with ganciclovir (GCV) or (S) -1-[3-hydroxy-(2-phosphonylmethoxy)propyl]cytosine (HPMPC) against murine cytomegalovirus (MCMV)

Mechanical wounding was shown to activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in the skin of transgenic mice. Both noninvasive rubbing and scratching of the skin resulted in a range of 4- to 44-fold increased levels of luciferase reporter gene activities when assayed 24-48 h after wounding. Moreover, long-term noninvasive rubbing each day for 17 days resulted in similar increased levels of luciferase activity. Experiments were done to determine whether the HIV-1 LTR-luciferase transgene might be activated when pups were nursed on the mammary tissues of transgenic mice. Luciferase reporter gene activity in mammary glands skin following nursing was significantly higher than in skin from non-pregnant transgenic mice or transgenic mice 20 days post-conception, which suggests that the natural abrasive action of nursing resulted in activation of the LTR. These results may have implications for sexual transmission and maternal-to-infant transmission of HIV-1.

A simple, sensitive, micromethod was developed to determine levels of ribavirin, or its active metabolic products, in human serum or urine. The procedure utilized the inhibition of measles virus cytopathic effect in BS-C-1 cells. Based upon maximum dilutions of human serum or urine containing ribavirin which inhibited the measles virus, the bioassay detected ribavirin in concentrations as low as 0.006 microgram/ml in serum or 0.03 microgram/ml in urine. Herpesvirus 1, parainfluenza virus 3 and reovirus 1 were also tested for sensitivity to ribavirin. Minimum inhibitory concentrations of ribavirin in serum or urine against these other viruses were no lower 0.32 microgram/ml.

1-β-d-Ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) had significant in vitro activity against type 1 parainfluenza (Sendai) and type 3 parainfluenza (HA-1) viruses. Activity was manifested as inhibition of both viral cytopathogenic effect and of recoverable virus or viral hemagglutinin titer. The minimum Sendai virus inhibitory concentration was determined to be approximately 3.2 µg/ml. Previous studies had determined the minimum concentration inhibiting HA-1 virus was approximately 1–10 µg/ml. The effect of time of addition of ribavirin to virus-infected cells was determined; maximal activity was seen when the drug was added just prior to either virus or within 4–8 h after each virus, although anti-Sendai viral effects were still apparent when ribavirin was added as late as 24 h after the virus. Ribavirin had no effect on adsorption of HA-1 or Sendai virus to cells. Lethal Sendai virus infections of mice were significantly inhibited by multiple intraperitoneal ribavirin treatment, starting either 4 h before or up to 24 h after virus inoculation. Therapy starting 48, 72 or 96 h after virus exposure had a moderate degree of efficacy. Treatment using an aerosol chamber also was of moderate effectiveness, although the procedure was considered traumatic to the animals. A nonlethal, principally upper respiratory tract infection of hamsters induced by the HA-1 virus was inhibited by ribavirin therapy. Treatment administered intraperitoneally, per os or by aerosol chamber resulted in reduced 23-day antibody titers to the virus, presumably because of reduction of virus in the animal. In a separate experiment, intraperitoneal ribavirin therapy resulted in a 1 log10 or less reduction in virus titer in nasal washings from HA-1 virus-infected hamsters, whereas, when the drug was administered intranasally in a dry powder aerosol spray, nasal virus titers were reduced up to 2 log10 and a moderate virus-induced lung consolidation was completely inhibited.

9-β-D-Arabinofuranosyladenine-5′-phosphate (ara-AMP) and 9-β-D-arabinofuranosyladenine 3′,5′-cyclic phosphate (cyclic ara-AMP) had significant in vitro activity against types 1 and 2 herpes simplex, pseudorabies, infectious bovine rhinotracheitis, murine and human cytomegalo, vaccinia and myxoma viruses. The drugs were not inhibitory to type 3 adeno, type 3 parainfluenza, or type 13 rhino virus in cell culture. The antiviral activity of the nucleotide and the cyclic nucleotide appeared equivalent to that seen using the known active purine nucleoside 9-β-D- Arabinofurnosyladenine (ara-A) in parallel experiments. Injection of each compound directly into the brains of mice infected intracerebrally with type 1 or type 2 herpes simplex viruses or with vaccinia virus resulted in a highly significant increase in survivors. The intracerebral dose of ara-A was limited by its relative insolubility in aqueous solutions. Intraperitoneal or per os ara-AMP, cyclic ara-AMP or ara-A treatment of mice infected intracerebrally with type 1 herpes simplex virus significantly prevented encephalitis-induced death or prolonged the mean survival time of the animals. Cyclic am-AMP was at least 10-fold more toxic than ara-A and ara-AMP when administered intraperitoneally, but this toxicity was not seen when it was administered per os. All three compounds were also active when administered per os against type 2 herpes simplex virus-induced encephalitis in mice. Topical application of ara-AMP or cyclic ara-AMP inhibited herpes keratitis in experimentally infected rabbits and herpes virus-induced cutaneous lesions in tails of mice. This activity was generally greater than that seen using ara-A tested in simultaneous experiments.