This invention relates to the treatment of animals which have been virally infected or which are at risk for exposure to viral infection. In particular, it is concerned with inducing in mammalian cells a state of resistance to viral infection.
Interferons have been used to varying effect for the prophylaxis or treatment of chronic, acute and/or experimental infections by viruses such as vaccinia, rubella, herpes simplex, varicella-zoster, chicken pox, cytomegalovirus, adenovirus, ebola virus, rabies and hepatitis B. Chronic cytomegalovirus infections have proven difficult to treat by interferons, even using much higher doses than were needed than for the prevention of CMV infections; these doses may involve undesirable side reactions such as neutropenia and suppression of weight gain. Accordingly, it would be desirable in patients with persistent or chronic viral infections to provide an interferon preparation that is more efficacious without inducing interferon side-effects.
Interferons also have been widely tested for their ability to prevent or treat the common cold (primarily rhinovirus infections). Most studies have intranasally administered daily doses ranging from 0.8.times.10.sup.6 to 42.8.times.10.sup.6 units (Finter et al., 1985, Interferon Vol. 4 pp. 186-187). However, it should be understood that the relationship between the specific activities reported by early workers and the International Standards now in use is unclear; the dosages employed when expressed in International Units could have been greater or lower. Intranasal administration generally was as an aerosol, although delivery by soaked pledget has been reported as more efficacious. Typically, the daily dosage is aliquoted and administered 1 to 3 times per day. Experience with recombinant interferons has shown that sprays delivering about 1.times.10.sup.6 units/dose (at 0.1 ml/nostril) were effective in conferring protection whereas doses at one-tenth or one-one hundredth of this had no detectable effect (Finter et al., op cit, p. 188). However, doses of about 1.times.10.sup.6 units of interferon have been associated with annoying, mild nasal irritation and greater doses are markedly irritating (Finter et al. Id.).
Interferons also have been administered in the form of eyedrops to treat herpes simplex virus conjunctivitis and intravenously or intraperitoneally as injections or infusions for the treatment of various viral infections. Eyedrops typically contained greater than about 1.times.10.sup.6 units of interferon/ml (one preparation containing 60,000 units/ml was reported to confer no clinical benefit; Sundmacher et al., 1976, "J. Infect. Dis." 133: A160-A164). Intravenous doses also generally exceeded 1.times.10.sup.6 units/patient, although earlier workers constrained by the crude interferon preparations then available necessarily used lower doses. As a result of these studies, interferons generally are not believed to be as effective in treating established viral infections as they are in preventing them. Interferon preparations are needed that demonstrate enhanced activity towards active infections and that exhibit higher protective potency in order that lower interferon doses can be used.
Tumor necrosis factor (Pennica et al., 20/27 December 1984, "Nature" 312: 724) and lymphotoxin (Gray et al., 20/27 December 1984, "Nature" 312: 721) are proteins produced by activated macrophages and lymphocytes, respectively designated "TNF" and "LT" herein. They are described in copending U.S. Ser. No. 06/677,454 and 06/608,316. Both are directly cytotoxic to tumor cells in vitro and in vivo, and synergize with interferons in this respect (Lee at al., 1984, "J. Immun." 133: 1083). However, neither TNF nor LT per se are presently known to have any direct antiviral protective activity. For the effect of cytotoxic substances on virally infected cells see Eifel et al., "Cell. Imm.", 47: 197-203 (1979) and Aderka et al., "Cell. Imm." 92: 218-225 (1985).
It is an object of this invention to enhance the antiviral activity of interferons without increasing the incidence of interferon side effects.
It is a further object to enhance the antiviral specificity of interferons.
It is an additional object to employ interferons in the prophylaxis of individuals against viral infection, particularly infection by DNA viruses.
These and other objects of the invention will be apparent from the invention as a whole.