In studying the influence exerted by lipoids upon viral activity, we could show that the presence of free fatty acids, especially polyunsaturated, induced changes opposite to those induced by the anti fatty acids.

In rabbits, administration of various preparations of fatty acids, especially polyunsaturated, induced an unusual degree of resistance. Animals previously given subcutaneous injections of fatty acid preparations showed a reduced general response to chicken pox inoculation as compared with controls, and practically no response in the skin at the site of the fatty acids injection. On the other hand, administration of insaponifiable lipid fractions obtained from tissues of receptive species was followed by manifest responses localized in the zone of injection, even in species otherwise refractive to viral infection. It is under this special influence of lipoids that we have further investigated the intervention of the viruses in carcinogenesis.

Cells vary in their content of lipids. We could see that richness in sterols of a group of cells increases their receptivity to, and favors the development of, viruses in general, while richness in fatty acids, especially polyunsaturated, has an opposite effect. The local increase in a tissue's richness in sterols makes it more susceptible to the localization and development of a virus, as is shown in the following experiment.

In rabbits, intracutaneous or subcutaneous injections of a colloidal suspension of cholesterol were made on epilated skin at several sites. Twenty four hours later, the animal was injected intravenously with suspension of smallpox vaccine. Characteristic lesions were observed to develop at the sites of the cholesterol injections.

The general effect of sterols upon receptivity to viruses, noted in many experiments in animals, was also recognized in humans. The following observation appears interesting. Mrs. D. R. had always appeared refractory to smallpox vaccines. Until the age of 40, repeated inoculations produced constantly negative responses. She was treated at that time with a cholesterol preparation for precordial pain, receiving daily 2-3 cc. of a 2.5% solution of cholesterol intramuscularly. After three weeks of this treatment, she was obliged to go abroad and it was necessary for her to have the routine smallpox vaccination. For the first time in her life, a characteristic positive result was obtained.

The relationship between sterols and viruses, which would explain the affinity of most viruses for the nervous system and skin, since both are of exodermic origin and particularly rich in free sterols, would also explain why young cells similarly richer in sterols are more susceptible to viruses, and the facility with which almost all viruses develop in embryos, such as in chicken embryos.

Changes in richness in lipids were observed under natural circumstances other than those related to age. Thus seasonal changes could be noted, the cold season leading to an increase of fatty acids while the summer season brought an increase of sterols. This would help to explain the seasonal changes usually observed in naturally occurring viral infections. (99)

The epidemiology of poliomyelitis may be related to the organism's richness in sterols in the summer, particularly on hotter days. Seasonal changes were noted in naturally occurring tumors in which a viral etiology is seen. A certain resistance appears in the fall and increases in the winter in the case of leukoses and possibly in other natural viral tumors. (100) This would explain the manifest seasonal changes observed by us in the transplanted Walker tumor in rats or in grafted tumors in mice in general, and in the induction of tumors through carcinogens. Similarly, the induction of teratomas in testes through local administration of zinc chloride was noted to be influenced by the seasons. (101)

The influence exerted by sterols would explain the fact that viruses able to act only at a higher level, as in the cytoplasm, tend to develop in animal cells abnormally rich in sterols. It is highly probably that once it has penetrated, a virus will develop within a cell only under favorable conditions, and these are insured by the presence of sterols. The virus will persist, interfering little with the fate of the cell until other changes occur at lower levels. These other changes take many months or even years to be completed, and only then would the influence of the virus be apparent through its activation of the noninvasive abnormal cell. Activation can occur regardless of seasonal changes in sterol richness. It seems superfluous to note that this relationship holds more for cytoplasmatic viruses than for those with broad scale activity. The latter are also more active in young animals.

Changes in age of the host and other circumstances can modify the character of viral carcinogenesis, leading to rapid or very slow development, or even to complete lack of response. This was often noted for Rous sarcoma. In young animals, small amounts induced rapidly growing tumors with multiple hemorrhagic metastases rich in filtrable virus. In adult animals, despite the large amount of virus necessary, tumors took months to appear, seldom metastasized, and could be transmitted with difficulty, or not at all, by filtrates or even by cells. (102)

The relationship between viral carcinogenesis and lipids has been the basis for a group of experiments in which we tried to influence the carcinogenic activity of a virus by administration of sterols. Experiments still in progress, using sterols obtained from chicken embryos, seem to indicate that lipids can strongly change viral carcinogenic activity. In general, they induce an increased response to viruses.

Many other peculiarities of the relationship between viruses and carcinogenesis have been analyzed in terms of intervention of lipids as an intermediary factor. The capacity of a virus to induce tumors in different organs—as seen for leukemic tissue cell free extracts in mice, which induce peculiar salivary gland tumors (103), or tumors in the adrenal gland or in the subcutaneous tissues (104)—can be explained by certain peculiar affinities of the viruses for differentiated tissues, possibly related to certain specific lipids found in these tissues. A similar affinity for the salivary gland is seen for rabies virus. There are also the affinities shown by the neuro and dermatotropic viruses, and by the neoplastic viruses for mammary gland, lymphatic tissue, neuroglia, etc. While affinity for the adrenal gland could be related to its richness in sterols, affinity to others sites could be related to other lipids.