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22.Tumor Viruses

Robert C. Gallo, MD
Marvin S. Reitz Jr, PhD

Retroviruses are enveloped viruses that contain a diploid ribonucleic acid (RNA) genome and are defined by the presence of reverse transcriptase (RT), a deoxyribonucleic acid (DNA) polymerase that transcribes RNA into DNA, which is then inserted into the host cell chromosome. These processes often lead to the capture andalteration of genetic material and the transfer of information between cells, with neoplastic transformation of the infected cell being an occasional outcome of infection. Retroviruses are also associated with immunodeficiencies and with neurologic diseases, although infection is often asymptomatic. Retroviruses can also enter the germ line and be present as a part of the genetic complement of all membersof a species. These viruses are called endogenous retroviruses.
Retroviruses were discovered early in the twentieth century. Ellerman and Bang showed the transmission of leukemia in chickens by a cell-free filtrate, [pic]1 and Rous was able to transmit sarcomas in chickens by a similar means. [pic]2 These findings were extended to mammals by Bittner in the case of breast tumors in mice3 and byGross for murine leukemias.4 Gross recognized the importance of inoculating newborn mice for development of leukemia and in many respects, his work heralded the beginning of modern studies of retroviruses. Jarrett showed that a similar virus was responsible for leukemia in cats, which was the first demonstration of naturally transmitted leukemia in an outbred species. [pic]5 Kawakami and Theilenand colleagues first showed that retroviruses could cause leukemia in primates, specifically in gibbon apes and new world monkeys.6–8
Biologic assays for these viruses were in use from the 1950s, but a more fundamental understanding of their life cycle was considerably advanced in the early 1970s by the discovery that they contained RT. [pic]9, [pic]10 This provided a far simpler and quicker assayfor retroviruses, as well as a sensitive and relatively simple tool for their general detection. Another important finding in the 1970s was that some retroviruses (eg, Rous sarcoma virus) contained genes for cell transformation and tumorigenesis (called oncogenes) that represented captured cellular genes (protooncogenes). [pic]11 This realization led to the identification of dozens of similargenes and to an appreciation of their roles in cell growth and neoplastic transformation.
Despite this work and the interest it engendered, it was widely believed during the 1970s that retroviruses did not play a role in human disease, and that they were likely not even present in the human population. Several discoveries made it clear that this was not the case. First, human T-cell leukemia virustype I (HTLV-I), the first infectious human retrovirus, was discovered by Gallo and his colleagues and shown to be a unique virus.12–15 HTLV-I was soon established as the etiologic agent of adult T-cell leukemia, a type of leukemia endemic to various locales, including southern Japan and the Caribbean.16–20 This was quickly followed by the discovery of HTLV-II, [pic]21 a related virus that (althoughwidespread) has not been compellingly associated with any disease.
Several years later, an epidemic of immunodeficiency and malignancies appeared within gay communities, especially in the United States. The first member of another group of human retroviruses was isolated from people with this disease, [pic]22 and when it became possible to culture the virus on a large scale, [pic]23 it wasproven to be the etiologic agent of the new disease, called acquired immunodeficiency syndrome (AIDS). [pic]24, [pic]25 The virus, now called human immunodeficiency virus type 1 (HIV-1), has become established over much of the world, as has AIDS itself, and HIV-1 represents a current global medical and economic catastrophe. As with HTLV-I, a related virus, HIV-2, was discovered. [pic]26 As with...
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