Two families of animal viruses utilize reverse transcrip-tase (RT) in the replication of their genome, the Retroviridae and the Hepadnaviridae. Two floating genera of plant viruses also use RT; their life cycles are more similar to the hepadnaviruses than to the retroviruses. The hepadnaviruses and the plant viruses are sometimes called pararetroviruses, because their life cycle resembles that of the retroviruses. For the viruses that use RT, the genetic information in the genome alternates between being present in RNA and present in DNA. RT, which is encoded in the viral genome, converts the RNA genome of retroviruses, or an RNA copy of the DNA genome of hepadnaviruses, into double-stranded (ds) DNA. In the nucleus of the infected cell, cellular RNA polymerase transcribes the DNA genome of hepadnaviruses, or the DNA copy of the retrovirus genome, to produce the RNA to be reverse transcribed. The retroviruses package this RNA in the virion and are allied to retrotransposons that form a prominent feature of eukaryotic genomes. The hepadnaviruses and the plant viruses reverse transcribe the RNA into DNA during packaging, so that the virion contains DNA. Thus, the replication of the genome of retroviruses can be described as RNA^ DNA^RNA, whereas the replication of the genome of hepadnaviruses can be described as DNA^ RNA^DNA. Although the two families differ in the timing of when reverse transcription takes place in their life cycles, this difference may not represent a fundamental distinction between them. Recent studies have indicated that one genus of retroviruses, the spumaviruses, may package DNA in the virion.

It is an interesting feature of reverse transcription that the RNA template is destroyed in the process of conversion to DNA. RT has associated with it an RNase H activity, which specifically degrades the RNA strand of a

DNA-RNA hybrid. This activity is essential for the production of a dsDNA copy of the viral RNA by RT. The destruction of the RNA template makes the process of reverse transcription fundamentally different from other mechanisms used for transcription or copying of nucleic acids, in which the template remains intact.

An essential feature of the infection of cells by retro-viruses is that the dsDNA copy of the genome is integrated into the host chromosome, where it is called a provirus. Only integrated DNA is stably and efficiently transcribed by the host machinery. Thus, integration is required for productive infection. During infection by hepadnaviruses, however, the viral DNA does not integrate. Instead, it is maintained in the nucleus as a non-replicating episome. In contrast to retroviruses, hepadnaviral episomal DNA is stably and efficiently transcribed by the host machinery.

The retroviruses have been intensively studied for years because researchers discovered early that avian retroviruses have the ability to induce leukemias and sarcomas in chickens. The study of these viruses led to the discovery of cellular oncogenes, of RT, and of mechanisms that regulate cycling of the animal cell, and several Nobel prizes have been awarded for work with the avian retroviruses (Chapter 1). Although clearly important for our understanding of biology, for many years after their discovery retroviruses were in some ways biological curiosities because no human disease was known to be associated with retroviral infection. This changed with the discovery of human T-cell leukemia viruses, now known as primate T-lymphotropic viruses (PTLV), which cause leukemia in man. More recently, the appearance of human immunodeficiency virus (HIV) and of acquired immunodeficiency syndrome (AIDS) in the human population has dramatically altered our understanding of the disease-causing potential of retro-viruses.

Viruses That Use Reverse Transcriptase

The most important hepadnavirus is hepatitis B virus, which is a major cause of hepatitis in man. Like hepatitis C virus, it often establishes a chronic infection that can result in cirrhosis or hepatocellular carcinoma.

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