A schematic outline of a typical retrovirus replication cycle, represented by HTLV, is shown in Figure 1. The pol gene encodes the unique polymerase (reverse transcriptase) protein that has four enzymatic activities (protease, polymerase, RNase H, and integrase). After virus particles have adsorbed to and penetrated host cells, the viral RNA serves as the template for the synthesis of viral DNA through the action of the viral enzyme reverse transcriptase, functioning as an RNA-dependent DNA polymerase. By a complex process, sequences from both ends of the viral RNA become duplicated, forming the long terminal repeat located at each end of the viral DNA (Figure 2). Long terminal repeats are present only in viral DNA. The newly formed viral DNA becomes integrated into the host cell DNA as a provirus. The structure of the provirus is constant, but its integration into host cell genomes can occur at different sites. The very precise orientation of the provirus after integration is achieved by specific sequences at the ends of both long terminal repeats.
Fig1. Overview of human T-lymphotropic virus (HTLV) replication cycle. The virus particle attaches to a cell surface receptor, and the viral capsid enters the cell. The viral reverse transcriptase enzyme produces a DNA copy of the genome RNA within the capsid in the cytoplasm. The DNA enters the nucleus and is integrated at random into cell DNA, forming the provirus. The integrated provirus serves as template for the synthesis of viral transcripts, some of which are unspliced and will be encapsidated as genomic RNAs and others and some of which are spliced and will serve as mRNAs. Viral proteins are synthesized; the proteins and genome RNAs assemble; and particles bud from the cell. Capsid proteins are proteolytically processed by the viral protease producing mature, infectious virions, shown schematically as conversion from a square to an icosahedral core. (Courtesy of SJ Marriott.)
Fig2. Comparison of structures of retrovirus RNA genome and integrated provirus DNA. A virus particle contains two identical copies of the single-stranded RNA genome. The 5′ terminal is capped, and the 3′ terminal is polyadenylated. A short sequence, R, is repeated at both ends; unique sequences are located near the 5′ (U5) and 3′ (U3) ends. U3 contains promoter and enhancer sequences. The integrated provirus DNA is flanked at each end by the long terminal repeat (LTR) structure generated during synthesis of the DNA copy by reverse transcription. Each LTR contains U3, R, and U5 sequences. The LTRs and coding regions of the retrovirus genome are not drawn to scale.
Progeny viral genomes may then be transcribed from the provirus DNA into viral RNA. The U3 sequence in the long terminal repeat contains both a promoter and an enhancer. The enhancer may help confer tissue specificity on viral expression. The proviral DNA is transcribed by the host enzyme, RNA polymerase II. Full-length transcripts (capped, polyadenylated) serve as genomic RNA for encapsidation in progeny virions. Some transcripts are spliced, and the sub-genomic messenger RNAs (mRNAs) are translated to produce viral precursor proteins that are modified and cleaved to form the final protein products.
If the virus happens to contain a transforming gene, the oncogene plays no role in replication. This is in marked contrast to the DNA tumor viruses, in which the transforming genes are also essential viral replication genes.
Virus particles assemble and emerge from infected host cells by budding from plasma membranes. The viral protease then cleaves the Gag and Pol proteins from the precursor polyprotein, producing a mature infectious virion prepared for reverse transcription when the next cell is infected.
A salient feature of retroviruses is that they are not cytolytic; that is, they do not kill the cells in which they replicate. The exceptions are the lentiviruses, which may be cytolytic. The provirus remains integrated within the cellular DNA for the life of the cell. There is no known way to cure a cell of a chronic retrovirus infection.
