Retrotroviruses are small RNA viruses containing a single strand of RNA in their genome. HIV, the virus that causes AIDS, is a retrovirus. A simple view of the retrovirus life cycle is shown in Figure 24.45. An essential part of the retrovirus life cycle is converting the RNA genomic material back to DNA. This involves an RNA-dependent DNA polymerase called reverse transcriptase that uses an RNA as a template to make DNA. Like other RNA-dependent polymerases, reverse transcriptase is very error prone because it contains no proofreading activity. The replication scheme is as follows:
1. Viral RNA in the host cell base pairs with a specific tRNA molecule to provide a primer for DNA replication.
2. Reverse transcriptase makes DNA towards the 5' end of the viral RNA.
3. RNase H partially degrades RNA from the RNA-DNA duplex, removing the 5' terminus.
4. The 3' terminus of the viral RNA base pairs with the overhanging DNA strand, forming a circle-like structure.
5. Reverse transcriptase makes a DNA copy of the entire genome, using the 3' end of the DNA strand as a primer.
6. The RNA strand of the duplex is removed and a DNA strand complementary to the first DNA strand is synthesized to form a duplex.
7. The duplex integrates into the host chromosome.
Once inside the genome, the integrated viral DNA can persist in a noninfectious state for many years, with most of its own genes turned off. Environmental stresses, still undetermined, can trigger excision of the integrated viral genome and return the virus to an infectious state.
One of the great difficulties in devising treatments against HIV is the absence of a proofreading exonuclease in HIV reverse transcriptase. This leads to frequent replication errors and high rates of spontaneous mutagenesis, allowing the virus to generate variants that have resistance to the treatment.
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