16.5: Retrovirus Life Cycles
Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the retrovirus to replicate. New retroviral RNA is transported to the cytoplasm, where it is translated into proteins that assemble new retroviruses.
Antiretroviral Drugs Target Different Stages of the HIV Life Cycle
Particular drugs have been developed to fight retroviral infections. These drugs target specific aspects of the life cycle. One class of antiretroviral drugs, fusion inhibitors, prevents the entry of the retrovirus into the host cell by inhibiting the fusion of the retrovirus with the host cell membrane. Another class of antiretrovirals, reverse transcriptase inhibitors, inhibits the reverse transcriptase enzymes that make DNA copies of the retroviral RNA genome. Reverse transcriptase inhibitors are competitive inhibitors; during the process of reverse transcription, the drug molecules are incorporated into the growing DNA strand instead of the usual DNA bases. Once incorporated, the drug molecules block further progress by the reverse transcriptase enzyme. The third class of drugs, integrase inhibitors, prevents the integrase enzymes from integrating the retroviral genome into the host genome. Finally, protease inhibitors interfere with the enzymatic reactions that are necessary for producing fully functioning retroviral particles.
Combinations (or “cocktails”) of antiretrovirals are used to fight Human Immunodeficiency Virus (HIV). If left untreated, this retrovirus causes AIDS. Cocktails of antiretrovirals are necessary to fight HIV infections because the retrovirus can quickly evolve resistance to any one drug. This capacity for rapid evolution stems from the single-stranded RNA genome of HIV, which accumulates mutations more rapidly than DNA or double-stranded genomes. Some of these mutations confer drug-resistance.
However, by combining drugs that target events at the beginning, middle, and end of the retroviral life cycle, antiretroviral cocktails (called highly active antiretroviral therapy, or HAART) dramatically reduce the HIV population in a patient. The likelihood of multiple mutations that confer resistance to various drugs in the HIV genome is much lower than that of a single resistant mutation, making the HAART strategy much more effective than single-drug therapies. This cocktail strategy has been enormously successful in treating HIV, such that it is now uncommon for treated individuals to develop AIDS.