The Reproductive Cycle of a Retrovirus—HIV
There are many variations on the basic scheme of the virus life cycles described in the last two slides. As one example, we will choose HIV (human immunodeficiency virus), the virus that causes AIDS. HIV has a complicated life cycle that, while following the basic pattern, has some interesting and unique features. HIV is an enveloped RNA virus. It is a member of the retrovirus family. All members of this family contain RNA genomes that are converted into double-stranded DNA before new viruses can be made. These viruses have a “reversed” flow of genetic information and must convert RNA to DNA (hence the name retro) to reproduce. This process, is in contrast to the central dogma of molecular biology that states that information is passed from DNA, to RNA, to protein. Because cells do not have an enzyme that will generate new DNA from the existing virus RNA, retroviruses carry their own enzyme, called reverse transcriptase (shown in green), that makes double-stranded DNA copies from the information encoded in the RNA genome.
As with all viruses, HIV must first enter a cell before it can begin to reproduce. The HIV envelope glycoproteins bind to a specific receptor, called a CD4 molecule, found on the surface of white blood cells, usually T cells. The viral envelope fuses with the plasma membrane of the cell, and the capsid, containing two copies of viral RNA and two copies of the reverse transcriptase enzyme, enters the cell. The capsid proteins are removed (in a step called uncoating) and the reverse transcriptase begins the process of making a double-stranded DNA copy of the viral genome. The double-stranded viral DNA then travels from the cytoplasm into the nucleus of the cell, where it becomes integrated into the host cell DNA with the help of a viral protein called integrase. Viral DNA incorporated into the cellular DNA is called a provirus, analogous to the prophage of a lysogenic bacteriophage. In this state, it can be duplicated along with cellular DNA. Proviral genes are transcribed into RNA using the host cell transcription machinery. The RNA is then exported from the nucleus to the cytoplasm, where it serves as messenger RNA for the translation of viral proteins. The RNA molecules also function as genomes for the new viruses that are produced. The viral proteins and RNA assemble into viral particles and bud from the cell, acquiring an envelope in the process. The particles become mature, infectious viruses after undergoing an additional step involving a virus protein, referred to as protease, that cuts the long pieces of newly made virus proteins into smaller functional units.
Because the reproductive cycle of HIV relies on several virus proteins to produce new infectious viruses, steps requiring these proteins have been targeted in the design of drugs that interfere with virus replication. Current anti-HIV drugs block the entry, reverse transcription (AZT is one example of a drug that blocks this step), and protease steps. Research on drugs to block other parts of the HIV reproductive cycle is ongoing.
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This work was supported by National Space Biomedical Research Institute through NASA cooperative agreement NCC 9-58.