Virus Replication
Replication depends on replication of the viral genome as well as the production of viral proteins which are assembled into progeny virions.
- DNA viruses will go to the nucleus (except poxviruses) where they use the cellular RNA polymerase to produce mRNA. Their genome is replicated by either host or viral DNA polymerase.
- RNA of positive strand RNA viruses is a mRNA (that is infectious) that can be translated. The RNA of positive strand RNA viruses is an mRNA (except retroviruses). Their genome is replicated by a viral RNA dependent RNA polymerase (transcriptase) in the cytoplasm.
- Negative strand RNA viruses carry in a virion transcriptase (RNA-dependent RNA polymerase) to produce a positive complementary mRNA as well as to replicate their genome in the cytoplasm.
- Retroviruses convert their RNA to DNA by a virion reverse transcriptase. DNA integrates into the host nuclear DNA followed by production of mRNA by the host RNA polymerase. Such viral reverse transcriptase that produces DNA from the viral RNA cannot correct nucleotide misincorporation errors. As a result, retroviruses acquire on average one point mutation every replication cycle. A typical untreated HIV infection may eventually involve HIV genomes with every possible point mutation. This explains why the virus can switch from infecting macrophages to infecting T cells and can quickly acquire resistance to drugs. The error rate, however, is not so high as to accumulate so rapidly that the virus can not survive. (rapid viral diversification in one host does not necessarily lead to rapid evolution of the virus in the population as a mutated virus may not be able to infect a new host). DNA integrates into the host DNA followed by production of mRNA by the host RNA polymerase.
Steps of Virus Replication
1) Entry and Uncoating: specific proteins of the virion display attachment proteins. The host cell may display surface cellular receptors composed of glycoproteins or polysaccharides. Viral attachment proteins (VAPs) that bind to erythrocytes are termed hemagglutinins.
Adsorption is mediated by high affinity interaction between the viral attachment proteins and receptors.
Viruses that infect animal cells typically use cell surface receptor molecules on the host cell that are either very abundant (such as sialic-acid containing oligosaccharides in the case of influenza) or those which are uniquely found on those types in which the virus can replicate.
Often a single type of receptor is used by many types of viruses and some viruses can use several different receptors. Different viruses that infect the same cell type may even use a different receptor. For example, hepatitis which is caused by at least 6 viruses all preferentially replicate in liver cells. Receptors for 4 of the hepatitis viruses are all different. Receptors do not need to be proteins, the herpes simplex virus, for example, binds to heparan sulfate proteoglycans through specific viral membrane proteins. Frequently, viruses require both a primary receptor and a secondary co-receptor for effective attachment and entry into host cells as is the case with HIV.
Viruses that bind to receptors expressed on specific cell types may be restricted to certain species (host range) like human or mouse or specific cell types. The susceptible target cell defines the tissue tropism (e.g., neurotropic, lymphtropic). Chemokine receptors are often used such as the B-chemokine receptor (CCR5) and alpha-chemokine receptor (CXCR4) which are used by HIV.
Most nonenveloped viruses enter the cell by receptor-mediated endocytosis or by viropexis (direct penetration of the membrane). Endocytosis is a normal process used by the cell for uptake of receptor-bound molecules such as hormones and low density lipoproteins.
Enveloped virus enter the host cell by fusing either with the plasma membrane (e.g., HIV) or with the endosomal membrane following endocytosis (e.g., influenza virus).. Fusion is thought to be similar to a SNARE mediated fusion of vesicles.
Once into the cell, DNA viruses go to the nucleus (except for poxviruses). RNA viruses remain in the cytoplasm (except for retroviruses).
2) Production of early mRNA and non-structural proteins
3) Production of viral genome
4) production of late mRNA and structural proteins
5) assembly and release: The site and mechanism of virion assembly in the cell depends on the location of genome replication and whether the final structure is a naked capsid or enveloped virus. The assembly process begins when the necessary pieces are synthesized and the concentration of structural proteins in the cell is sufficient to thermodynamically drive the process, much like a crystallization reaction.
- cubical viruses: first a pro-capsid forms and then nucleic acid is spooled into the capsid (bacteriophages use this mechanism of assembly).
- retrovirus structural proteins accumulate at the virus glycoprotein saturated cell membrane and form the virion during "budding".
- release of new virus by budding or exocytosis: Here, the nucleocapsid takes up a coat of the cell membrane while exiting the cell. This occurs with enveloped viruses. For example, the herpes simplex virus nucleocapsid assembles in the nucleus and buds at the nuclear membrane.
- naked capsid viruses are generally released after lysis of the cell.
