Replication Strategies

In 1971, David Baltimore divided viruses into seven groups based on genetic material, polarity, and mRNA synthesis.1 Insight into the replication strategy of a virus can be gained by understanding how other well-studied viruses in the same group replicate. The following is a brief description of the seven groups; included where possible, are examples of viruses belonging to each

FIGURE 4.1 Schematic illustrating the replication strategies and means of gene expression for the various Baltimore classes. Reprinted with permission from Ref. (56). (See color insert.)

given group. Note that in the following sections nucleic acid genomes will be discussed in terms of strand polarity, where positive, (+), strand nucleic acid has a polarity identical to mRNA and negative, (-), strand nucleic acid is complementary to mRNA. In cases of (-) strand polarity, the virus must synthesize a complementary (+) strand for gene expression to occur. A simplified schematic is presented in Figure 4.1.

Double-stranded DNA viruses (Class I): Viruses of this class have double-stranded DNA genomes and are subdivided into two groups. The first contains viruses that require replication to take place in the nucleus; the second class contains viruses that replicate in the cytoplasm. Variola major, the cause of smallpox, is an example of an enveloped double-stranded DNA virus that replicates in the cytoplasm; its linear DNA genome is directly transcribed to mRNA, which is then translated by host machinery to produce viral proteins. In contrast, genome replication of herpesviruses occurs in the nucleus.

Single-stranded DNA viruses (Class II): These viruses have single-stranded DNA genomes. Host proteins transcribe mRNAs from the viral genome, which are subsequently translated to viral proteins.

Double-stranded RNA viruses (Class III): Viruses in this class contain double-stranded, segmented RNA genomes. mRNA is synthesized by a virally encoded RNA-dependent RNA polymerase (RdRp) that is, like the RNA genome, contained within the capsid. Most eukaryotic cells do not encode RdRps, so in order for the virus to replicate itself, it must provide this enzyme for RNA replication. The common etiologic agent causing severe infectious diarrhea in children, rotavirus, has a double-stranded, segmented RNA genome.

Positive-strand RNA viruses (Class IV): These viruses have single-stranded (+)-strand RNA that is directly translated by the host cell to produce viral proteins. The (+)-strand genomic RNA from these viruses can be infectious, in contrast to (—)-strand RNA, which cannot. To generate multiple copies of the genome, these viruses synthesize (-)-strand complementary RNA species that are subsequently transcribed by viral RdRps, to produce more (+) strands. Examples of viruses in this class include poliovirus, West Nile virus, the SARS coronavirus, and hepatitis A virus.

Negative-strand RNA viruses (Class V): In contrast to class IV, viruses of this group contain negative polarity single-stranded RNA molecules as their genome. These viruses are all enveloped and can have genomes that are either segmented or continuous. Some members have ambisense genomes with portions of the genome acting as (+) strands and other portions of the genome having (—) polarity. All members of this class, such as influenza virus, hantavirus, and Ebola virus package both genome RNA and an RdRp into their virion.

Retroviruses (Class VI): This unique class of viruses uses a totally novel scheme for replication and expression. These viruses have two identical copies of single-stranded (+)-polarity RNA molecules as their genome. These RNA molecules are reverse transcribed by the enzyme reverse transcriptase (RT), generating complementary DNA molecules from their RNA templates. Members of this class are called retroviruses, reflecting the fact that their replicative cycle is retrograde (RNA^DNA^mRNA^protein) relative to the central dogma of modern biology, in which the DNA is transcribed to mRNA, which is then translated to protein (DNA^mRNA^protein). A very important virus in this class is the human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS).

Hepadnaviruses (Class VII): Members of this group have partially double-stranded DNA molecules as their genome. These viruses replicate via an RNA intermediate, similar to the retroviruses. RNA is packaged into immature particles where reverse transcriptase uses the RNA template to generate the DNA genome. An example is hepatitis B virus, an important human pathogen that can cause chronic infection and consequent liver damage.

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