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How Viruses Enter Cells, Replicate, and Evade Immunity

1Viral Architecture and the Logic of the Life Cycle2Attachment and Entry: Crossing the Membrane3Genome Replication and Gene Expression4Assembly, Egress, and Transmission5Innate Immune Detection of Viral Infection6Adaptive Immunity: Antiviral Antibodies and T Cells7Immune Evasion Strategies8From Mechanism to Intervention: Antivirals and Vaccines
Genome Replication and Gene Expression

From RNA Genome to Protein: Positive-Sense Versus Negative-Sense

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Start with the positive-sense genome. Because it matches the sense of mRNA, the host ribosome can bind it immediately and start making protein. The first proteins include the viral RNA-dependent RNA polymerase, which then copies the genome into a negative-sense template and back into many new positive-sense genomes. Now watch the negative-sense genome. The ribosome cannot read it, so the virion must carry its own polymerase. That packaged enzyme transcribes the genome into positive-sense mRNAs, which are translated, and some of those proteins build new polymerases that copy the genome for packaging. The same principle applies to double-stranded RNA: the virion carries the polymerase, which transcribes the double-stranded genome into mRNA inside the capsid. Notice the rule: the sense of the genome decides whether the virus must bring its own polymerase.
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A positive-sense RNA genome is, by definition, the same sense as mRNA. When it enters the cytosol, host ribosomes bind it directly and translate it into protein. The first proteins made are usually the components of the viral RNA-dependent RNA polymerase (RdRp), the enzyme that copies RNA into RNA. Once assembled, that polymerase makes a negative-sense complementary strand, which serves as a template for synthesizing many new positive-sense genomes. The new positive-sense genomes can then be translated again or packaged into progeny virions.

A negative-sense RNA genome is the opposite sense of mRNA, so host ribosomes cannot read it. The virion must therefore carry its own RdRp, because the cell has no enzyme that can copy RNA into RNA. After entry, the packaged polymerase transcribes the negative-sense genome into positive-sense mRNAs, which are translated into viral proteins. Some of those proteins include new polymerase subunits, which then copy the negative-sense genome into more negative-sense genomes for packaging. Double-stranded RNA viruses follow a similar logic: the virion carries an RdRp that transcribes the double-stranded genome into positive-sense mRNAs inside the capsid, and those mRNAs are translated and also serve as templates for making new double-stranded genomes. In all three cases, the key rule is that the sense of the genome determines whether the incoming virion must bring its own polymerase.

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