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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

Reverse Transcription and Integration: The DNA Intermediate

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Watch the RNA genome being copied by reverse transcriptase. The enzyme first makes a DNA strand complementary to the RNA, then degrades the RNA with its RNase H activity, and finally synthesizes the second DNA strand. The product is a double-stranded DNA copy of the viral genome. That DNA moves into the nucleus, where integrase inserts it into a host chromosome. Once integrated, it is called a provirus. The provirus is now part of the host DNA: it is copied every time the cell divides and transcribed by the host's own RNA polymerase into viral mRNAs and new genomic RNA. This is why retroviral infections persist for life. The integrated provirus is a permanent reservoir that cannot be cleared just by eliminating free virus particles.
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Retroviruses and other reverse-transcribing viruses carry an RNA genome, but they do not use it directly as mRNA. Instead, the virion packages an enzyme called reverse transcriptase, which copies the RNA genome into a complementary DNA (cDNA) strand. Reverse transcriptase has three activities: it acts as an RNA-dependent DNA polymerase to make the first DNA strand, as an RNase H to degrade the original RNA strand, and as a DNA-dependent DNA polymerase to make the second DNA strand. The result is a double-stranded DNA copy of the viral genome.

That DNA copy is then transported into the nucleus, where another viral enzyme, integrase, inserts it into a host chromosome. Once integrated, the viral DNA is called a provirus. The provirus is replicated along with the host DNA every time the cell divides, and it is transcribed by host RNA polymerase II into viral mRNAs and new genomic RNA. This strategy explains why retroviral infections can persist for the lifetime of the host: the viral genome becomes a permanent part of the host's genetic material. Integration also means that the virus cannot be cleared simply by eliminating free virions; the provirus remains as a reservoir.

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