Questions: Viral Replication Strategies: RNA vs DNA Viruses

Question 1

A newly isolated virus enters a cell and immediately begins producing viral proteins without any prior RNA synthesis step. Its genome can be directly read by host ribosomes. Which type of virus is this, and why is no prior RNA synthesis needed?

• A. A negative-sense RNA virus that pre-loaded its RdRp and immediately transcribed its genome upon entry
• B. A positive-sense RNA virus whose genome is already in the same orientation as mRNA and can be directly translated by ribosomes the moment it enters the cytoplasm
• C. A retrovirus that integrated its genome before this observation was made
• D. A DNA virus whose genome was already in the nucleus being transcribed by host RNA polymerase

Answer: (B)

The key diagnostic features are: immediate protein production, no RNA synthesis step first, and the genome directly readable by ribosomes. Only a positive-sense RNA genome satisfies all three conditions — it is chemically equivalent to mRNA and can be engaged by ribosomes immediately. Negative-sense RNA viruses (option A) must first be transcribed into positive-sense mRNA by pre-packaged RdRp before any translation can occur. Retroviruses must first reverse-transcribe and integrate before gene expression. DNA viruses require nuclear entry and transcription by RNA polymerase. The head start that positive-sense genomes provide — immediate translation without a prior synthesis step — is a significant advantage in the early stages of infection.

Question 2

Why must negative-sense RNA viruses package RdRp molecules inside their virions, while positive-sense RNA viruses do not need to do this?

• A. Negative-sense RNA is chemically unstable and requires enzymatic protection during cell entry and uncoating
• B. Negative-sense RNA cannot be read by host ribosomes — it must be transcribed into complementary positive-sense mRNA first; without pre-packaged RdRp, no viral proteins could ever be made; positive-sense RNA viruses encode RdRp as one of the first proteins ribosomes produce from the incoming genome
• C. Positive-sense RNA viruses replicate in the nucleus where host polymerases are available, while negative-sense viruses replicate in the cytoplasm where no polymerases exist
• D. Host cells degrade negative-sense RNA with antiviral RNases unless it is bound to RdRp for protection

Answer: (B)

This question targets the logic of genome polarity. A negative-sense genome is the antisense strand — host ribosomes cannot translate it. Before any viral protein can be made, the genome must be copied into positive-sense mRNA. But making that copy requires RdRp, and RdRp is a viral protein — which cannot yet exist because no viral proteins have been made. This chicken-and-egg problem is solved by packaging RdRp molecules inside the virion itself, so they are immediately available upon cell entry. Positive-sense RNA viruses bypass this entirely: the incoming genome is translated directly, and RdRp is among the first proteins produced.

Question 3

All RNA viruses must encode their own RNA-dependent RNA polymerase because host cells contain no enzyme capable of copying RNA from an RNA template.

• T. True
• F. False

Answer: True

This is a foundational constraint on RNA virus biology. The central dogma of molecular biology — DNA → RNA → protein — describes the normal information flow in cells, but cells have no need to copy RNA from an RNA template in their normal metabolism. Therefore, no host RdRp exists. Every RNA virus, regardless of whether it is positive-sense, negative-sense, double-stranded, or segmented, must either encode its own RdRp in its genome or carry pre-made RdRp molecules in the virion. This also explains why RdRp is a primary antiviral drug target — it has no host equivalent, so inhibiting it is highly selective.

Question 4

HIV achieves persistent lifelong infection by integrating into the host chromosome as a provirus; antiretroviral drugs that block reverse transcription will eliminate the integrated provirus from most infected cells.

• T. True
• F. False

Answer: False

Antiretroviral drugs block active reverse transcription — they prevent new infections of cells and prevent already-infected actively replicating cells from producing new virions. But they have no effect on cells that are already latently infected, where the provirus sits quietly in the chromosome with no active viral replication. Long-lived latently infected CD4⁺ T cells form a stable reservoir that persists indefinitely, unaffected by drugs that target viral enzymes. Any interruption of therapy allows these reservoirs to reactivate. Eliminating the proviral reservoir — not just suppressing active replication — is the central challenge in achieving a functional HIV cure.

Question 5

Explain why HIV is extremely difficult to cure despite the availability of highly effective antiretroviral therapy, based on its replication strategy.

Model answer: HIV is a retrovirus that uses reverse transcriptase to copy its RNA genome into DNA, which then integrates permanently into the host cell's chromosome as a provirus. Once integrated, the provirus is indistinguishable from normal host genomic DNA and is replicated passively every time the cell divides. Antiretroviral therapy blocks reverse transcription and viral assembly in actively replicating virus, preventing new infections and maintaining low viral load. However, it has no mechanism to act on latently infected cells where the provirus is dormant — no viral enzymes are active, no viral proteins are made, and the immune system has nothing to target. Long-lived latently infected memory T cells harbor these proviruses for decades. If treatment stops, latent proviruses reactivate and produce new virus. A cure would require either purging the latent reservoir ('shock and kill' strategies) or permanently silencing it, neither of which has been achieved reliably.

The lack of proofreading by reverse transcriptase also means HIV mutates at a very high rate during active replication, which drives rapid evolution of drug resistance and makes vaccine design extremely difficult. These two features — integration and high mutation rate — both stem directly from the retroviral replication strategy.