Questions: DNA Virus Replication Strategies and Polymerases

Question 1

Acyclovir selectively kills herpesvirus-infected cells rather than healthy host cells. What best explains this selectivity?

• A. Acyclovir inhibits only cytoplasmic DNA synthesis, and herpesviruses replicate in the cytoplasm
• B. Acyclovir is first phosphorylated by a virus-encoded thymidine kinase, then selectively inhibits viral DNA polymerase over host polymerase
• C. Acyclovir prevents viral attachment, blocking entry before replication begins
• D. Host cells actively export acyclovir before it can reach the nucleus

Answer: (B)

The two-step selectivity is the key insight. First, herpesvirus encodes its own thymidine kinase that phosphorylates acyclovir far more efficiently than the host enzyme does — so the active form accumulates specifically in infected cells. Second, the resulting acyclovir triphosphate preferentially inhibits the herpesvirus DNA polymerase over host DNA polymerases. Without viral thymidine kinase, acyclovir is barely activated, which is why drug-resistant herpesvirus strains often carry thymidine kinase mutations.

Question 2

Small DNA viruses like papillomaviruses encode oncoproteins that push host cells into S phase. What is the direct replication reason they need to do this?

• A. S phase provides the nuclear membrane-free environment needed for viral DNA to enter the nucleus
• B. Host DNA polymerase is only active during S phase, and these viruses rely on it to replicate their genomes
• C. S phase suppresses the innate immune response, allowing viral replication to proceed undetected
• D. Viral capsid proteins are only produced during S phase due to cell-cycle-dependent promoters

Answer: (B)

Small DNA viruses carry compact genomes and depend on the host's replication machinery rather than encoding their own polymerases. The problem is that host DNA polymerase is tightly regulated — it is only highly active during S phase when the cell is replicating its own genome. These viruses therefore evolved oncoproteins (like HPV E6 and E7) that degrade tumor suppressors and drive cell cycle entry. This obligate link between viral replication and cell proliferation is a key reason why persistent papillomavirus infection can lead to cancer.

Question 3

DNA viruses that encode their own DNA polymerase and replicate in the cytoplasm are completely independent of the host cell cycle.

• T. True
• F. False

Answer: True

Poxviruses, the prime example, carry a full replication toolkit — their own DNA polymerase, primase, and other enzymes — so they never need to access host nuclear machinery. This allows them to replicate in cytoplasmic compartments called viral factories at any point in the cell cycle. By contrast, viruses relying on host polymerase must wait for or induce S phase. The independence comes at a cost: encoding all this machinery requires a large genome, which is why poxviruses are among the largest animal viruses.

Question 4

High mutation rates in viral DNA polymerases are harmful to viruses because they destroy genetic information faster than beneficial mutations can arise.

• T. True
• F. False

Answer: False

While most mutations are individually deleterious, viruses produce enormous numbers of progeny, meaning that advantageous mutations — enabling immune evasion, drug resistance, or expanded host range — arise constantly and are rapidly selected for. This is the basis of antigenic drift: gradual accumulation of surface protein changes that lets persistent viruses like herpesviruses evade immune surveillance over years of chronic infection. From the virus's population perspective, high mutation rate is not a liability but a source of evolutionary agility. Antiviral drug resistance emerging during treatment in a single patient illustrates this exactly.

Question 5

Why does a DNA virus that carries its own DNA polymerase have more independence than one relying on host polymerase, and what are the tradeoffs of each strategy?

Model answer: A virus with its own polymerase can replicate regardless of the host cell cycle phase and — if the polymerase works in the cytoplasm — without needing the nucleus at all. This grants independence from host cell-cycle regulation. The tradeoff is genome size: encoding a polymerase plus accessory enzymes requires many more genes, leading to larger virions and more complex replication. Viruses relying on host polymerase keep genomes compact but must wait for or manipulate S phase, often by encoding oncoproteins — which can cause cancer as a side effect.

The strategic divide shapes the entire biology of each virus type. Small viruses (compact genome, host-dependent) exploit existing host infrastructure but lose control over timing and become entangled with cell-cycle regulation. Large viruses (own polymerase, independent) gain replicative autonomy but invest heavily in encoding and packaging their machinery. This tradeoff appears repeatedly in biology: specialization versus generalization, dependence versus independence. Understanding which side a virus falls on predicts its replication site, cell-cycle sensitivity, antiviral drug targets, and evolutionary flexibility.