Antiviral therapy: the viral replication cycle and drug targets
Viruses use our own cells to copy themselves. Antivirals block the few steps that belong only to the virus.
Viruses have no metabolism of their own: they enter a cell, release their genome, copy it with viral or host enzymes, build new particles and leave. Antivirals work by hitting steps that rely on virus-specific proteins, which is where selectivity comes from. Most antivirals suppress replication rather than kill the virus, so timing, the immune system and resistance strongly shape how well they work.
Steps of the viral replication cycle
- Attachment and entry: the virus binds a cell receptor and enters by fusion or endocytosis (HIV entry inhibitors, monoclonal antibodies against viral surface proteins).
- Uncoating: the genome is released from its capsid.
- Genome replication: DNA or RNA polymerases copy the genome (aciclovir, ganciclovir, foscarnet, cidofovir, sofosbuvir, remdesivir, nucleos(t)ide HIV and HBV drugs).
- Protein processing: viral proteases cut polyproteins into working parts (HIV and HCV protease inhibitors, nirmatrelvir for SARS-CoV-2).
- Assembly and packaging: genomes are packed into new particles (letermovir blocks the cytomegalovirus terminase that packs DNA).
- Release: new virions leave the cell (neuraminidase inhibitors such as oseltamivir and zanamivir stop influenza from being freed from the cell surface; tecovirimat stops orthopoxviruses from wrapping and spreading).
Where selectivity comes from
Because the virus borrows so much from the cell, a good antiviral must hit something the cell does not need. Aciclovir is the classic example: herpes simplex and varicella-zoster viruses encode a thymidine kinase that adds the first phosphate, host enzymes finish activation, and the triphosphate inhibits the viral DNA polymerase and ends the chain. Uninfected cells barely activate it. Other strategies include prodrugs that are already phosphorylated (cidofovir, sofosbuvir), drugs that bind unique viral pockets (NNRTIs, NS5A inhibitors) and drugs that trap the virus at the cell surface (neuraminidase inhibitors).
Classes by virus family
- Herpesviruses: aciclovir and valaciclovir (HSV, VZV); ganciclovir and valganciclovir (cytomegalovirus); foscarnet and cidofovir when resistance is present; letermovir for CMV prophylaxis.
- Influenza: neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) and baloxavir, which inhibits the viral cap-dependent endonuclease needed to start viral mRNA.
- Coronaviruses: remdesivir (RNA polymerase), nirmatrelvir with ritonavir (main protease), molnupiravir (induces copying errors).
- Hepatitis B and C, and HIV: see their own pages; they are the most developed examples of target-based therapy.
- Broad or host-directed: interferons boost the cell's antiviral state; ribavirin has several poorly defined actions.
Timing and the immune system
Most antivirals stop new rounds of replication; they cannot repair cells already damaged. For acute infections such as influenza or herpes zoster, the benefit is largest when treatment starts early; the oseltamivir label, for example, ties treatment and post-exposure use to the first two days. In people with weak immunity the virus replicates longer, treatment courses are longer, and resistance is more likely. Antivirals for prevention are no substitute for vaccines where vaccines exist.
Resistance
Viral resistance follows from mutation and selection. Herpesviruses resist aciclovir mainly by losing or altering thymidine kinase, which also blocks ganciclovir; foscarnet and cidofovir do not need that kinase and remain options. Changes in the viral DNA polymerase can cause broader resistance. Influenza can acquire neuraminidase changes such as H275Y, which reduce oseltamivir activity but not zanamivir. Resistance is commonest in immunocompromised patients and in long or repeated treatment.
Typical toxicities that follow from the mechanism
- Aciclovir can crystallise in kidney tubules when given rapidly intravenously or to a dehydrated person; hydration and renal dosing reduce this, and confusion or other neurotoxicity can occur, especially in older people or with poor kidney function.
- Ganciclovir and valganciclovir suppress bone marrow.
- Foscarnet and cidofovir are nephrotoxic; foscarnet also disturbs calcium, magnesium and other electrolytes.
- Neuropsychiatric events have been reported with oseltamivir, mostly in children, although influenza itself can cause them.
Test yourself
Think of the answer, then tap the question to see it.
Why does aciclovir act mostly in herpes-infected cells?
Its first phosphorylation needs the viral thymidine kinase of HSV or VZV, so it is activated mainly where the virus is present.
Which step of the influenza life cycle do oseltamivir and zanamivir block?
Release: by inhibiting neuraminidase they keep new virions stuck to the infected cell surface.
A herpes isolate lacks thymidine kinase. Which drugs are still expected to work?
Foscarnet and cidofovir, because they do not need activation by viral thymidine kinase.
Why do antivirals for acute infections work best when started early?
They block new rounds of replication rather than repair damage, so the benefit is greatest while the virus is still multiplying rapidly.
Example drugs
- Aciclovir
- Valaciclovir
- Ganciclovir
- Valganciclovir
- Foscarnet
- Cidofovir
- Letermovir
- Oseltamivir
- Zanamivir
- Baloxavir marboxil
- Remdesivir
- Nirmatrelvir + ritonavir
- Molnupiravir
- Tecovirimat
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - ACYCLOVIR injection, solution (DailyMed (U.S. National Library of Medicine), 2026); DailyMed - OSELTAMIVIR capsule (DailyMed (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.