Antiviral Resistance in Influenza and HIV

Antiviral resistance in influenza and HIV is the loss of susceptibility of these viruses to the drugs that target them. Both viruses replicate rapidly and with low fidelity, generating diverse populations from which drug pressure selects resistant variants - in influenza, mutations in the neuraminidase or polymerase targets, and in HIV, mutations across reverse transcriptase, protease, and integrase. They are the two classic teaching examples of antiviral resistance.

Definition

Antiviral resistance in influenza and HIV refers to genetically encoded reductions in viral susceptibility to antiviral or antiretroviral drugs, arising as resistance mutations in the drug's target protein are selected under drug pressure.

Scope

This topic uses influenza and HIV to illustrate how antiviral resistance arises, is detected, and is managed conceptually at a population level. It covers the targets of the major drug classes, the mutations that confer resistance, and the distinction between transmitted and acquired resistance. It is a microbiology and antimicrobial-resistance reference, not a guide to selecting antiviral therapy.

Core questions

• Why do error-prone replication and large population sizes make influenza and HIV prone to resistance?
• Which drug targets and mutations underlie resistance in each virus?
• What is the difference between transmitted (primary) and acquired (secondary) drug resistance?

Key concepts

• Viral quasispecies and mutation under selection
• Neuraminidase inhibitor resistance (e.g. H275Y)
• Adamantane resistance (M2 ion channel)
• Reverse-transcriptase, protease, and integrase inhibitor resistance
• Transmitted versus acquired drug resistance
• Genotypic resistance testing
• Combination therapy and the genetic barrier to resistance
• Treatment adherence and resistance selection

Mechanisms

Influenza and HIV both replicate with low fidelity and produce enormous numbers of progeny, so pre-existing and newly arising variants are abundant; antiviral drugs then select those carrying resistance mutations. In influenza, neuraminidase-inhibitor resistance arises from neuraminidase substitutions such as H275Y in the N1 subtype, while older adamantanes are limited by widespread M2 ion-channel resistance (Moscona 2005; De Clercq 2016). In HIV, resistance mutations accumulate in the reverse transcriptase, protease, and integrase targets of the respective drug classes; combination antiretroviral therapy raises the genetic barrier to resistance by requiring multiple simultaneous mutations, which is why multidrug regimens and good adherence are central to durable suppression (Arts 2012; De Clercq 2016).

Clinical relevance

Resistance shapes how influenza antivirals are stockpiled and how antiretroviral regimens are designed and monitored at a population level, including the role of resistance testing in surveillance (De Clercq 2016; Arts 2012). This entry explains the principles and mechanisms for reference and education; it does not provide regimen selection, dosing, or individualised treatment recommendations, which depend on current clinical guidelines and resistance testing.

Epidemiology

Influenza antiviral resistance has appeared in waves, including a season of widespread oseltamivir resistance in seasonal H1N1 before 2009, prompting ongoing global surveillance of neuraminidase-inhibitor susceptibility (Moscona 2005; De Clercq 2016). In HIV, both transmitted and acquired drug resistance are monitored worldwide because they affect the durability of first-line antiretroviral therapy and the choice of population-level regimens (Arts 2012).

History

Resistance was recognised for each successive antiviral class as it came into use - the adamantanes, then the neuraminidase inhibitors in influenza, and the reverse-transcriptase, protease, and integrase inhibitors in HIV. The shift from single-agent to combination antiretroviral therapy in the 1990s was driven in large part by the need to raise the genetic barrier against HIV drug resistance (Arts 2012; De Clercq 2016).

Key figures

• Anne Moscona
• Erik De Clercq
• Eric J. Arts
• Daria J. Hazuda

Seminal works

• moscona-2005
• declercq-2016
• arts-hazuda-2012

Frequently asked questions

Why are influenza and HIV especially prone to antiviral resistance?

Both viruses replicate quickly and copy their genomes with many errors, producing large, genetically diverse populations. When an antiviral drug is present, variants that happen to carry resistance mutations are selected and can come to dominate.

Why is HIV treated with combinations of drugs?

Combination antiretroviral therapy targets several viral proteins at once, so the virus would need multiple simultaneous mutations to escape. This higher genetic barrier, together with good adherence, makes durable viral suppression possible; specific regimen choices are a matter for clinical guidelines, not this reference entry.