Resistance mutations

Drug resistance is caused by changes in the genetic material of HIV. Just as the human body is based on the genetic code in its DNA, HIV is based on the genetic code in its RNA. Random changes (mutations) in these genes cause changes in the resultant virus and some mutations lead to drug resistance.

HIV uses complex proteins, called enzymes, as a 'toolkit' with which to operate. A viral gene is actually a set of instructions for building a particular enzyme.

The gene is a long chain of RNA laid out like a string of beads, in which each 'bead' (called a codon and made up of three nucleotides) describes the amino acid that follows in the enzyme-building sequence. Each enzyme (for example, reverse transcriptase) is a specific sequence of amino acids. There are twenty different amino acids, each referred to by a single-letter code.

Just one amino acid change can alter the resulting shape of the completed enzyme. This physical and chemical property change can block an ARV drug from binding to the correct viral enzyme. Drug resistance occurs over time when an ARV can no longer bind to the virus because of its mutations.

Resistance mutations are referred to by a number which identifies the codon, that is, the position along the gene where the mutation has taken place. The number often has letters before and/or after it; e.g., M184V. The first letter refers to the amino acid found in non-mutated or 'wild-type' HIV. The second letter refers to the new amino acid that is inserted by the mutant HIV. The first letter is sometimes omitted (e.g. 41L).

M184V is a mutation in the reverse transcriptase (RT) gene that causes resistance to 3TC (lamivudine, Epivir). It is caused by a mutation at codon number 184 in the RT gene. This mutation means that an amino acid called methionine (M) is replaced by valine (V) in the RT enzyme. Virus with the M184 mutation is able to replicate despite the presence of 3TC.