What Exactly Is a Mutation? And What Are All Those Numbers About?

Part of A Guide to HIV Drug Resistance

December 2006

• Meet the Mutations: A Class-by-Class Breakdown

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To make it easier to work with HIV resistance tests, researchers have a shorthand system for naming HIV mutations.

An HIV "mutation" is actually just a slight change in a specific section of HIV's RNA, the genetic code that provides all the instructions for how HIV works. Mutations occur naturally, not just in HIV, but in other viruses as well -- not to mention within the cells of every other living thing, humans included. Every HIV mutation is given a unique name to help researchers identify it.

Let's look at K103N, the most common mutation found in people who are taking medications in the NNRTI class. The number in the middle is called a "codon" -- it identifies the specific position within HIV's RNA where the mutation is located. The first letter stands for the amino acid that is normally found at that position (in wild-type HIV); the last letter stands for the amino acid that's there instead (which is the mutation).



So, in the case of K103N, we have a mutation at codon 103 in HIV's reverse transcriptase gene. In that particular spot, the amino acid K (which stands for lysine) has been replaced by the amino acid N (which stands for asparagine), which makes that particular copy of HIV into a mutation. It just so happens that this particular mutation, K103N, is one of the worst mutations to have, since it makes HIV highly resistant to all approved drugs in the NNRTI class. Not all mutations, of course, are so dangerous. Most mutations will have no impact at all on how well your medications work.

Meet the Mutations: A Class-by-Class Breakdown

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Researchers have identified 20 or so mutations that make HIV resistant to one or more NRTIs. The effects of these mutations can be complicated. The M184V mutation, for example, will make HIV resistant to 3TC (Epivir) and FTC (Emtriva), but it will also make HIV more vulnerable to AZT, d4T (Zerit) and tenofovir. This is why it's important to have detailed knowledge of how mutations impact your treatment regimen.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Researchers have identified 14 or so mutations that make HIV resistant to one or more NNRTIs. A single mutation, K103N, will make you highly resistant to all three NNRTIs: efavirenz, nevirapine and delavirdine (Rescriptor). Even if you don't have the K103N mutation, a combination of other mutations can also make your HIV resistant to NNRTIs.

Protease Inhibitors (PIs)

Researchers have identified around 60 mutations associated with PIs. The good news? Most of these mutations contribute to resistance, but only in small ways. Although a single mutation can cause resistance to one PI, no single mutation has yet occurred that causes resistance to all PIs. The bad news? These small mutations can add up: It takes only three specific mutations to make HIV resistant to most PIs. To avoid this, researchers are examining ways to closely monitor the concentration of PIs in your body. If the concentration seems to be a little on the low side, a doctor would "boost" the PI up to a higher level. This would not only reduce the number of mutations occurring, but, of course, would reduce the amount of HIV in your body as well.

Fusion Inhibitors

This is the newest class of medications. Resistance to the only approved drug in this class, T-20 (Fuzeon), is still being studied. Ten mutations are known to cause resistance to T-20, but they do not affect sensitivity to other medications in other classes. There is also a special genotypic resistance test that can detect T-20 resistance. It looks for mutations in a different part of HIV RNA.