What Exactly Is a Mutation? And What Are All Those Numbers About?
Part of A Guide to HIV Drug Resistance
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 such as Atripla, Sustiva and Viramune. 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 In that particular spot, the amino acid K (which stands for lysine) has been replaced by the amino acid N (which stands for asparagine), which makes that particular copy of HIV into a mutation.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 many of the 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.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Researchers have identified 34 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 Epivir and Emtriva, but it will also make HIV more vulnerable to Retrovir and Viread. 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 19 or so mutations that make HIV resistant to one or more NNRTIs. A single mutation, K103N, will make you highly resistant to Sustiva and Viramune. 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 40 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.
Resistance to the only approved drug in this class, Fuzeon, is still being studied. Ten mutations are known to cause resistance to Fuzeon, but they do not affect sensitivity to other medications in other classes. There is also a special genotypic resistance test that can detect Fuzeon resistance. It looks for mutations in a different part of HIV RNA.
These drugs block the entry of HIV into human DNA, the irreversible step of HIV infection. Resistance to integrase inhibitors seems to be somewhat similar to that of protease inhibitors, where one of three recognized changes gives significant resistance, and then additional mutations give high-level resistance. One inhibitor, Isentress, is available now, but at least two others are under development, one of which is expected to work if Isentress resistance has developed.
Most HIV strains use the CXCR4 co-receptor and the CCR5 co-receptor to enter a CD4 cell. Selzentry (the only approved CCR5 inhibitor) works by preventing HIV from using the CCR5 co-receptor to enter CD4 cells. Resistance to Selzentry can sometimes occur if the virus learns to use the CCR5 co-receptor despite the presence of Selzentry. However, more often, CCR5 inhibitors fail if an HIV strain appears that can enter the CD4 cell using the CXCR4 co-receptor instead of the CCR5 co-receptor (this HIV strain is known as X4-tropic or dual-tropic). You must take a special test called a tropism test before you can use Selzentry. You should also take this test if Selzentry stops working for you in order to determine whether your strain of HIV has changed.