The widespread availability of antiretroviral therapy has made the fight against HIV a great deal easier. But these medications can’t go the distance alone. Working closely with your doctor, you’ll need to choose and monitor your treatment carefully. This is because of obstacles that can arise before and during treatment—one of the most important is HIV drug resistance. Fortunately, we now know a lot about how to reduce the risk of drug resistance and treat drug-resistant virus. We also have access to important technologies that look for drug-resistant virus and help us make important treatment decisions. These drug-resistance tests have become a routine part of HIV care. In simple terms, drug resistance refers to the ability of disease-causing germs—such as bacteria and viruses—to continue multiplying despite the presence of drugs that usually kill them. With HIV, drug resistance is caused by changes (mutations) in the virus’s genetic structure. These mutations can lead to changes in certain proteins, most commonly enzymes, which help HIV reproduce (replicate). Mutations are very common in HIV. This is because HIV replicates at an extremely rapid rate and does not contain the proteins needed to correct the mistakes it makes during copying. Mutations occur randomly, on a daily basis, but many are harmless. In fact, most mutations actually put HIV at a disadvantage—they reduce the virus’s “fitness” and slow its ability to infect CD4 cells in the body. However, a number of mutations can actually give HIV a survival advantage when HIV medications are used, because these mutations can block drugs from working against the HIV enzymes they are designed to target. These are the mutations we are concerned about when we talk about drug resistance. HIV relies on many enzymes to replicate inside a human cell. It also relies on proteins, including gp41, to latch on to CD4 cells and infect them. Mutations can occur in any of these parts of the virus and cause drug resistance.