The human immunodeficiency virus (HIV) can contain dozens of different mutations, called polymorphisms. In a recent study an international team of researchers, including University of Missouri scientists, found that one of those mutations, called 172K, made certain forms of the virus more susceptible to treatment. Soon, doctors will be able to use this knowledge to improve the drug regimen they prescribe to HIV-infected individuals.
“The 172K polymorphism makes certain forms of HIV less resistant to drugs,” said Stefan Sarafianos, corresponding author of the study and researcher at MU’s Bond Life Sciences Center. “172K doesn’t affect the virus’ normal activities. In some varieties of HIV that have developed resistance to drugs, when the 172K mutation is present, resistance to two classes of anti-HIV drugs is suppressed. We estimate up to 3 percent of HIV strains carry the 172K polymorphism.”
HIV is a retrovirus, meaning it uses an enzyme called reverse transcriptase to create copies of its own genetic code. These copies are inserted into the victim’s own genes, where the virus highjacks the host’s cellular machinery in order to reproduce itself. Two classes of drugs, nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), can stop this process in its tracks.
However, some HIV strains have developed resistance to NRTIs and NNRTIs. The 172K polymorphism suppresses this resistance and allows both classes of drugs to fight HIV more efficiently. The mutation is believed to be the first of its kind that blocks resistance to two families of drugs.
“Clinical doctors use a database of HIV mutations and the drugs they are susceptible to when they prescribe treatments to an HIV-infected patient,” Sarafianos said. “Our finding will be integrated into this database. Once that happens, when doctors learn that their patients have HIV strains that carry the 172K polymorphism, they will know that the infections can be fought better with NRTIs and NNRTIs.”
HIV drug resistance
The ability of HIV to mutate and reproduce itself in the presence of antiretroviral drugs is called HIV drug resistance. The consequences of drug resistance include treatment failure, increased direct and indirect health costs associated with the need to start more costly second-line treatment for patients, the spread of resistant strains of HIV and the need to develop new anti-HIV drugs. The extent of HIV drug resistance resulting from recent ART scale up in resource-limited countries has not systematically been quantified due to the lack of reliable data and information.
WHO and its HIV ResNet group of experts and organizations have developed a Global strategy for prevention and assessment of HIV drug resistance. The strategy aims to build evidence on the scale of HIV drug resistance and equip and prepare countries with knowledge, skills and systems to respond should drug-resistant HIV epidemics emerge.
One of Sarafianos’ colleagues at the AIDS Clinical Center in Japan found the 172K polymorphism by accident. The mutation was first discovered in a patient, and the researchers were able to recreate it in the laboratory.
The study “HIV-1 Reverse Transcriptase Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Nonnucleoside RT Inhibitors,” was published in the Journal of Biological Chemistry. The lead author was Atsuko Hachiya of the AIDS Clinical Center at Japan’s National Center for Global Health and Medicine in Tokyo. Stefan Sarafianos is an associate professor of molecular microbiology and immunology in the MU School of Medicine and an associate professor of biochemistry in the MU College of Arts and Science. Sarafianos also is associated with the Bond Life Sciences Center.
How Does Resistance Affect Your Treatment Options?
Some HIV mutations, as we’ve mentioned, are more dangerous than others. Some will cause resistance to just one drug. But other HIV mutations can cause resistance to two or more drugs - or even to an entire class of drugs.
This is especially true for older NNRTIs. Just one specific type of mutation will make HIV resistant to the NNRTIs Sustiva and Viramune. This is called “cross-resistance” because the drug resistance “crosses over” from one drug to another, in the same way a bug that’s immune to one bug spray might also be immune to other bug sprays.
Sometimes, though, it takes more than one mutation for HIV to become resistant to a drug. This is true for several HIV meds, particularly most of the protease inhibitors and the new second-generation NNRTI Intelence.
Resistance to a drug does not automatically mean you can no longer use it. There are different degrees of resistance. Sometimes the medication will still work, just not as well as it used to. How will you know if it’s still worth taking a drug that your HIV has become resistant to? There are many factors for you and your doctor to consider, including which HIV medications you’ve taken in the past, which specific medications your HIV is resistant to, your current CD4 count and viral load, and which medications you haven’t tried yet.