Why are some HIV patients resistant to drug therapy?
Why are some HIV patients resistant to drug therapy?
Clinicians now see ample evidence that some HIV patients have developed resistance to one or more antiretroviral medications. But why does this happen? Researchers in Tennessee have identified an answer that may shed light on how drug companies can create more effective medications.
"We’ve identified in T-cells a gene that can transport the monophosphorylated form of AZT out of the cell," says John Schuetz, PhD, principal investigator of a study published in the September issue of Nature Medicine. Schuetz is an associate member of St. Jude Children’s Research Hospital in Memphis, TN.
"Once AZT gets into a cell, in order for it to be retained and then inhibit viral replication, it needs to have a series of phosphate groups added onto it," Schuetz explains. "There are three phosphate groups added on, and that results in inhibition of the virus."
Schuetz and his colleagues’ research shows that AZT-resistant cells will transport the AZT out of the cell as soon as the first phosphate is added because this feature is recognized by the transporter. The conduit for this revolving door action is a cellular gene called MRP4.
"What MRP4 does is circumvent effective therapy before it’s even begun, because you are decreasing the amount of that drug in the cell," Schuetz says.
Researchers have preliminary data suggesting there is a variation among individuals in the amount of MRP4 in their lymphocytes and how effectively it gets rid of the AZT phosphates.
A future study will investigate whether there is a relationship between patients who have high levels of MRP4 and low levels of AZT mono-phosphates or patients who have low levels of MRP4 and high levels of AZT monophosphates. Then it will compare all of these groups by their viral loads, Schuetz says.
If research shows a significant relationship between MRP4 levels and AZT monophosphate levels, then clinicians one day may be able to screen HIV patients for MRP4 and prescribe medications accordingly, he adds. "For example, dideoxyinosine [ddI] was not affected by MRP4, unlike AZT, so that might suggest if you have an individual with high MRP4, you might use ddI instead of AZT."
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