Sep. 2, 1999 Study sheds light on how cells evade anti-HIV drugs in absence of drug-resistant virus
(August 30, 1999) The gene MRP4 appears to help T cells, key components of the human immune system, "pump out" certain anti-HIV drugs and may allow the development of drug-resistant strains of HIV, report a team of St. Jude Children's Research Hospital scientists in the September issue of Nature Medicine.
"We have found a significant clue to explain why some HIV-infected patients resist therapy even when they have no detectable levels of drug-resistant strains of the virus," said John Schuetz, Ph.D., St. Jude pharmaceutical sciences, principal investigator of the study. Resistance to nucleoside drugs, which are the backbone of anti-HIV and other anti-viral therapy, is a serious threat to HIV patients. The team's findings could lead to developing new therapies to fight HIV infection, several viral diseases and certain cancers.
Scientists have known that drug-resistant HIV strains caused by genetic mutation have thwarted the effectiveness of drug therapy. However, for the past few years, scientists have noted HIV patients with normal forms of the virus have not responded to the standard therapy, which includes the drugs AZT, ddC, ddI, d4T, 3TC and abacavir. St. Jude scientists began looking into the cellular reasons why.
"It's like gazing into a black box. What could it be?" Schuetz said.
Their hunt for answers led them to the gene MRP4. This study is the first to describe its function. "It was just a sequence in the database prior to this," Schuetz said.
While studying T cells that were resistant to AZT and the experimental drug PMEA, researchers found that overexpression and amplification of MRP4 was responsible for drug resistance. The MRP4 protein "pumps out" nucleoside drugs from cells. Normally when nucleoside drugs enter T cells, an enzyme adds on a phosphate group -- keeping the drug in the cell so it can prevent HIV replication. In the resistant T-cells, the nucleoside drugs with mono-phosphate groups escaped from the cells, leading to lower levels of the drug. These lower concentrations of active drug are less effective in preventing replication of HIV and lead to uncontrollable proliferation of the deadly virus. Another implication of these findings -- individuals with high levels of MRP4 in their T cells may fail standard HIV drug therapy while those with low MRP4 may respond successfully to treatment.
"Now we've been able to put a handle on something," Schuetz said. "We have a bonafide cellular reason why some cells are non-responsive to conventional HIV therapy."
Now that scientists have pinpointed the problem, they can begin the search for an inhibitor that will stop MRP4 from purging drugs from T cells. This study could also shed light on the responsiveness of other diseases to nucleoside drug therapy, including Hepatitis B, cytomegalovirus, herpesvirus and cancer, Schuetz said.
St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by the American Lebanese Syrian Associated Charities (ALSAC). All St. Jude patients are treated regardless of their ability to pay. ALSAC covers all costs of treatment beyond those reimbursed by third party insurers, and total costs for families who have no insurance.
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