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Immunology: Biologist Finds HIV Gene Makes a Human Gene Turn Bad
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CDC HIV Prevention News AIDS Weekly (09.08.03)
A recent study by researchers in New York and Utah discoveredhow a gene in the AIDS virus hijacks a human gene that normallyprevents the replication of damaged cells. The new study "puts usa big step closer to understanding how HIV dismantles the immunesystem," said molecular biologist Vicente Planelles, associateprofessor of pathology at the University of Utah School ofMedicine, and it raises the prospects for new kinds of treatmentsfor AIDS and cancer.
Scientists knew that an HIV gene, vpr, led to the depletionof CD4 cells and lymphocytes. This study suggests vpr achievesthat by activating the ATR gene found in all human cells,including white blood cells. Normally, ATR detects genetic damageto cells caused by radiation, toxic chemicals and chemotherapyand stops the damaged cells from replicating until they canrepair themselves. Planelles and colleagues at the University ofRochester, New York; DNAX Research, Inc. of California; andHarvard University found evidence that the vpr gene - one of ninein the AIDS virus - exploits this normal repair process to stopvital white blood cells from replicating, thus disabling theimmune system.
The research raises possibilities of treating AIDS-relatedimmune system damage with drugs to prevent vpr from activatingthe ATR gene. "We would like to find a method or a substance thatwould allow us to interfere with the ability of HIV to kill thewhite blood cells using this mechanism," Planelles said, notingthat it could take 5-10 years to develop such treatment.
In 1995, Planelles discovered that vpr acted as HIV's "lethal weapon" by preventing CD4 and white blood cells fromdividing and replicating, leaving AIDS patients with crippledimmune systems. The new study shows how vpr triggers ATR bysetting off a "cascade" or "pathway" in which other genes andproteins work in a chain reaction to keep white blood cells fromdividing. Scientists need to find a way to interfere with ATRonly in white blood cells, without serious side effects, in orderto convert the findings into a clinically and commercially usefulHIV/AIDS treatment, Planelles said.
The findings also reinforce Planelle's 1999 discovery thatAIDS' vpr gene can kill cancer cells in culture, which raises the prospect of developing a drug that mimics vpr's ability toactivate ATR and stop the replication of cancer cells. He said itwould take at least five years to develop such a drug.
The study, "Activation of the ATR-Mediated DNA DamageResponse by the HIV-1 Viral Protein R," appeared in the Journalof Biological Chemistry (2003;278;(28):25879-25886).
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