New UCLA AIDS Instituteresearch reveals that stress enables HIV to spread more quickly in infectedpersons and prevents antiretroviral drugs from restoring immune systemfunction. Reported in the Oct. 23 Proceedings of the National Academy ofSciences, the UCLA study is the first to pinpoint the molecular mechanismslinking stress and HIV infection.
"Popular science haswidely suspected that stress weakens the immune system," said Dr. Steve Cole,lead author and UCLA assistant professor of hematology-oncology. "Now we'veuncovered two reasons why."
The UCLA team studied agroup of 13 HIV-positive men, ages 25 to 54, who had never taken combinationantiretroviral drugs. After drawing samples of the men's blood, the researchersmeasured the subjects' baseline AIDS viral load and CD4 cell count. HIV targetsthese T-cells in order to destroy the immune system.
The UCLA scientistsnext gauged the men's levels of autonomic nervous system (ANS) activity bycalculating their blood pressure, skin moisture, heart rate and pulse rate atrest.
"Persons with higherANS activity tend to be more high-strung and easily stressed out," said Dr.Jerome Zack, UCLA professor of medicine and associate director for basicsciences at the UCLA AIDS Institute."We wanted to see what effect — if any — this had on our subjects'ability to fight HIV infection."
The UCLA team measuredeach man's ANS activity in response to a series of tests, including unexpectednoises, deep breathing and mental arithmetic exercises under pressure. The researchers compared these responses tothe baseline findings and ranked the men by their degree of change in ANSactivity — their physiologic response to stress.
All 13 men were given apowerful antiretroviral drug regimen to combat their HIV infection. Over thenext three to 11 months, Cole and Zack again measured each man's viral load andCD4-cell count — indicators of how much the HIV had spread and how well theirimmune systems were fighting the infection. The UCLA team compared thesefigures to the men's stress level ranking before they took the drugs.
Their results proveddramatic. The higher the man's stress level, the less he responded to theantiretroviral drugs. In fact, the average decline in viral load dropped morethan 40 times for men with low ANS activity — yet less than 10 times for menwith high ANS activity.
"After several monthson antiretroviral drugs, the viral loads of five of the seven men with low ANSactivity plummeted to undetectable levels in their blood," said Cole. "Thishappened to only one of the six men who exhibited high ANS activity."
Cole and Zack observedsimilar patterns in CD4 cell count recovery. On average, men with low ANSactivity showed the most striking cell-count increases. In comparison, men withhigh ANS activity displayed negligible CD4 cell rebound — or none at all.
Subjects with low ANSactivity rebounded from 396 to 550 CD4 cells per cubic millimeter of bloodafter treatment, researchers said. The immune systems of men in the high ANSgroup recovered far fewer — from 611 to 627 cells per cubic millimeter ofblood.
"Those at the top ofthe high ANS activity group showed no immune recovery at all," Zack said. "Somecontinued to lose CD4 cells despite following the aggressive drugregimen."
How Stress Weakens the Immune System
When a person is understress, the nervous system's "fight or flight" syndrome kicks in. The body'snerves release the hormone norepinephrine into the lymph nodes, where theimmune system's T-cells reside.
The UCLA team recreatedthis scenario in the laboratory, exposing T-cells in culture to the sameconcentrations of norepinephrine released by the nerves during stress. Theydiscovered that the hormone increased viral replication 10-fold via twomolecular mechanisms.
First, norepinephrineincreases T-cells' vulnerability to infection fivefold by increasing levels ofCCR5 and CXCR4 -- two co-receptor molecules that enable HIV to bind to thecell's surface and invade the T-cell. Second, the hormone increases HIV's rateof viral gene expression in the cells it has already infected. This allows theAIDS virus to spread five times more quickly.
"It's a double whammy,"Zack said. "Norepinephrine enables HIV to enter the immune cell more easily andto reproduce more readily. So more virus gets in and more virus comes out,resulting in a 10-fold increase in the amount of virus produced."
Implications for Other Diseases
"Our findings suggestthat the nervous system has a direct effect on viral replication," Cole said."This implies we may be able to alter that effect by reducing stress levels.Even anti-HIV drugs prove more effective in people with low ANS activity."
Cole and Zack believethat their findings may hold broader implications for future study of stress'role in physical health.
"Molecules such as CCR5and CXCR4 help steer immune cells to areas of infection," said Cole. "If stresschanges how these molecules function, it may alter the body's ability torespond to a wide range of infections beyond HIV."
"Our findings proposethat high levels of stress, day in and day out, may eventually wear down theimmune system," said Cole. "It's like a wave hitting a rock on the beach. Onewave won't do much damage. But years later, that rock gets ground down intosand."
Cole and Zack'sresearch associates included Drs. Bruce Naliboff, Margaret Kemeny, MarshallGriswold and John Fahey. The National Institute ofAllergy and Infectious Disease, UCLA AIDS Institute and UCLA Norman CousinsCenter for Psychoneuroimmunology funded the research.
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