UCLA Scientists Discover Stress Accelerates AIDS Progression, Undermines Anti-HIV Drugs' Effect
New UCLA AIDS Institute research reveals that stress enables HIV to spread more quickly in infected persons and prevents antiretroviral drugs from restoring immune system function. Reported in the Oct. 23 Proceedings of the National Academy of Sciences, the UCLA study is the first to pinpoint the molecular mechanisms linking stress and HIV infection.
"Popular science has widely suspected that stress weakens the immune system," said Dr. Steve Cole, lead author and UCLA assistant professor of hematology-oncology. "Now we've uncovered two reasons why."
The UCLA team studied a group of 13 HIV-positive men, ages 25 to 54, who had never taken combination antiretroviral drugs. After drawing samples of the men's blood, the researchers measured the subjects' baseline AIDS viral load and CD4 cell count. HIV targets these T-cells in order to destroy the immune system.
The UCLA scientists next gauged the men's levels of autonomic nervous system (ANS) activity by calculating their blood pressure, skin moisture, heart rate and pulse rate at rest.
"Persons with higher ANS activity tend to be more high-strung and easily stressed out," said Dr. Jerome Zack, UCLA professor of medicine and associate director for basic sciences 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 measured each man's ANS activity in response to a series of tests, including unexpected noises, deep breathing and mental arithmetic exercises under pressure. The researchers compared these responses to the baseline findings and ranked the men by their degree of change in ANS activity — their physiologic response to stress.
All 13 men were given a powerful antiretroviral drug regimen to combat their HIV infection. Over the next three to 11 months, Cole and Zack again measured each man's viral load and CD4-cell count — indicators of how much the HIV had spread and how well their immune systems were fighting the infection. The UCLA team compared these figures to the men's stress level ranking before they took the drugs.
Their results proved dramatic. The higher the man's stress level, the less he responded to the antiretroviral drugs. In fact, the average decline in viral load dropped more than 40 times for men with low ANS activity — yet less than 10 times for men with high ANS activity.
"After several months on antiretroviral drugs, the viral loads of five of the seven men with low ANS activity plummeted to undetectable levels in their blood," said Cole. "This happened to only one of the six men who exhibited high ANS activity."
Cole and Zack observed similar patterns in CD4 cell count recovery. On average, men with low ANS activity showed the most striking cell-count increases. In comparison, men with high ANS activity displayed negligible CD4 cell rebound — or none at all.
Subjects with low ANS activity rebounded from 396 to 550 CD4 cells per cubic millimeter of blood after treatment, researchers said. The immune systems of men in the high ANS group recovered far fewer — from 611 to 627 cells per cubic millimeter of blood.
"Those at the top of the high ANS activity group showed no immune recovery at all," Zack said. "Some continued to lose CD4 cells despite following the aggressive drug regimen."
How Stress Weakens the Immune System
When a person is under stress, the nervous system's "fight or flight" syndrome kicks in. The body's nerves release the hormone norepinephrine into the lymph nodes, where the immune system's T-cells reside.
The UCLA team recreated this scenario in the laboratory, exposing T-cells in culture to the same concentrations of norepinephrine released by the nerves during stress. They discovered that the hormone increased viral replication 10-fold via two molecular mechanisms.
First, norepinephrine increases T-cells' vulnerability to infection fivefold by increasing levels of CCR5 and CXCR4 -- two co-receptor molecules that enable HIV to bind to the cell's surface and invade the T-cell. Second, the hormone increases HIV's rate of viral gene expression in the cells it has already infected. This allows the AIDS virus to spread five times more quickly.
"It's a double whammy," Zack said. "Norepinephrine enables HIV to enter the immune cell more easily and to 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 suggest that 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 believe that their findings may hold broader implications for future study of stress' role in physical health.
"Molecules such as CCR5 and CXCR4 help steer immune cells to areas of infection," said Cole. "If stress changes how these molecules function, it may alter the body's ability to respond to a wide range of infections beyond HIV."
"Our findings propose that high levels of stress, day in and day out, may eventually wear down the immune system," said Cole. "It's like a wave hitting a rock on the beach. One wave won't do much damage. But years later, that rock gets ground down into sand."
Cole and Zack's research associates included Drs. Bruce Naliboff, Margaret Kemeny, Marshall Griswold and John Fahey. The National Institute of Allergy and Infectious Disease, UCLA AIDS Institute and UCLA Norman Cousins Center for Psychoneuroimmunology funded the research.
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