Disease progresses more quickly in introverts

Shy, inhibited personalities may fare worse

Los Angeles researchers recently have discovered clinical evidence that HIV-positive people with shy and introverted personalities tend to have a faster disease progression and less optimal outcomes under antiretroviral treatment than do people with extroverted personalities.

"It’s well known to physicians that a fraction of patients don’t show suitable response to medications, and it’s not always apparent why," says Steve Cole, PhD, assistant professor of medicine in the division of hematology-oncology in the department of medicine at the University of California, Los Angeles School of Medicine. "A lot of times, the problem is not drug resistance, and the patients are adherent but aren’t showing great clinical benefit."

Cole and co-investigators decided to examine from a biological standpoint why a regimen does not work for certain people. Based on epidemiological evidence back when they began this research in the mid-1990s, they decided there was good circumstantial evidence that activity in a person’s autonomic nervous system is an important factor.

"We developed a hypothesis that showed that shy and introverted people were getting sicker and dying faster. We knew from other studies on basic temperament that people who have this kind of shy and sensitive personality also seem to have high levels of activity in the autonomic system." Researchers investigated whether chemicals were being released during periods of stress that might impact the autonomic nervous system and a body’s ability to handle HIV infection, Cole says.

"We took healthy white cells and infected them with HIV we grew in the lab," he explains. "There was no variability in virus." The cultured cells were divided between those growing under normal conditions and those growing under conditions that included norepinephrine, which are what an infected cell might encounter in a lymph node, Cole says. "The virus grew 10 times as well under the [norepinephrine] conditions. Norepinephrine would signal chemo-cell receptors — HIV gene expression in cells already infected — and made them more efficient at making new virus once they were infected."

Given these results, investigators decided to see whether the test-tube results would be valid in HIV patients. They studied a cohort of HIV-infected gay men who all were in early stages of infection, he adds. "They all were healthy individuals, and this was right before combination antiretroviral therapies were available, so all had detectable levels of virus."

Researchers found that neurotransmitters can accelerate HIV-1 replication, and patients who consistently showed high levels of autonomic nervous system activity before their antiretroviral therapy had poorer plasma viral load suppression over three to 11 months of therapy.1

Investigators studied their blood pressure, heart rates, and other measures of autonomic response under a variety of conditions, including resting quietly, breathing deeply, standing from a sitting position, and performing a difficult arithmetic test, Cole explains. Introverted vs. extroverted personalities were determined with a standard, 60-question tool designed to measure this personality factor, he adds. "We found how active and reactive each person’s autonomic system was. We could answer the question of whether introverted individuals had higher autonomic nervous system activity."

The result provided the first clinical evidence that such neural activity shows a relationship between psychological risk factors and infectious disease progression.2 Essentially, the people who measured on the psychological test as being introverted or shy were significantly more likely to have high levels of autonomic nervous system activity than were those who measured extroverted. The introverted individuals’ autonomic nervous systems were more active when they were stressed, such as trying to answer math questions rapidly on a test designed to make them feel as though they didn’t do well, Cole says.

"I think that the underlying biology of stress is applicable to everybody," he notes. "The reason it shows so much in introverts is because they are by temperament more stress responsive than other people." As such, their viral loads were higher. "People with high autonomic nervous system activity had high viral set point — free-running virus in blood. We had a subset who went on to combination therapy during a follow-up period of 12-18 months, and so we were able to look and see how well antiretroviral therapy worked in suppressing their viral load. What we saw was a striking correlation between response to therapy being good and having low levels of autonomic nervous system activity," Cole points out.

Those individuals with the lowest levels of autonomic nervous system activity had eight times better responses to antiretroviral therapy than those with the highest levels of autonomic activity, he explains. "One of the things these studies have reinforced is the notion that autonomic nervous system activity and the effect of norepinephrine on viral replication is clinically important. So we got a grant to try beta-blockers."

The theory is: Beta-blockers, which interfere with norepinephrine, will counteract a patient’s stress, he says. "No one thought about using these drugs for an infectious disease because it wasn’t clear that the autonomic nervous system was playing a role in infectious disease, but these data suggest they are." The goal of the new research will be to see if beta-blockers help patients increase their suppression of HIV, so the beta-blockers would be administered to patients who are on antiretroviral therapy regimens, but who are not achieving optimal responses, he explains.

While holistic medical approaches to reducing stress have not shown consistent positive results, this probably is because activities, such as acupuncture and mediation, are short-term answers to stress, Cole speculates.

"Those holistic, nondrug therapies can play an important role in getting people in an unstressed state for a short period of time."

Because HIV patients will have to deal with stress throughout their days, it would take a much more dramatic approach to holistic stress reduction to make an impact. Those who make major changes to their lifestyle, such as quitting high-stress jobs, spending more time with the people they love, and revamping their lives have been shown to have some success in reducing cardiovascular disease; and the same could be true for HIV patients, he says.

"We’re trying a drug strategy to treat stress, and if a patient tries a psychological strategy, then that may be successful, as well," Cole adds.


  1. Cole SW, Naliboff BD, Kemeny ME, et al. Impaired response to HAART in HIV-infected individuals with high autonomic nervous system activity. Proc Natl Acad Sci USA 2001; 98(22):12,695-12,700.
  2. Cole SW, Kemeny ME, Fahey JL, et al. Psychological risk factors for HIV pathogenesis: Mediation by the autonomic nervous system. Biol Psychiatry 2003; 54(12):1,444-1,456.