Immune System Activation Boosts HIV Replication in HIV-Infected People
In people infected with the human immunodeficiency virus (HIV), activation of the immune system by other stimuli boosts HIV replication, according to a study by investigators at the National Institute of Allergy and Infectious Diseases (NIAID).
The research, which builds on previous work at NIAID and elsewhere, helps explain why HIV disease typically progresses faster in areas of the world where a person's immune system may constantly be challenged by parasites and other microorganisms. Immune responses to persistent infections also may leave people more vulnerable to HIV infection.
Sharilyn Stanley, M.D., and her colleagues report their current findings in the May 9, 1996 issue of The New England Journal of Medicine. Dr. Stanley is currently the special assistant for science policy in the office of NIAID Director Anthony S. Fauci, M.D. She performed this study last year when she was a member of NIAID's Laboratory of Immunoregulation.
"The normal activation of the immune system in response to microbes results in a transient increase in HIV replication, a phenomenon that we feel is important to the pathogenesis of HIV disease," says Dr. Fauci, senior author on the paper. "Chronic immune activation, or the cumulative effect of multiple episodes of immune activation and bursts of virus production, probably contribute to the progression of HIV disease."
In their study, the researchers inoculated 13 asymptomatic HIV-infected people and 10 uninfected volunteers with tetanus booster shots to stimulate their immune systems, and drew blood samples on the day of the injection and 3, 7, 14, 21, 28 and 42 days later.
In the 13 HIV-infected volunteers, the amount of HIV in the bloodstream increased two-fold to 36-fold following immunization, reaching a peak at a mean of 13 days. In all patients, virus levels returned to the baseline level within six weeks.
Ten of the 13 patients had moderate (two- to four-fold) increases in the numbers of circulating blood cells that contained HIV. Notably, the virus was much more readily grown from the blood cells of nine of the HIV-infected patients after immunization than before immunization. Two of the 13 HIV-infected patients underwent lymph node biopsies before and after immunization, and the researchers found that lymph node viral burden was higher in these people after immunization than before immunization.
"Interestingly, the patients with the strongest immune systems had the largest increases in virus," says Dr. Stanley. "This underscores the diabolical nature of HIV: the normal efforts of the immune system to mobilize itself and fight an invader results in HIV being revved up as well, with a stronger immune system paradoxically leading to more viral replication."
The researchers also examined immune system cells of the uninfected volunteers. They found that cells from seven of these 10 people were more easily infected with HIV in the test tube after immunization than before immunization. In addition, the researchers found that cells from an uninfected subject became highly susceptible to HIV infection during an acute respiratory tract illness.
"Taken together with previous studies, our data suggest that ongoing immune activation may play a part in HIV pathogenesis, and may also enhance the susceptibility of uninfected people to HIV," says Dr. Stanley.
"It will be important to develop therapies directed at those microbes that contribute to a state of chronic and persistent immune activation in HIV-infected people," she adds. "Drugs that could be used at certain times to dampen immune activation may also have a role in the treatment of HIV-infected people."
The researchers note that increases in HIV following immunization were transient in their study, and that the protection afforded by immunization against a pathogenic organism most likely outweighs the potential risks from the resulting transient increase in HIV.
None of the HIV-infected people in the current study were receiving antiretroviral therapy, so the results cannot be generalized to all HIV-infected people, says Dr. Stanley. NIAID investigators are planning a study to assess whether short-term antiretroviral therapy to block the transient viremia associated with immunizations can benefit HIV-infected people.
NIAID is a component of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Reference: Stanley SK, Ostrowski MA, Justement JS, Gantt K, Hedayati S, Mannix M, Roche K, Schwartzentruber DJ, Fox CH, Fauci AS. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996;334:1222-30.
NIAID press releases, fact sheets and other materials are available on the internet via the NIAID home page. The address is http://www.niaid.nih.gov.
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