A new study suggests that, contrary to current belief, the immune system
eliminates most hepatitis B virus (HBV) without resorting to large-scale
destruction of infected liver cells. A report of the study, conducted by
National Institute of Allergy and Infectious Diseases (NIAID) grantees and
scientists, appears in the April 30, 1999, issue of Science.
"This is an intriguing finding," notes NIAID Director Anthony S. Fauci,
M.D. "By advancing our understanding of how HBV is cleared from the liver,
it could lead to better treatments for HBV infection. It also sheds light
on how the body protects against spread of an ongoing infection without
destroying vital organs."
Scientists have thought that cell-killing T cells bring hepatitis B virus
infections to an end by destroying infected liver cells. The current study,
however, points to a noncytolytic process that targets the virus' ability to
reproduce and leaves the liver relatively unscathed.
Luca G. Guidotti, D.V.M., Ph.D., and Francis V. Chisari, M.D., of the
Scripps Research Institute in La Jolla, Calif., led the study, in
collaboration with Robert H. Purcell, M.D., chief of NIAID's hepatitis
viruses section, and other scientists. The researchers infected two healthy
chimpanzees with HBV, then performed weekly blood and liver tests on the
animals throughout the course of the infection.
The chimp HBV infections ran their course and the animals recovered without
further complications. Most HBV infections in adult humans are similarly
uncomplicated. However, between 5 and 10 percent of the estimated 320,000
new HBV infections in the United States each year become persistent, chronic
infections. Annually, chronic HBV infection kills as many as 6,000 people
in this country.
The researchers found the amount of hepatitis B virus DNA in the chimps'
blood and livers peaked eight weeks after infection. The HBV DNA levels
then rapidly decreased - by week 12 more than 90 percent of the HBV DNA had
been eliminated. Surprisingly, the dramatic reduction in HBV DNA occurred
before the chimps' immune systems counter-attacked with a barrage of T
cells, which fight hepatitis B by destroying cells that contain the virus.
Thus, few HBV-infected cells remained for the T cells to attack.
The authors assert that the T cell-mediated killing of HBV-infected liver
cells, an acquired immune mechanism that develops upon exposure to HBV,
probably cooperates with the antiviral process that rids the blood and liver
of hepatitis B virus DNA to control the infection fully.
"This tissue-sparing, noncytolytic antiviral process can be viewed as a host
survival strategy to control infections of vital organs that would otherwise
be destroyed if the only way to eliminate the infections was to kill all of
the infected cells," they note.
"Considerable attention currently is focused on the development of therapies
designed to bolster the cytolytic response to HBV," adds Dr. Purcell. "Our
finding suggests that therapies that exploit noncytolytic immune processes
could become an important focus of HBV therapeutics research."
The authors conclude that by limiting HBV's vulnerability to T-cell attack,
the same noncytolytic process could be beneficial to the virus, and
contribute to persistent HBV infection.
"Indeed, both scenarios could even be operative in the same individual at
the same time," say the researchers. "If so, the noncytolytic process
should be strongly favored during evolution and possibly extend to other
pathogens, because it provides a strong survival advantage for both virus
NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses such
as HIV disease and other sexually transmitted diseases, tuberculosis,
malaria, asthma and allergies. NIH is an agency of the U.S. Department of
Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.