April 29, 1999
"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 and host."
LG Guidotti, R Rochford, J Chung, M Shapiro, R Purcell, and FV Chisari. Viral clearance without desctruction of infected cells during acute HBV infection. Science April 30, 1999:825-829.
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