Deficiencies in the Acute-Phase Cell-Mediated Immune Response to Viral Antigens Are Associated with Development of Chronic Woodchuck Hepatitis Virus Infection following Neonatal Inoculation

Abstract

In vitro proliferation of peripheral blood mononuclear cells was used to measure virus-specific cell-mediated immunity (vCMI) following neonatal woodchuck hepatitis virus (WHV) infection. Fifteen neonates were inoculated with the W8 strain of WHV. In 11, infection was resolved, and 4 became chronic carriers. Nineteen neonates were inoculated with the W7 strain and all became chronic carriers. Seven age-matched uninfected woodchucks served as controls. Virologic and vCMI profiles among the W8 and W7 infections were compared and related to the outcome of infection. Resolving woodchucks had robust, acute-phase vCMI to WHV antigens (core, surface, and x) and to several nonoverlapping core peptides. The acute-phase vCMI was associated temporally with the clearance of viral DNA and of surface antigen from serum at 14 to 22 weeks postinfection. In contrast, in approximately half of the W8 and W7 infections that progressed to chronicity, no significant acute-phase vCMI was detected. In the remaining carriers, acute-phase vCMI was observed, but it was less frequent and incomplete compared to that of resolved woodchucks. Serum viral load developed less rapidly in those carriers that had evidence of acute-phase vCMI, but it was still increased compared to that of resolving woodchucks. Thus, vigorous and multispecific acute-phase vCMI was associated with resolution of neonatal WHV infection. Absent or incomplete acute-phase vCMI was associated with the progression to chronic infection. By analogy, these results suggest that the onset of chronic hepatitis B virus (HBV) infection in humans may be associated with deficiencies in the primary T-cell response to acute HBV infection.Adult humans infected with the hepatitis B virus (HBV) usually undergo an acute infection followed by recovery (i.e., resolution). Progression to chronic HBV infection is unusual in adults but frequent among unvaccinated children born to HBV-carrier mothers. Chronic HBV infection is characterized by severe hepatic disease sequelae, including chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma (reviewed in reference 2). The early immunologic mechanisms that predispose to the development of chronic HBV infection are not completely understood (reviewed in references 2, 3, and 15).Resolution of acute HBV infection is associated with the early induction of virus-specific, cell-mediated immunity (vCMI), which involves T helper (Th) cells and cytotoxic T lymphocytes. The successful cell-mediated immune response culminates in acute hepatitis, elimination of the virus from the liver, and subsequent recovery (reviewed in references 2, 3, and 32).

Kinetics of the immune response during HBV and HCV infection

“…28,81 Animals that develop chronicity lack the acute phase response and fail to prime an adequate adaptive response. 26,82,83 Thus, activation of innate components of the immune system seems to represent a key element in the control of the initial HBV burst. Available data do not allow the contribution of the individual components of the innate immunity to be dissected out.…”

Role of type 1 versus type 2 immune responses in liver during the onset of chronic woodchuck hepatitis virus infection

“…Our hypothesis in the neonatal model is that chronic WHV infection develops due to a diminished host response to acute infection, and several of our initial studies were consistent with this hypothesis. [13][14][15] Experimental infection of neonatal woodchucks enables cotemporal comparisons of naturally occurring acute responses before the self-limited and chronic outcomes become obvious by conventional serologic criteria. [12][13][14][15]18,19 To facilitate such studies, we maintain a bank of control and WHV-infected liver specimens that were obtained surgically at 2 representative acute-phase time points in each outcome setting.…”

“…[13][14][15] Experimental infection of neonatal woodchucks enables cotemporal comparisons of naturally occurring acute responses before the self-limited and chronic outcomes become obvious by conventional serologic criteria. [12][13][14][15]18,19 To facilitate such studies, we maintain a bank of control and WHV-infected liver specimens that were obtained surgically at 2 representative acute-phase time points in each outcome setting. 13 This eliminates the need to obtain small biopsy specimens each year from infected neonatal woodchucks and enables comparisons of increasingly well-characterized samples as new markers become available.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18][19][20] Experimental WHV infections in adult woodchucks are mostly self limited, whereas those in neonatal woodchucks result in higher proportions of chronic (60%-75%) versus self-limited (25%-40%) infections. 12 Understanding how these outcomes evolve and diverge will enable the identification of early mechanisms that cause chronicity, which should facilitate the development of rational immunotherapies for chronic HBV infection.…”

Advantages to the use of rodent hepadnavirus core proteins as vaccine platforms

“…Because aa 1-20 and aa 50-69 are not well conserved between the rodent core proteins and the HBcAg, a low level of T cell crossreactivity between the rodent core proteins and the HBcAg by human CD4 + T cells is predictable. Furthermore, a number of Th cell sites have been mapped on WHcAg in outbred WHV-infected woodchucks [21]. A large variety of Th cell recognition sites were defined on WHcAg and the frequency and fine specificity of the sites recognized correlated with acute versus chronic WHV infection [21].…”