GENETIC IMMUNIZATION OF CHIMPANZEES CHRONICALLY INFECTED WITH THE HEPATITIS-B VIRUS, USING A RECOMBINANT RETROVIRAL VECTOR ENCODING THE HEPATITIS-B VIRUS CORE ANTIGEN

Cytotoxic T lymphocyte (CTL) activity and CD4(+) helper T cell respons es to the hepatitis B virus (HBV) core antigen (HBcAg) have been impli cated in clearance of acute and chronic HBV infections. We showed that intramuscular injections of a novel recombinant retroviral vector exp ressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion prote in induces HBc/eAg-specific antibodies and CD4(+) and CD8(+) T cell re sponses in mice and rhesus monkeys. We have now immunized three chroni cally infected chimpanzees, each with 10(10) CFU of nonreplicating ret roviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg -specific CTLs and showed marginal, transient elevations of alanine am inotransferase (ALT) levels following injection. However, both chimpan zees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load thr oughout the study. In contrast, the third chimpanzee exhibited a tradi tional seroconversion evidenced by a loss of serum HBeAg and the subse quent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitati ons, the present study demonstrates (1) the safety of treatment with h igh titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immuni zation may be therapeutically beneficial in the treatment of chronic H BV infection.