Properties of Subviral Particles of Hepatitis B Virus

Abstract

In the sera of patients infected with hepatitis B virus (HBV), in addition to infectious particles, there is an excess (typically 1,000-to 100,000-fold) of empty subviral particles (SVP) composed solely of HBV envelope proteins in the form of relatively smaller spheres and filaments of variable length. Hepatitis delta virus (HDV) assembly also uses the envelope proteins of HBV to produce an infectious particle. Rate-zonal sedimentation was used to study the particles released from liver cell lines that produced SVP only, HDV plus SVP, and HBV plus SVP. The SVP made in the absence of HBV or HDV were further examined by electron microscopy. They bound efficiently to heparin columns, consistent with an ability to bind cell surface glycosaminoglycans. However, unlike soluble forms of HBV envelope protein that were potent inhibitors, the SVP did not inhibit the ability of HBV and HDV to infect primary human hepatocytes.In natural infections with hepatitis B virus (HBV), there is an excess of empty noninfectious subviral particles (SVP) that do not contain the viral capsid. SVP are typically present in a 1,000-to 100,000-fold excess relative to the infectious particles (12, 13). They exist in two main forms: spheres of 25 nm in diameter and filaments of 22 nm in diameter with variable length (15,17). They can contain all three forms of the HBV envelope proteins: L, M, and S. These share a common C terminus, with M containing the pre-S2 domain relative to S and L containing the pre-S1 domain relative to M (15). There is good evidence that during infection a domain within the pre-S1 of L is what interacts with an as-yet-unidentified host receptor(s) (15). Hepatitis delta virus (HDV), which is assembled using the envelope proteins of HBV, also depends upon this pre-S1 domain (26). HDV can be assembled using only the S protein of HBV, but the particles are noninfectious.SVP from patients are immunogenic and were used with success in the first HBV vaccine (1). Most current HBV vaccines are prepared in yeast from SVP assembled using just the HBV S protein; such SVP are sufficient to protect individuals against HBV and HDV.The basis for the excess of SVP detected in patients is unexplained, and the biological function of this excess has been largely ignored. Some authors have suggested that SVP might sop up neutralizing antibodies produced by the host and thus increase the ability of the infectious particles to reach susceptible cells (11,25). It has also been suggested that SVP contribute to a state of immune tolerance that is a precondition for highly productive persistent infection (13). One study with SVP of duck HBV indicated that for infections at low multiplicity SVP could enhance infection, but when present in large amounts they were inhibitory (3). Another study showed that SVP containing the large envelope protein interfered with duck HBV infection (19).For the present studies we chose to use SVP as produced by transfection procedures. For the following reasons we consider these more defined than SVP obtained from ...

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