Temporal regulation of influenza hemagglutinin expression in vaccinia virus recombinants and effects on the immune response

Abstract

Regulation of the expression of influenza A/PR/8/34 hemagglutinin (HA) by the vaccinia virus promoters PF (early), P7.5 (early and late) and PL11 (late) has been demonstrated using HA-vaccinia recombinant viruses VV-PR8-HA3, VV-PR8-HA6 and VV-PR8-HA, respectively. Levels of HA on the surface of VV-PR8-HA3 (PF)-infected cells were lower than with either VV-PR8-HA6 (P7.5) or VV-PR8-HA8 (PL11). Expression of HA under the control of the late promoter PL11 was inhibited in the absence of DNA replication. All three recombinant viruses stimulated a specific antibody response in mice which was dependent on the presence of infectious virus. Recognition of HA by cytotoxic T lymphocytes (CTL) was assessed by the ability of the viruses to stimulate naive precursors in vivo, to restimulate primed CTL in vitro and by target cell recognition. HA expressed under the control of either of the promoters with early function (PF or P7.5) was recognized by CTL when VV-PR8-HA3 or VV-PR8-HA6 were used to prime or restimulate splenocytes or to infect target cells. On the other hand, HA expressed by VV-PR8-HA8 (PL11) failed to prime for a CTL response in naive CBA/H mice, was ineffective at restimulation of primed splenocytes and failed to produce target cells for recognition by specific CTL. However, in BALB/c mice VV-PR8-HA8 did prime for a specific CTL response. These studies show that HA synthesized early in infection was recognized by both B and T cells while HA expressed after DNA replication was not generally recognized by T cells. The implications of the observations with the late promoter with respect to the use of late promoters in potential vaccinia virus-based vaccines are considered.

Nucleotide sequence of 42 kbp of vaccinia virus strain WR from near the right inverted terminal repeat

“…Vaccinia virus serpins B13R and B18R cause a reduced antibody response to a foreign antigen expressed by recombinant vaccinia virus (Zhou et al, 1990). They have also been proposed to prevent the processing of intracellular virus antigens and explain why some epitopes are not presented to class I major histocompatibility complex-restricted T cells from vaccinia virusinfected cells (Coupar et al, 1986;Townsend et al, 1988;Smith et al, 1989a). A study of these virus evasion strategies may contribute to our knowledge of normal immune mechanisms.…”

Antigen expression by dendritic cells correlates with the therapeutic effectiveness of a model recombinant poxvirus tumor vaccine

“…Whereas it may appear intuitive that the enhanced expression of antigens under the control of the more powerful late promoters will induce strong immunity, in some cases, early promoters elicited a greater cytotoxic T lymphocyte (CTL) response than late promoters perhaps because of vaccinia's interference directly or indirectly with major histocompatibility complex (MHC) class I presentation by late times (13)(14)(15). An alternative possibility considered here is that vaccinia virus infection may be abortive in ''professional'' antigen-presenting cells (APC) so that only the early phase of the replication cycle occurs.…”

Increased antibody responses to human papillomavirus type 16 L1 protein expressed by recombinant vaccinia virus lacking serine protease inhibitor genes

“…Consistent with this, much greater levels of L1 expression were obtained from the 4b (major late) rather than 7-5K (early and late) vaccinia virus promoter (Browne et al, 1988). Secondly, stimulation of T cell responses may be better if the antigen is expressed from early rather than from late vaccinia virus promoters, whereas B cell responses may result from the use of either class of promoter (Coupar et al, 1986). Early promoters may therefore be preferable if stimulation of both humoral and cell-mediated immunity is required.…”

“…Another proposed function for the serpin genes is the inhibition of cellular proteases which are involved in the proteolytic degradation of intracellular antigens (Smith et al, 1989). The observation that vaccinia virus may block the presentation of some antigens to class I major histocompatibility complex-restricted cytotoxic T cells (Coupar et al, 1986) and that this blockage may be overcome by expressing unstable proteins (Townsend et al, 1988) or peptide fragments (Gould et al, 1989) is consistent with this proposal. The potential for successful immunoprophylaxis of HPV infections is encouraged by the fact that bovine papillomavirus type 1 L1 expressed in E. coli protects cattle from development of warts due to virus infection (Pilacinski et al, 1985).…”