Should accessory proteins be structural components of lentiviral vaccines?: Lessons learned from the accessory ORF-A protein of FIV

The FIV regulatory protein Rev and accessory proteins Vif and ORF-A are essential for efficient viral replication and full-blown pathogenesis. Expressed at very low level during viral replication, they are nevertheless processed for recognition by cytotoxic T-lymphocytes (CTLs) and trigger cellular immune responses in FIV-infected cats. The observation that the accessory ORF-A protein of FIV is continuously expressed during viral replication and targeted by cellular immune responses in natural FIV infection, prompted us to investigate the protective potential of this protein. To this aim cats were immunized with three different strategies (protein alone in alum adjuvant, DNA alone, or DNA prime-protein boost) and generated clearly detectable immune responses. Upon challenge with ex vivo homologous FIV, ORF-A immunized cats showed distinct enhancement of acute-phase infection possibly due to an increased expression of the FIV receptor CD134. However, at subsequent sampling points plasma viremia was reduced and CD4+ T-lymphocytes in the circulation declined more slowly in ORF-A immunized than in control animals. These findings support the contention that a multicomponent vaccine, with the inclusion of both accessory and structural proteins, can not only improve the hostʹs ability to control lentivirus replication and slow down disease progression but also draw attention to the fact that even simple immunogens that eventually contribute to protective activity can transiently exacerbate subsequent lentiviral infections.