Macaques infected with attenuated simian immunodeficiency virus resist superinfection with virulence-revertant virus

Researchers investigated superinfection resistance in macaques infected with attenuated simian immunodefiency virus (SIVmac). Three macaques previously infected with attenuated SIVmacC8 were challenged with blood from a macaque (29R) in which a virulent revertant virus had emerged through repair of a 12 bp deletion in the nef gene. The three vaccinated macaques successfully resisted superinfection with the revertant virus, while four naive control animals became persistently infected. Sequence analysis revealed that macaque 29R had accumulated multiple mutations following repair of the attenuating lesion, coinciding with clinical decline and development of AIDS-like pathology. Notably, nef-specific cytotoxic T lymphocyte (CTL) responses were detected in 29R before reversion but were lost after the repair event, suggesting possible escape from CTL-driven selection pressure. The findings demonstrate that superinfection resistance persists against in vivo-reverted virus, supporting the potential of attenuated SIV as a vaccine model. However, the results suggest that viral niche occupation rather than antibody-mediated immunity may be critical for protection, raising important questions about safe vaccine development.

Key findings

• Macaques infected with attenuated SIVmacC8 successfully resisted superinfection with virulent revertant virus that arose in vivo through repair of a 12 bp nef deletion.
• A virulent revertant virus emerged in one macaque (29R) despite superinfection resistance in other vaccinated animals, accumulating multiple mutations in nef that correlated with disease progression and AIDS pathology.
• Loss of nef-specific CTL responses preceded virulence reversion, suggesting the virus may have escaped from CTL-driven immune pressure.
• Passive transfer of serum and evidence against CTL depletion studies suggest humoral immunity is unlikely to be the primary mechanism of superinfection resistance.
• The dominant mechanism of superinfection resistance may involve viral niche occupation by the resident attenuated virus rather than specific immune responses.