Epstein-Barr virus (
EBV) infection persists for life in humans, similar to other gammaherpesviruses in the same lymphocryptovirus (LCV) genus that naturally infect Old World nonhuman primates. The specific immune elements required for control of
EBV infection and potential immune evasion strategies essential for persistent
EBV infection are not well defined. We evaluated the cellular immune response to
latent infection proteins in rhesus macaques with naturally and experimentally acquired rhesus LCV (rhLCV)
infection. RhLCV
EBNA-1 (rhEBNA-1) was the most frequently targeted
latent infection protein and induced the most robust responses by peripheral blood mononuclear cells tested ex vivo using the
gamma interferon ELISPOT assay. In contrast, although in vitro stimulation and expansion of rhLCV-specific T lymphocytes demonstrated cytotoxic T-lymphocyte (CTL) activity against autologous rhLCV-infected B cells, rhEBNA-1-specific CTL activity could not be detected. rhEBNA-1 CTL
epitopes were identified and demonstrated that rhEBNA-1-specific CTL were stimulated and expanded in vitro but did not lyse targets expressing rhEBNA-1. Similarly, rhEBNA-1-specific CTL clones were able to lyse targets pulsed with rhEBNA-1
peptides or expressing rhEBNA-1 deleted for the
glycine-
alanine repeat (GAR) but not full-length rhEBNA-1 or rhLCV-infected B cells. These studies show that the rhLCV-specific immune response to
latent infection proteins is similar to the EBV response in humans, and a potential immune evasion mechanism for
EBNA-1 has been conserved in rhLCV. Thus, the rhLCV animal model can be used to analyze the immune responses important for control of persistent LCV
infection and the role of the
EBNA-1 GAR for immune evasion in vivo.