Background:  Induction of cytotoxic T lymphocyte (CTL) responses is a promising strategy for AIDS vaccine development. Recent trials of prophylactic CTL-based vaccines have shown transient, partial control of primary simian immunodeficiency virus (SIV) replication in Indian rhesus macaques. However, it is still unclear as to how non-sterile protection conferred by CTL-based vaccines can result in long-term viral containment and disease control. In our previous trial of DNA-prime/Gag-expressing Sendai virus vector-boost vaccine in Burmese rhesus macaques, we have shown CTL-based control of primary SIV_mac239 replication in 5 of 8 vaccinees. Here, we have examined whether or how this viral control was maintained in the chronic phase in these 5 controllers.

Methods:  We followed these 5 controllers for more than 3 years. We measured Gag-specific and SIV-specific CTL frequencies by flow-cytometric analysis of interferon-gamma (INF-g) induction. CD8⁺ cell depletion experiments were performed by using a monoclonal anti-CD8 antibody, cM-T807 (Centocor Inc). We performed statistical analysis to compare peripheral central memory CD4⁺ T-cell counts between 7 non-controllers (4 unvaccinated controls and 3 vaccinees) and 5 controllers by t-test and Mann-Whitney U-test.

Results:  Of the 5 controllers, 3 maintained viral control without AIDS progression for more than 3 years (referred to as sustained-controllers), whereas the other 2 showed reappearance of plasma viremia with accumulation of CTL escape mutations in viral genomes around week 60 post-challenge. In 1 of 3 sustained-controllers, vaccine-induced Gag-specific CTL responses were crucial for viral control even in the chronic phase. Interestingly, however, post-challenge-induced CTL specific for non-Gag SIV antigens, instead, played a central role in viral control in the chronic phase in the other 2 sustained-controllers. Finally, statistical analysis revealed association of sustained viremia control with central memory CD4⁺ T-cell preservation in the chronic phase as well as the acute phase.

Conclusions:  This study shows that non-sterile protection by a prophylactic CTL-based AIDS vaccine can result in long-term viral control by adapted CTL responses and preservation of central memory CD4⁺ T cells. Our results suggest the potential of CTL-based AIDS vaccines for leading to long-term viral containment and disease control.