Background:
Dysfunctional T cells and persistent viral reservoir under anti-retroviral therapy (ART) are the two major challenges to HIV cure. Towards this, here we evaluated therapeutic potential of intramuscular (IM) or intravenous (IV) vaccination combined with a latency reversal agent (LRA) and PD-1 blockade in SIV infected macaques.
Methods:
A total of 28 RMs were infected with SIVmac251, placed on daily ART at 2 weeks post infection (wpi) and divided into three groups. Two groups received two DNA/SIV vaccinations (34, 40 wpi; ID) followed by two modified vaccinia Ankara (MVA)/SIV vaccines (46, 66 wpi) via either IM (MVA-IM, n=14) or IV (MVA-IV, n=7), and the third group did not receive any vaccination (ART, n=7). All RMs received five weekly IV infusions of AZD5582 from weeks 52 to 56 under ART as an LRA after the 1st MVA. On the day of ATI (75 wpi), 7 RMs from MVA-IM group received six infusions of a primatized anti-PD-1 antibody (10mg/kg body wt.) at three-week intervals (MVA-IM+PD-1). Viral rebound kinetics were studied for up to 32 weeks post ATI. In-depth immunological, virological, and reservoir analyses were performed throughout the study.
Results:
Both IM and IV routes of therapeutic vaccination generated broad and polyfunctional SIV specific CD4 and CD8 T cells in blood and lymph nodes. Surprisingly, administration of AZD5582 under ART led to a significant loss of vaccine-induced effector CD8 T cells but were restored to high frequencies following the 2nd MVA. Post ATI, all animals showed a strong viral rebound. The ART, MVA-IM and MVA-IV animals, irrespective of Mamu-A01 status, did not control rebounding viremia. However, anti-PD-1 Ab treated Mamu-A01(+) animals (n=4) showed a profound suppression (below 60 copies with small blips under 1000 copies/ml) of reemerging viremia up to 32 weeks post ATI. The PD-1 blockade also induced high frequencies of polyfunctional SIV-specific cytolytic (granzyme B+, perforin+) CD8 T cells in the T-cell zone and B cell follicles of LNs, which were associated with sustained viral control.
Conclusions:
A combination of vaccination during ART and PD-1 blockade post ATI can achieve a sustained functional cure for SIV in the presence of a potent anti-viral CD8 T cell response. These results also highlight the need for optimization of AZD5582 treatments in conjunction with vaccination to prevent the loss of vaccine-induced CD8 T cells.
