Background
Enhancing immune-mediated clearance of latently infected cells is a key strategy to achieving an HIV cure. Here we evaluated CD8+ T cell responses to a potent vaccine regimen administered to rhesus macaques (RMs) prior to SIV infection or after viral suppression mediated by antiretroviral therapy (ART) to define how vaccine-elicited CD8+ T cells impact SIV reservoir establishment or maintenance.
Methods
Forty RMs were intravenously infected with SIVmac239M, started ART at 2 weeks post-infection (wpi), and underwent analytical treatment interruption (ATI) at 64 wpi. RMs were divided into 4 groups: ART-only, pre-infection vaccine, post-infection vaccine, and pre & post-infection vaccine. The vaccine regimen consisted of 3 sequential immunizations with heterologous viral vector expressing SIV Gag (Vesicular Stomatitis Virus, Vaccinia Virus, and Adenovirus type 5 or lipid nanoparticle (LNP) DNA, Modified Vaccinia Ankara and RNA-LNP for the second cycle of the double vaccination group). Plasma viral loads (PVL) and immune responses in peripheral blood (PB) and rectal biopsies (RB) were monitored longitudinally.
Results
Pre-infection vaccination induced (i) increased in frequencies of circulating CD8+ T cells (P<0.05), their activation/proliferation (HLA-DR+: P<0.05; Ki67+: P<0.001), and cytotoxic functions (Pfn+GzmB+: P<0.001), (ii) expansion of Gag-specific IFNγ-producing CD8+ T cells (PB, RB: P<0.05) compared to baseline, (iii) amplified Gag-specific CD8⁺ T cell in PB (P<0.001) and lymph node (p<0.05) following SIV infection leading to lower PVL at 2 to 4 wpi compared to unvaccinated (P<0.01, Fig.1).
RMs vaccinated after ART-suppression showed CD8+ T cell responses similar to the pre-infection vaccine group. They exhibited higher frequencies of circulating CD8+ T cells (P<0.001), and activated/proliferating (P<0.001), cytotoxic (P<0.001) and IFNγ-producing CD8+ T cells (PB: P<0.001, RB: P<0.01) at 51-55 wpi but similar post-ATI viral dynamics as compared to ART-only controls.
Conclusions
Our results demonstrate vaccine induction of robust SIV-specific CD8+ T cells responses before and after SIV infection. While vaccination during ART did not enhance viral control after ATI, ART has not yet been interrupted in RMs vaccinated pre-infection that showed lower PVL during acute infection and ART initiation. Monitoring of viral dynamics post-ATI in this group as well as reservoir characterization in all RMs will establish the ability of vaccine-elicited cells to alter SIV persistence.
Table or Figure
