Induction of CD8+ Regulatory T Cells Protects Macaques against SIV Challenge

SummaryEfforts to develop a vaccine against HIV have so far met with limited success. Given that CD4+ T cell activation drives the initial burst of viral replication, we explored in macaques whether an oral vaccine comprised of Lactobacillus plantarum, a commensal bacterium that favors immune tolerance, and inactivated simian immunodeficiency virus mac239 (SIVmac239) would induce CD4+ T cell unresponsiveness/tolerance toward SIV antigens and thereby prevent the establishment of SIV infection. The tolerogenic vaccine induced MHC-Ib/E-restricted CD8+ regulatory T cells (Tregs) that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15 of 16 animals without inducing SIV-specific antibodies or cytotoxic T lymphocytes. Of 16 macaques that were intrarectally challenged with SIVmac239 or heterologous strain SIVB670, 15 were sterilely protected. In four macaques that were rechallenged intravenously, plasma SIV levels peaked slightly and then dropped to undetectable levels, although the animals subsequently harbored intracellular SIV DNA. Infusion of CD8 antibodies confirmed the role of CD8+ Tregs in preventing/suppressing SIV in vivo. These findings suggest a new avenue of research toward developing an HIV-1 vaccine.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Oral inactivated SIV adjuvanted by Lactobacillus plantarum induces tolerance to SIV
► MHC Ib/E-restricted CD8+ Tregs prevent SIV-harboring CD4+ T cell activation
► CD8+ Tregs suppress SIV replication in newly infected CD4+ T cells ex vivo
► CD8+ Tregs protect macaques from mucosal SIV challenge