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

Abstract

Efforts 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.

Paradigm Changes and the Future of HIV Vaccine Research: A Summary of a Workshop Held in Baltimore on 20 November 2013

“…This vaccine was found to induce a previously unrecognized class of non-cytolytic MHC 1b/E restricted CD8 regulatory T cells (Tregs) which specifically suppressed the activation of SIV positive CD4 T lymphocytes. This suppression which prevented the initial burst of virus replication in vivo, permanently protected 15 out of 16 macaques from infection [22]. This strong protective effect induced by CD8 + Tregs was obtained in experiments that were based on an "out of the box" innovative paradigm, confirming the assumption that SIV requires activated immune cells for its replication.…”

“…13) The surprising extensive protection against SIV achieved in macaques with an oral tolerogenic vaccine that did not elicit SIVspecific antibodies nor CTLs was obtained by an investigator-driven research project that was not funded by a governmental or large scale international research organization [22]. It was entirely sponsored by a private benefactor who agreed to fund a risky project based on an unorthodox paradigm for which minimal preliminary data existed.…”

Delivery strategies to enhance oral vaccination against enteric infections

“…Another novel oral adjuvant strategy has been the administration of live bacterial adjuvants such as Bacillus Calmette-Guérin (BCG), Lactobacillus plantarum or L. rhamnosus together with inactivated simian immunodeficiency virus (SIV). This led to the protection of macaques against intra-rectal SIV challenge, albeit by a novel means of tolerance induction rather than antibody or cytotoxic lymphocyte (CTL)-mediated protection [137].…”

HIV-1 vaccines

“…These findings suggest a new avenue of research toward developing an HIV-1 vaccine. 107 Interestingly, human dimeric IgA1 mAb-treated rhesus macaques remained free of virus after intrarectal SHIV challenge while treatment with dimeric IgA2 was much less effective. Protection was correlated with virus capture and inhibition of transcytosis of cell-free virus.…”