Transcriptional profiling of peripheral CD8+T cell responses to SIVΔnef and SIVmac251 challenge reveals a link between protective immunity and induction of systemic immunoregulatory mechanisms

Abstract

Immunization of macaques with attenuated simian immunodeficiency virus (SIV) with deletions in nef (SIVΔnef) is shown to elicit protective immunity to infection by pathogenic SIV, yet the mechanisms that orchestrate protection and prevent pathogenesis remains unknown. We utilized whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8+ T cells of rhesus macaques vaccinated with SIVmac239Δnef and challenged with pathogenic SIVmac251. Our findings suggest that protective immunity to pathogenic SIV infection induced by SIVmac239Δnef is associated with balanced induction of T cell activation and immunoregulatory mechanisms and dampened activation of interferon-induced signaling pathways and cytolytic enzyme production as compared with pathogenic SIVmac251 infection of unvaccinated controls. We provide evidence that protective immunity to SIVmac251 correlates with induction of biomarkers of T cell activation, differentiation, signaling, and adhesion that were down regulated in unvaccinated controls. The study highlights potential immunomodulatory networks associated with protective immunity against the virus.

Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

“…A critical future question will be to determine whether immune responses that are effective in controlling ⌬GY will enable pig-tailed macaques to resist pathogenic challenge viruses. Although the SIV ⌬Nef model, in which SIVmac239 is attenuated by deletion of its nef gene, remains the best model for protection from homologous SIV challenges (116)(117)(118), ⌬Nef provides less effective protection from heterologous SIV or simian-human immunodeficiency virus (SHIV) challenges (119)(120)(121). Studies in pig-tailed macaques that assess the ability of ⌬GY infection to elicit protective immune responses are in progress.…”

Transcription profiling of CD4+ T cells in rhesus macaques that infected with simian‐human immunodeficiency virus and re‐challenged with SIVmac251

“…The impact of the induction of IFN signaling pathways in CD8 + T cell transcriptional responses of vaccinated and unvaccinated animals has been demonstrated and vaccine‐based protective immunity to HIV/SIV infection in CD8 + T cells is associated with differential regulation of interferon signaling pathways . George et al.…”

“…George et al. , reported that although significant changes in transcription of IFNα were not detected during the vaccination period or following challenge of the vaccinated animals, numerous IFN‐induced factors were up regulated in circulating CD8 + T cells of unvaccinated animals at 3 weeks post infection including IFITM3, IFI6, IFI27, IFI35, and IFI44. Similar induction of IFN associated genes was comparatively absent at all time points during the vaccination period and again at 3 weeks post challenge in SIV Δnef vaccinated animals.…”

“…The impact of the induction of IFN signaling pathways in CD8 + T cell transcriptional responses of vaccinated and unvaccinated animals has been demonstrated and vaccine-based protective immunity to HIV/SIV infection in CD8 + T cells is associated with differential regulation of interferon signaling pathways [9]. George et al [9], reported that although significant changes in transcription of IFNa were not detected during the vaccination period or following challenge of the vaccinated animals, numerous IFN-induced factors were up regulated in circulating CD8 + T cells of unvaccinated animals at 3 weeks post infection including IFITM3, IFI6, IFI27, IFI35, and IFI44. Similar induction of IFN associated genes was comparatively absent at all time points during the vaccination period and again at 3 weeks post challenge in SIV Dnef vaccinated animals.…”

“…Immunization of rhesus macaques with a live-attenuated SIV Dnef vaccine has been shown to elicit protective immunity against pathogenic SIV strains [13,32]. Protective immunity in CD8 + T cells of rhesus macaques vaccinated with SIVmac239Dnef and challenged with pathogenic SIVmac251 were evaluated using global transcription profiles and protective immunity of vaccinated animals identified a number of genes associated with balanced induction of T-cell activation, immunoregulatory mechanisms, dampened activation of interferon-induced signaling pathways, and cytolytic enzyme production [9]. Most recently, using SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors, Hansen et al [15], reported protection of macaques from highly pathogenic SIVmac239 challenge through enhancement of the magnitude of the peak SIV-specific CD8 + T-cell responses in the vaccine phase which occurred without anamnestic T-cell responses.…”