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Multiple changes at the mucosal surface are induced by protective SIV vaccination

ABSTRACT: Systemic vaccination with the attenuated virus SIVmac239-∆Nef provides sterilizing or partial protection to rhesus monkeys challenged with WT SIV strains, providing important opportunities to study key immunological components of a protective host response. Here we show that intravenous vaccination with SIVmac239-∆Nef provides two potentially crucial immunological barriers localized at mucosal surfaces that correlate with the vaccine’s protective effects against WT SIVmac251 vaginal challenge: 1) a conditioned and coordinated response from the mucosal epithelium that blunts the early inflammatory and chemotactic signalling cascade that aids virus propagation and expansion; 2) early on-site generation/diversification of SIV-specific Abs from ectopic germinal center-like lymphoid aggregates. This unique host response to WT SIVmac251 in the female reproductive tract of SIVmac239-∆Nef-vaccinated animals points to a multi-layered strategy for a protective host response during immunodeficiency virus exposure—rapid induction of humroal immunity at mucosal surfaces without the deleterious inflammatory side effects tied to innate recognition of virus. This vaccine-induced host response highlights potential key protective mechanisms needed for an effective HIV vaccine

ORGANISM(S): Macaca mulatta

PROVIDER: GSE33251 | GEO | 2012/05/31

SECONDARY ACCESSION(S): PRJNA149033

REPOSITORIES: GEO

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Multiple changes at the mucosal surface are induced by protective SIV vaccination

Project description:Systemic vaccination with the attenuated virus SIVmac239-∆Nef provides sterilizing or partial protection to rhesus monkeys challenged with WT SIV strains, providing important opportunities to study key immunological components of a protective host response. Here we show that intravenous vaccination with SIVmac239-∆Nef provides two potentially crucial immunological barriers localized at mucosal surfaces that correlate with the vaccine’s protective effects against WT SIVmac251 vaginal challenge: 1) a conditioned and coordinated response from the mucosal epithelium that blunts the early inflammatory and chemotactic signalling cascade that aids virus propagation and expansion; 2) early on-site generation/diversification of SIV-specific Abs from ectopic germinal center-like lymphoid aggregates. This unique host response to WT SIVmac251 in the female reproductive tract of SIVmac239-∆Nef-vaccinated animals points to a multi-layered strategy for a protective host response during immunodeficiency virus exposure—rapid induction of humroal immunity at mucosal surfaces without the deleterious inflammatory side effects tied to innate recognition of virus. This vaccine-induced host response highlights potential key protective mechanisms needed for an effective HIV vaccine Total RNA was isolated from the cervix of 17 Indian Rhesus macaques (3 uninfected animals; 5 unvaccinated animals 4-5 days post vaginal exposure with SIVmac251; 4 SIVmac239-∆Nef-vaccinated animals before challenge; 5 SIVmac239-∆Nef-vaccinated animals 4-5 days post vaginal exposure with SIVmac251) and prepared for hybridization on Affymetrix GeneChip Rhesus Macaque Genome Arrays. Replicate arrays were performed for a number of the samples to minimize assay noise and significant host genes altered during virus exposure in female reproductive tract tissue were identified by their associated q-values (< 0.2) and fold change in expression (> 1.2).

2012-05-30 | E-GEOD-33251 | biostudies-arrayexpress

Expression data from rhesus macaque blood CD8+ T cells

Project description:Immunization of macaques with simian immunodeficiency virus with deletions in nef (SIV?nef) has been shown to elicit protective immunity to infection by pathogenic SIV, yet our understanding of the mechanisms that orchestrate protection and prevent pathogenesis remains limited. In the study, we utilize whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8+ T cells of rhesus macaques vaccinated with SIVmac239?nef and challenged with pathogenic SIVmac251. Microarrays were used to characterize changes in gene expression in blood CD8+ T cells that occur following vaccination of rhesus macaques with attenuated SIV?nef and subsequent challenge with pathogenic SIVmac251, in comparison to corresponding changes in healthy controls and unvaccinated animals infected with pathogenic SIVmac251 CD8+ T cells were isolated by magnetic beads from the blood of healthy uninfected macaques, macaques vaccinated with SIV?nef, and unvaccinated controls infected with SIVmac251, and used for RNA extraction and hybridization on Affymetrix microarrays. Blood samples from vaccinated animals were collected prior to vaccination, at 3, 20, and 40 weeks following vaccination. After the 40 week vaccination period, macaques were challenged with SIVmac251, and blood was again collected at 3 weeks following challenge. Blood was collected from the unvaccinated controls at 3 weeks following infection with SIVmac251

2014-09-26 | E-GEOD-61766 | biostudies-arrayexpress

Expression data from rhesus macaque blood CD8+ T cells

Project description:Immunization of macaques with simian immunodeficiency virus with deletions in nef (SIVΔnef) has been shown to elicit protective immunity to infection by pathogenic SIV, yet our understanding of the mechanisms that orchestrate protection and prevent pathogenesis remains limited. In the study, we utilize 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. Microarrays were used to characterize changes in gene expression in blood CD8+ T cells that occur following vaccination of rhesus macaques with attenuated SIV∆nef and subsequent challenge with pathogenic SIVmac251, in comparison to corresponding changes in healthy controls and unvaccinated animals infected with pathogenic SIVmac251

2014-09-26 | GSE61766 | GEO

Gene expression profile in CD4+ T-cell infection with a SIV mutant related to altered humoral immune responses

Project description:A mutant simian immunodeficiency (SIVmac239) virus, found to be selected within chronically SIV-infected Burmese rhesus monkeys with relatively enhanced SIV-specific antibody responses, was reconstituted as a molecular clone. The virus (SIV Nef G63E) was then subjected to a preliminary analysis for their intracellular signal transduction and gene expression modulation patterns (as compared with wild type SIVmac239) within infected CD4+ T cells. Analysis implicated that the mutant virus had a moderately enhanced cytopathic phenotype. A SIV mutation (SIVmac239 Nef G63E) found to be enriched in rhesus monkeys with enhanced SIV-specific antibody responses was reconstituted on a pBR-based SIV molecular clone pBRmac239. HSC-F cynomolgus macaque central memory Th2-like T cells were infected with mutant and wild type SIVmac239 at MOI 5 in triplicate along with uninfected controls (i.e. a total of 9 samples) for 24 hours and subjected to analysis of their gene expression patterns.

2016-07-03 | E-GEOD-65806 | biostudies-arrayexpress

Gene expression profile in CD4+ T-cell infection with a SIV mutant related to altered humoral immune responses

2016-01-01 | GSE65806 | GEO

Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation

Project description:Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity is restricting viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by mRNA deep sequencing (mRNA-seq) at 3 and 12 days post inoculation (DPI) in 4 animals for each time point. The eight RMs were intrarectally challenged with SIVmac251 using 1 mL of a high-dose inoculum (6000 TCID50/mL). SIV inoculates were deposited at a rectal depth of 25 mm from the anus. Baseline rectal samples were obtained 14 days prior to viral challenge by pinch biopsy.

2014-04-17 | E-GEOD-56845 | biostudies-arrayexpress

Nef-mediated downmodulation of CD3 dampens immune activation and is critical for maintenance of high virus loads in SIV-infected macaques

Project description:The inability of Nef to downmodulate the T cell receptor CD3 distinguishes HIV-1 from most other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in viral immune evasion and pathogenicity remained speculative. Here, we selectively disrupted this Nef activity in SIVmac239 and analyzed the consequences for the virological, immunological and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3 did not affect viral replication during acute infection but was associated with increased immune activation and antiviral gene expression. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to SIV infection and is critical for viral immune evasion.

2020-03-09 | GSE141626 | GEO

Transcription profiling by high throughput sequencing of rhesus macaques vaccinated with two regimens to define correlates of protection against repeated low dose simian immunodeficiency virus challenges

Project description:The study was undertaken to define correlates of protection against repeated low dose rectal SIVmac251 challenges in rhesus macaques (RMs) vaccinated with two regimens. Two groups of six RMs were immunized with either the attenuated SIVdeltanef virus, which establishes a persistent low-level infection and induces protective immunity against high dose challenges with SIVmac, or with two doses of an AdHu5 vector expressing Gag of SIVmac239 (AdHu5gag), that was given at a two-month interval.

2013-09-28 | E-MTAB-1130 | biostudies-arrayexpress

Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation

2014-04-17 | GSE56845 | GEO

Transcriptomic profiling of rhesus macaques vaccinated with ALVAC-SIV/gp120 adjuvanted in Alum or MF59.

Project description:The Canarypox/gp120/Alum vaccines decreased the risk of HIV acquisition in humans. We demonstrate here the efficacy of this vaccine regimen also in the SIVmac251 macaque model when we used the alum but not the MF59 adjuvant. Analysis of innate and adaptive cell responses, envelope antibodies Fc profiles and glycoforms demonstrated a lower inflammatory response with alum than MF59. Alum elicited mucosal V2 peptide-specific IgG associated with vaccine efficacy whereas the MF59 induced mucosal V2 peptide-specific IgG associated with increased risk of infection. Alum modulated the expression of 12 genes, 7 of which are part of the RAS pathway, that correlates with vaccine efficacy and were linked to innate responses that preserve mucosal integrity and adaptive mucosal antibody response to V2. Thus, activation of the RAS pathway, preservation of mucosal integrity and mucosal antibody to V2 in concert, reduce the risk of SIVmac251 acquisition. Fifty-four (54) rhesus macaques were randomized into two vaccination groups. One group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in MF59 adjuvant (at week 12 and week 24). The second group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in Alum adjuvant (at week 12 and week 24). Blood samples were taken pre-vaccination, 24 hours after the first prime (post-1st imunization at week 0) and 24 hours after the first boost (post-3rd immunization at week 12). All the samples were taken before SIV challenge. Blood samples were conserved in PAXgene tubes. RNA was extracted and hybridized to Illumina beadchips. technical replicate: P162_P382_post1st, P162_P382_post1st_rep1

2016-05-29 | E-GEOD-72624 | biostudies-arrayexpress

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