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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional profiles of sorted CD8+ and CD4+ memory T cells from CP and NP and unvaccinated control RM 7 days prior to, and 4 and 14 days after wt SIVmac239 challenge by microarray analysis.

ABSTRACT: Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses. There are two protection outcome groups, complete protect (CP) and non-protect (NP) animals. Memory T cells (CD4+ or CD8+) were sorted for three time points, seven days pre-challenge, four days post-challenge and fourteen days post-challenge.

ORGANISM(S): Macaca mulatta

SUBMITTER: Francois Lefebvre

PROVIDER: E-GEOD-39968 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptional profiles of unfractionated lymph nodes cells obtained from completely protected, non protected and unvaccinated control rhesus macaques seven days prior to, and four and fourteen days after wt SIVmac239 challenge by microarray analysis.

Project description:Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses. There are four protection outcome groups: unvaccinated control (C), complete protect (CP), non-protect (NP) and partial protect (PP). Respectively for these groups, there are 7, 9, 6 and 4 animals sampled seven days pre-challenge (minus7PCD); 9, 13, 5 and 5 animals sampled four days post-challenge (4PCD) and 8, 11, 5 and 3 fourteen days post-challenge (14PCD).

2012-08-08 | E-GEOD-39967 | biostudies-arrayexpress

Transcriptional profiles of sorted CD8+ and CD4+ memory T cells from CP and NP and unvaccinated control RM 7 days prior to, and 4 and 14 days after wt SIVmac239 challenge by microarray analysis.

2012-08-09 | GSE39968 | GEO

2012-08-09 | GSE39967 | 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

Rapid SIV Env-specific mucosal and serum antibody induction augments cellular immunity in protecting immunized, elite-controller macaques against high dose heterologous SIV challenge

Project description:Goal of this study was to assess the levels of protection and investigate cellular, humoral, and mucosal immune correlates on the functional and gene transcriptional levels in elite-controller macaques following high dose SIV challenge. Three experimental, post SIV smE660 challenge macaque jejunal samples were individually compared to four pre SIV smE660 challenge baseline samples.

2010-08-23 | E-GEOD-23722 | biostudies-arrayexpress

VIA of EM CD8 T cells in vaccinated monkeys

Project description:The goal of an effective AIDS vaccine is to generate immunity that will prevent HIV-1 acquisition. Despite limited progress towards this goal, renewed optimism has followed the recent success of the RV144 vaccine trial in Thailand. However, the lack of complete protection in this trial suggests that breakthroughs, where infection occurs despite adequate vaccination, will be a reality for many vaccine candidates. We previously reported that neutralizing antibodies elicited by DNA prime/rAd5 boost vaccination with SIVmac239 Gag/Pol and Env provided protection against pathogenic SIVsmE660 acquisition after repeated mucosal challenge. Here, we report that SIV-specific CD8+ T cells elicited by that vaccine lowered both peak and set-point viral loads in macaques that became infected despite vaccination. These SIV-specific CD8+ T cells showed strong virus inhibitory activity (VIA) and displayed an effector memory (EM) phenotype. VIA correlated with high levels of CD107a mobilization and perforin expression in SIV-specific CD8+ T cells. Remarkably, both the frequency and the number of Gag CM9-specific public clonotypes were strongly correlated with VIA mediated by EM CD8+ T cells. The ability to elicit such virus-specific EM CD8+ T cells might contribute substantially to an efficacious HIV/AIDS vaccine, even after breakthrough infection. Gag CM9-specific EM CD8+ T cells (CD28 low CD95 high tetramer+) from SIV-negative macaques at 12 wks post-DNA/rAd5 immunization were sorted by flow cytometry for microarray studies. RNA samples from strong VIA animals with (n=3) or without (n=6) CM9 peptide stimulation, along with CM9 peptide stimulated samples from weak VIA animals (n=2) were prepared using the Illumina beads station assay and hybridized to the Illumina HumanHT-12 version 4 Expression BeadChip.

2012-06-14 | E-GEOD-35628 | biostudies-arrayexpress

Vaccine-Elicited CD4 T Cells Induce Immunopathology Following Chronic LCMV Infection

Project description:CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent form of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. Splenic GP66-specific CD4 T cells from mice immunized with either a LMwt vaccine (sham) or LMgp61 vaccine (CD4 vaccine) were purified by FACS on day 8 post-infection with LCMV clone 13

2014-12-04 | E-GEOD-63825 | biostudies-arrayexpress

Vaccine-Elicited CD4 T Cells Induce Immunopathology Following Chronic LCMV Infection

2014-12-04 | GSE63825 | GEO

Transcriptome Profiles of Gag-Specific CD8+ T Cells Induced by Live Attenuated SIV Vaccine

Project description:SIVmac239Δnef (SIVΔnef) live attenuated vaccine (LAV) induces the best protection among all the vaccine modalities tested in rhesus macaque model of HIV-1 infection. Time-dependent protection is a unique feature of this vaccine: macaques are not protected at 3-5 weeks post vaccination (WPV), whereas immune protection emerges between 15 and 20 WPV. To elucidate the protection mechanisms induced by SIVΔnef vaccine, we longitudinally compared the global gene expression profiles of SIV Gag-CM9+ CD8+ (Gag-specific CD8+) T cells from peripheral blood of Mamu-A*01 rhesus macaques at 3 and 20 WPV using rhesus microarray. We found that gene expression profiles of Gag-specific CD8+ T cells at 20 WPV are qualitatively different from those at 3 WPV. At 20 WPV, the most significant transcriptional changes of Gag-specific CD8+ T cells were genes involved in cell activation, differentiation and maturation toward central memory cells. Our study indicates that a higher quality of SIV-specific CD8+ T cells elicited by SIVΔnef over time may contribute to the maturation of time dependent protection.

2015-12-02 | GSE75567 | GEO

Correlates of protection against SIVmac239 infection in rhesus macaques immunized with chimpanzee-derived adenovirus vectors

Project description:An efficacious vaccine to HIV-1 remains elusive. We tested two vaccine regimens based on prime-boosting with two chimpanzee-origin adenovirus (Ad) vectors (SAdV) of serotypes SAdV24 and SAdV23 or two distinct human serotype Ad vectors (HAdV), i.e., HAdV5 and HAdV26, expressing Gag and gp160 of SIVmac239 for induction of protection against repeated low dose rectal SIVmac251 challenges in Indian rhesus macaques (RMs). Animals were rendered seropositive to the HAdV vectors prior to vaccination. In RMs with non-controller genotypes, the SAdV vectors achieved significant reduction in viral acquisition. In RMs with controller genotypes, both vaccine regimens reduced set-point and peak viral loads and accelerated viral clearance. In SAdV-vaccinated RMs resistance against infection correlated with levels of circulating envelope (Env)-specific antibody (Ab) titers. In both vaccine groups CD8+T cells controlled viral loads upon infection. Circulating CD4+ and CD8+ T cells showed significant changes in their transcriptome over time following vaccination, which differed between the vaccine groups. T cells from SIV-resistant RMs had unique transcriptional profiles indicating that both follicular T helper (TFH) cell responses and highly activated CD8+ T cells may play a role in protection. Our results demonstrate that SAdV-based candidate AIDS vaccines provide protection from virus acquisition and replication in a stringent SIV challenge model in RMs and may thus outperform HIV-1 vaccines that have undergone large-scale clinical efficacy testing in humans.

2019-05-21 | GSE102115 | GEO

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