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Mucosal innate gene signature associated with a mucosal SHIV vaccine and reduced SHIV risk in vaccinated macaques

ABSTRACT: An orally delivered HIV vaccine, which is composed of nanoparticles containing a full-length gp120-CD4 single chain (FLSC) fusion construct plus MVA and molecular adjuvants, has demonstrated 44% vaccine efficacy (p = 0.028) against repeated low-dose intrarectal challenge of rhesus macaques with SHIVSF162P4. From our previous study, we found that the innate immune responses in the rectal mucosa might contribute significantly to the protection. Since the vaccine was administered mucosally, it is critical to evaluate the innate responses in the rectal mucosa. To investigate the possible correlates of protection, we isolated total RNA from the rectal single-cell suspension and ran bulk RNAseq analysis. We distinguished the differentially expressed genes (DEGs) induced by the vaccination and found that gut metabolic pathways, extracellular matrix and antimicrobial humoral responses were altered by mucosal HIV vaccine. We further assessed the genes that were correlated with the number of challenges needed for the animals to be infected. We observed that cytoskeleton genes such as fibronectin 1, Interleukin-4 and Interleukin-13 signaling, O-linked glycosylation were among the gene signatures that inversely correlated with viral infection risk . These data provide key information on the potential biomarkers to predict the outcome of HIV vaccines and shed light on possible protection mechanisms of mucosal HIV vaccines.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE309635 | GEO | 2025/11/01

REPOSITORIES: GEO

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Project description:We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. We immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses. For the protected RM, blood was collected before vaccination, on the day of first virus exposure and six weeks after last virus challenge. Lymph node and rectal pinch biopsies were performed before vaccination and six weeks after last virus challenge. Blood was collected in tempus tubes and processed immediately according to the manufacturer’s instructions and stored at -80C. The biopsy specimens were cut into small pieces and immediately placed into RNAlater solution (Qiagen, Valencia, CA) and also stored at -80C. Total RNA from blood, lymph node and rectal biopsies was extracted using RNAeasy extraction kits (Qiagen, Valencia, CA). cDNA labeling, hybridization, staining and scanning were performed according to the manufacturer’s instructions (Affymetrix, Santa Clara, CA) for rhesus gene expression arrays.

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Mucosal innate gene signature associated with a mucosal SHIV vaccine and reduced SHIV risk in vaccinated macaques

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