Unknown,Transcriptomics,Genomics,Proteomics

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Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction

ABSTRACT: In this study three Indian rhesus macaques were infected with Simian Immunodeficiency Virus (SIVmac251). This generates a chronic infection mirroring AIDS in the animals. Prior to infection (day 0) and at two different time-points post-infection (day 21 and day 90), intestinal resection biopsies were performed. The intestinal tissue was then separated into different sub-sections including lamina-propria lymphocytes (LPL), intra-epithelial lymphocytes (IEL), stroma or matrix and epithelium. In this study we report the genome-wide transcriptional response at the two different time-points, specific to LPL, relative to pre-infection samples. For this purpose we have used the Affymetrix Rhesus Macaque GeneChip. 3 Rhesus Macaques prior to infection and 21 and 90 days of infection

ORGANISM(S): Macaca mulatta

SUBMITTER: Deepak Kaushal

PROVIDER: E-GEOD-34300 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:CD8+ T-cells inhibit virus replication in SIV-infected rhesus macaques (RM). However, it is unclear to what extent the viral suppression mediated by CD8+ T-cells reflects direct killing of infected cells as opposed to indirect, non-cytolytic mechanisms. In this study, we used functional genomics to investigate potential mechanisms of in vivo viral suppression mediated by CD8+ lymphocytes. Eight chronically SIVmac239-infected RMs underwent CD8+ lymphocyte depletion, and RNA from whole blood was obtained prior to depletion, at the nadir of CD8+ lymphocytes (5 days post-depletion), and during the repopulation phase (11 days post-depletion). Principal components analysis demonstrated that overall gene expression during the nadir of CD8+ T-cells was highly divergent from other intervals. Conversely, the genomic signature of samples from the CD8+ cell rebound phase was similar to that of pre-depletion samples. During CD8+ lymphocyte depletion we detected a strongly significant decrease in the expression of the genes encoding CD8α and CD8β chains, consistent with the near complete CD8+ T-cell depletion measured by flow cytometry. Of note, we observed significant down-regulation of the expression of genes encoding for factors that can suppress SIV replication, including the CCR5-binding chemokine CCL5/Rantes, several retroviral restriction factors (TRIM10, TRIM15, APOBEC3G/H) and defensins. Reduced expression of various genes related to T cell activation and proliferation was also observed. Collectively, these data indicate that depletion of CD8+ lymphocytes in SIV-infected RMs is associated with the establishment of a pattern of gene expression that may result in increased intrinsic permissivity to virus replication. A total of 60 RNA samples were hybridized on to Rhesus Affymetrix 3' Expression arrays. The study was composed of 8 replicate rhesus macaques subjected to SIVmac239 infection and followed over infection, during subsequent treatment with monocloncal antibody OKT8F to deplete CD8+ T lymphocytes, antiretroviral therapy to suppress virus. Samples were taken at various time points during acute and chronic infection, after CD8+ cell depletion, after CD8+ cell reconstition, and during ART suppression of virus.

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Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction

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