Global Transcriptional Analysis of Plasmacytoid Dendritic Cells (pDCs) in Pathogenic and Non-Pathogenic SIV Infection of Non-Human Primate Model Species Open Access

Grech, Christine Michelle (2016)

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In contrast to pathogenic HIV infections of humans and SIV rhesus macaques (RM), natural SIV infection of sooty mangabeys (SM) is typically non-pathogenic despite high viremia. Although it has been established that CD4 T cell loss is a direct result of over activation of immune system for pathogenic HIV/SIV infection as of yet, the mechanism by which SMs avoid SIV pathogenesis to AIDS is unknown. Previous studies have suggested that the modulated innate and adaptive immune response for SMs between acute and chronic infection is a result of the activation of immunoregulatory genes that arise during this period such that interferon-stimulated genes (ISGs) remain muted during chronic SIV infection in SMs. To investigate the possible mechanism by which SM avoid over activation of their immune system we sorted and RNA-sequenced (RNA-seq) plasmacytoid dendritic cells (pDCs) from blood in infected and uninfected SM and RM. pDCs are a small subset of peripheral blood mononuclear cells (PBMCs) that have been established as interferon (IFN) producing cells during acute SIV infection. To this end, we found significant up regulation ISGs in SIV-infected RM, but not in SMs. Therefore confirming the model that innate response to SIV is attenuated during chronic infection in SM. We found no expression of IFN across all four species, suggesting that pDCs in the blood are not the IFN producers during chronic infection. Thus, further exploration must be conducted in order to determine IFN producers during chronic infection.

Table of Contents

Abstract: 1

Introduction: 2

HIV pathogenesis 2

SIV infection is non-pathogenic in the majority of non-human primate models naturally infected in the wild; whereas pathogenic SIV infections only occur in experimental settings in Asian Macaca species 3

SIV pathogenesis is the result of continued over activation of the immune system 6

SIV infection of SM drives a massive IFN response that rapidly resolves 7

pDCs may cause pathogenesis in HIV and SIV infection 12

Purpose 14

Materials and Methods: 15

Overall Experimental Design 15

Animals 16

Samples 16

Flow Cytometry and Surface Cell Staining 17

Sorting 20

RNA Extraction and Library Preparation 20

RNA-Sequencing (RNA-Seq) and Analysis 21

Results: 21

RNA-Seq of purified pDCs recapitulates lineage defining features 21

Gene Expression Profiles of pDCS 25

Up regulation of ISGs in pDCs from RM, but not SM in chronic SIV-infection 26

No Significance in expression of Inhibitory genes or Restriction factors 27

pDCs from the blood lack IFN-α expression across species and infection status 30

Discussion: 31

References: 39

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