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Apolipoprotein E-Dependent Differences in Innate Immune Responses of Maturing Human Neuroepithelial Progenitor Cells Exposed to HIV-1

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Abstract

HIV enters the brain early during infection and induces a chronic inflammatory state that can result in neurological abnormalities in a subset of infected individuals. To investigate the effects of HIV exposure on neurogenesis and neuronal survival in the brain, we have used a model system consisting of human neuroepithelial progenitor (NEP) cells that undergo directed differentiation into astrocytes and neurons in vitro. Changes in gene expression in NEP cultures as a result of HIV exposure were investigated using gene expression microarrays with the Illumina HT-12 V4_0_R1 platform array. Through this approach, we identified a group of genes specifically upregulated by exposure to virus that are strongly related to interferon induced responses and antigen presentation. When the data were stratified by their apolipoprotein genotype, this innate immune response was more robust in the apolipoprotein E3/E3 genotype cultures than in the apolipoprotein E3/E4 counterparts. Biological processes as defined by the gene ontology (GO) program were also differently affected upon virus exposure in cultures of the two genotypes, particularly those related to antigen presentation and the actions of interferons. Differences occurred in both in numbers of genes affected and their significance in the GO processes in which they participate, with apoE3/E3 > apoE3/E4. These data suggest that maturing NEP cultures recognize HIV and respond to it by mounting an innate immune response with a vigor that is influenced by the apolipoprotein E genotype of the cells.

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Acknowledgments

This study was supported by a generous grant from the Campbell Foundation (to MMc), and by the Department of Veteran Affairs Merit Review Program. We thank Toumy Guettouche and Loida Navarro at the Oncogenomics Core Facility, Sylvester Cancer Center, for their help with the gene expression microarrays. We also thank Chunjing Wu and Alina Fernandez for excellent technical assistance with cell culture, and Jesus Fernandez for initial technical assistance with apoE genotyping, Human brain tissue specimens were obtained from the Laboratory of Developmental Biology, University of Washington School of Medicine, Seattle, WA. The Laboratory of Developmental Biology program is supported by NIH Award Number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Research Service, Bruce W. Carter Veterans Affairs Medical Center, 1201 NW 16th Street, Miami, FL, 33125, USA

    Rebeca Geffin, Ricardo Martinez, Roberto Perez & Micheline McCarthy

  2. Department of Neurology, Miller School of Medicine, University of Miami, 1120 NW 14th St, Miami, FL, 33136, USA

    Rebeca Geffin & Micheline McCarthy

  3. Biostatistics and Bioinformatics Core/Division of Bioinformatics, University of Miami/Sylvester Comprehensive Cancer Center, Clinical Research Building, 1120 NW 14th Street, 6th Floor, Room 610 L, Miami, FL, 33136, USA

    Biju Issac

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  1. Rebeca Geffin
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  2. Ricardo Martinez
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  5. Micheline McCarthy
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Corresponding author

Correspondence to Micheline McCarthy.

Electronic supplementary material

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Table S1

Genes differentially regulated in cells differentiated from apoE4/E4 NEP: fold change for virus vs. mock and mock vs. untreated, FC ≥1.5 (DOC 33 kb)

Table S2

Top ten enrichment pathways differentially regulated between virus and mock treatments in cells differentiated from NEP, independent of their apoE genotype (DOC 36 kb)

Table S3

Top ten GO processes differentially regulated between virus and mock treatments in cells differentiated from NEP, independent of their of apoE genotype (DOC 40 kb)

Table S4

Top ten enrichment pathways differentially regulated between virus and mock treatments in cells differentiated from apoE3/E3 NEP (DOC 36 kb)

Table S5

Top ten GO processes differentially regulated between virus and mock treatments in cells differentiated from apoE3/E3 NEP (DOC 38 kb)

Table S6

Top ten enrichment pathways differentially regulated between virus and mock treatments in cells differentiated from apoE3/E4 NEP (DOC 35 kb)

Table S7

Top ten GO processes differentially regulated between virus and mock treatments in cells differentiated from apoE3/E4 NEP (DOC 41 kb)

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Geffin, R., Martinez, R., Perez, R. et al. Apolipoprotein E-Dependent Differences in Innate Immune Responses of Maturing Human Neuroepithelial Progenitor Cells Exposed to HIV-1. J Neuroimmune Pharmacol 8, 1010–1026 (2013). https://doi.org/10.1007/s11481-013-9478-0

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