Abstract
Cellular permissiveness to HIV infection is highly heterogeneous across individuals. Heterogeneity is also found across CD4+ T cells from the same individual, where only a fraction of cells gets infected. To explore the basis of permissiveness, we performed single-cell RNA-seq analysis of non-infected CD4+ T cells from high and low permissive individuals. Transcriptional heterogeneity translated in a continuum of cell states, driven by T-cell receptor-mediated cell activation and was strongly linked to permissiveness. Proteins expressed at the cell surface and displaying the highest correlation with T cell activation were tested as biomarkers of cellular permissiveness to HIV. FACS sorting using antibodies against several biomarkers of permissiveness led to an increase of HIV cellular infection rates. Top candidate biomarkers included CD25, a canonical activation marker. The combination of CD25 high expression with other candidate biomarkers led to the identification of CD298, CD63 and CD317 as the best biomarkers for permissiveness. CD25highCD298highCD63highCD317high cell population showed an enrichment of HIV-infection of up to 28 fold as compared to the unsorted cell population. The purified hyper-permissive cell subpopulation was characterized by a downregulation of interferon-induced genes and several known restriction factors. Single-cell RNA-seq analysis coupled with functional characterization of cell biomarkers provides signatures of the “HIV-permissive cell”.
Highlights
In vivo and in vitro data indicates that only a small fraction of the CD4+ T cell population is successfully infected by human immunodeficiency virus (HIV)
CD4+ T cells are the main target of human immunodeficiency virus (HIV) infection
We explored cellular heterogeneity by analyzing the transcriptome profile of CD4+ T cells at single-cell level
Summary
In vivo and in vitro data indicates that only a small fraction of the CD4+ T cell population is successfully infected by HIV. Cellular heterogeneity within an individual can arise from the presence of different subsets of CD4+ T cells [14, 15], differences in response to TCR activation [16], or other determinants such as the expression of innate immunity genes [17,18,19,20]. This suggests a model where a highly permissive individual possesses CD4+ T cells that are enriched in a given cell lineage, activate more rapidly or differently, express less antiviral factors, or a combination of factors
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