Abstract
Depletion of CD4+ T cells during HIV-1 infection is mostly mediated by inflammatory cells via indirect but not clearly defined mechanisms. In this report, we used single-cell RNA-Seq (scRNA-Seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-Seq on hCD45+hCD3-hCD19- human leukocytes isolated from spleens of humanized NOD/Rag2-/-γc-/- (NRG) mice transplanted with human CD34+ hematopoietic stem progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells, including plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), macrophages, NK cells, and innate lymphoid cells (ILCs). HIV-1 infection significantly upregulated genes involved in type I IFN inflammatory pathways in each of the innate immune subsets. Interestingly, we found that TRAIL was upregulated in the innate immune populations, including pDCs, mDCs, macrophages, NK cells, and ILCs. We further demonstrated that blockade of the TRAIL signaling pathway in NRG-hu HSC mice prevented HIV-1-induced CD4+ T cell depletion in vivo. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells, and defined an important role of the TRAIL signaling pathway in HIV-1-induced CD4+ T cell depletion in vivo.
Highlights
HIV-1 infection leads to depletion and dysregulation of CD4+ T cells in patients [1]
We found that HIV1 infection upregulated the expression of TRAIL receptor death receptor 5 (DR5) but not death receptor 4 (DR4) on CD4+ T cells from spleens of humanized mice (Figure 4A)
We investigated how HIV-1 infection changed the transcriptome of human innate immune cells in lymphoid organs in NRG-hu HSC mice at the single-cell level by scRNA-Seq
Summary
HIV-1 infection leads to depletion and dysregulation of CD4+ T cells in patients [1]. We and others have reported that HIV-1 infection causes depletion and functional impairment of innate lymphoid cells (ILCs), which may contribute to systemic immune activation and CD4+ T cell depletion [12,13,14]. These studies suggest that a dysregulated innate immune response plays an important role in HIV-1 pathogenesis. Further understanding of how HIV infection leads to alterations of innate immune cells is critical for the development of new therapeutic interventions of HIV-associated diseases
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