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HIV viral transcription and immune perturbations in the CNS of people with HIV despite ART
Shelli F. Farhadian, … , Yuval Kluger, Serena Spudich
Shelli F. Farhadian, … , Yuval Kluger, Serena Spudich
Published July 8, 2022
Citation Information: JCI Insight. 2022;7(13):e160267. https://doi.org/10.1172/jci.insight.160267.
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Research Article AIDS/HIV Neuroscience

HIV viral transcription and immune perturbations in the CNS of people with HIV despite ART

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Abstract

People with HIV (PWH) on antiretroviral therapy (ART) experience elevated rates of neurological impairment, despite controlling for demographic factors and comorbidities, suggesting viral or neuroimmune etiologies for these deficits. Here, we apply multimodal and cross-compartmental single-cell analyses of paired cerebrospinal fluid (CSF) and peripheral blood in PWH and uninfected controls. We demonstrate that a subset of central memory CD4+ T cells in the CSF produced HIV-1 RNA, despite apparent systemic viral suppression, and that HIV-1–infected cells were more frequently found in the CSF than in the blood. Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we show that the cell surface marker CD204 is a reliable marker for rare microglia-like cells in the CSF, which have been implicated in HIV neuropathogenesis, but which we did not find to contain HIV transcripts. Through a feature selection method for supervised deep learning of single-cell transcriptomes, we find that abnormal CD8+ T cell activation, rather than CD4+ T cell abnormalities, predominated in the CSF of PWH compared with controls. Overall, these findings suggest ongoing CNS viral persistence and compartmentalized CNS neuroimmune effects of HIV infection during ART and demonstrate the power of single-cell studies of CSF to better understand the CNS reservoir during HIV infection.

Authors

Shelli F. Farhadian, Ofir Lindenbaum, Jun Zhao, Michael J. Corley, Yunju Im, Hannah Walsh, Alyssa Vecchio, Rolando Garcia-Milian, Jennifer Chiarella, Michelle Chintanaphol, Rachela Calvi, Guilin Wang, Lishomwa C. Ndhlovu, Jennifer Yoon, Diane Trotta, Shuangge Ma, Yuval Kluger, Serena Spudich

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Figure 1

Single-cell RNA sequencing of CSF and blood from PWH and uninfected controls.

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Single-cell RNA sequencing of CSF and blood from PWH and uninfected cont...
(A) Combined (left) and split (right) uniform manifold approximation and projection (UMAP) of CSF cells and PBMCs (blood, BLD) from PWH and uninfected controls (CTRL). n = 75,734 cells (30,040 CSF cells and 35,694 PBMCs). (B) Frequency of immune cell types in the CSF in PWH compared with uninfected controls demonstrating significantly (P < 0.05, χ2 test) more CD8+ and fewer CD4+ T cells in the CSF of PWH compared with uninfected controls (n = 17,685 cells from 5 PWH and n = 12,355 cells from 4 uninfected controls). (C) HIV transcript expression levels in blood (PBMCs) and CSF single cells mapped to consensus HXB2 HIV reference sequence. (D) HIV transcript expression within annotated immune cell subsets using reference-based mapping. Shown in pink is violin plot with black dots representing individual cells in which HIV transcripts were detected. For C and D, data are combined from 4 PWH (n = 16,147 CSF cells, and n = 17,061 PBMCs). (E) Alignment track of HIV transcripts in all single cells from CSF and blood of 1 participant (HIV-1044) across the annotated HXB2 consensus sequence. Top panel with read coverage displayed as histogram and below is pile-up view of the individual reads. pDC, plasmacytoid DC; TCM, T central memory; CTL, cytoxic T lymphocyte.

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