Elevation of cell-associated HIV-1 transcripts in CSF CD4+T cells, despite effective antiretroviral therapy, is linked to brain injury
Proceedings of the National Academy of Sciences of the United States of America(2022)
摘要
Antiretroviral therapy (ART) can attain prolonged undetectable HIV- 1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (H-1 MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p (<) 0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std beta=-0.73; p=0.007) and posterior cingulate (Std beta=-0.61; p= 0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3(+)CD49d(+)integrin beta 7-, CCR5(+)CD4(+) T-cells were highly enriched in CSF, compared with PBMC (p.0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4(+) T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.
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关键词
cerebrospinal fluid,neuropathogenesis,intracellular HIV-1 RNA-transcripts,CD4+T cells,brain injury
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