期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2210584119
关键词
cerebrospinal fluid; neuropathogenesis; intracellular HIV-1 RNA-transcripts; CD4+T cells; brain injury
资金
- St Vincent's Clinic Foundation Research Grant
- AMR Translational Research Grant
- NHMRC [ID1105808]
- Australian Centre for HIV and Hepatitis Virology Research (ACH2)
- UNSW Interlude grant
- Denka Co. Ltd.
This study investigated the association between elevated HIV-1 RNA transcripts in cerebrospinal fluid (CSF) cells and brain injury in people living with HIV-1 infection. The findings suggest that the cellular source of these transcripts is likely memory CD4(+) T cells from blood rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce potential neurotoxic and inflammatory viral products.
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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