| Popis: |
ObjectiveDespite effective antiretroviral therapy (ART), brain injury remains prevalent in people living with HIV-1 infection (PLHIV) possibly due to ART’s lack of direct inhibition of transcription with continued local production of viral transcripts and neurotoxic proteins, such as Tat, rather than cell-free whole virion toxicity. We quantified cell-associated (CA) HIV-1 RNA-transcripts in CSF and blood, in relation to proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in well characterised PLHIV.MethodsRNA was extracted from cells in 16 paired samples of CSF and blood, from PLHIV on fully suppressive ART. HIV-1 CA-RNA copies were measured using the highly sensitive Double-R assay and normalized /106 CD4+ T cells. 18-colour flow cytometry was used to count and analyse CD4+ T cells and monocytes in CSF and blood. The concentrations of major brain metabolites from 1H MRS in frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate areas were measured. Brain injury in each voxel was defined using a composite score derived by principal component analysis.Results14/16 CSF cell samples had quantifiable HIV-1 CA-RNA transcripts, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T cells; p90% CD14+CD16+ phenotype). CXCR3+CD49d+integrin ß7-negative, CCR5+ CD4+ T cells were significantly enriched in CSF, compared with PBMC (p ConclusionsElevated HIV-1 transcripts in CSF cells were associated with in vivo brain injury, despite suppressive ART. The cellular source is most likely the predominant CXCR3+ CD49d+ integrinß7-CCR5+ memory CD4+ T cells, not monocytes. Inhibitors of transcription to reduce local production of potentially neurotoxic proteins, should be developed. |
