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HIV transcription persists in the brain of virally suppressed people with HIV
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PLoS Pathog Published: August 8, 2024
Abstract
HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders. Whether HIV transcription persists in the brain despite viral suppression with antiretroviral therapy (ART) and is subject to the same blocks to transcription seen in other tissues and blood, is unclear. Here, we quantified the level of HIV transcripts in frontal cortex tissue from virally suppressed or non-virally suppressed people with HIV (PWH).
HIV transcriptional profiling of frontal cortex brain tissue (and PBMCs where available) from virally suppressed (n = 11) and non-virally suppressed PWH (n = 13) was performed using digital polymerase chain reaction assays (dPCR). CD68+ myeloid cells or CD3+ T cells expressing HIV p24 protein present in frontal cortex tissue was detected using multiplex immunofluorescence imaging.
Frontal cortex brain tissue from PWH had HIV TAR (n = 23/24) and Long-LTR (n = 20/24) transcripts. Completion of HIV transcription was evident in brain tissue from 12/13 non-virally suppressed PWH and from 5/11 virally suppressed PWH, with HIV p24+CD68+ cells detected in these individuals. While a block to proximal elongation was present in frontal cortex tissue from both PWH groups, this block was more extensive in virally suppressed PWH.
These findings suggest that the brain is a transcriptionally active HIV reservoir in a subset of virally suppressed PWH.
Notably, the total levels of each HIV RNA transcript was associated with total HIV DNA levels in the brain (P<0.05 for all; Fig 2), demonstrating that the level of HIV transcription is associated with reservoir size within the brain. HIV RNA transcripts were also associated with levels of intact proviral DNA (S2 Fig). Together, these data suggest that transcriptional activity is directly associated with HIV reservoir size in the brain.
Author summary
HIV reservoirs have been shown to persist within the brain of people with HIV (PWH) despite antiretroviral therapy (ART). Whether this reservoir is transcriptionally or translationally active within the brain during ART remains unclear. We demonstrated that transcription persists in brain of virally suppressed PWH, although at a lower level than reservoirs in circulating CD4+ T cells. Furthermore, while HIV transcripts related to initiation of HIV transcription were detected in brain tissue from all virally suppressed PWH assessed, transcripts related to the completion of transcription was only evident in a small subset. Within this subset, we further demonstrated the presence of HIV proteins within resident brain cells. Our study characterises the persistence of ongoing HIV transcription and translation within the brain of PWH despite viral suppression. This may provide a source of neuroinflammation and contribute to the development of HIV associated neurocognitive disorders.
CROI 2021: NEURON DAMAGE AND RESERVOIR ARE SECONDARY TO HIV TRANSCRIPTS DESPITE SUPPRESSIVE ART
CSF is an HIV reservoir with high transcription activity despite ART. It is biologically significant because of compromised neuron integrity likely mediated by transcription products (tat). Therapies targeting transcription should be developed.
CROI 2022: HIV-1 RNA TRANSCRIPTS IN CSF CD4+ T CELLS, NOT MONOCYTES, ARE LINKED TO BRAIN INJURY
CROI2024: HIV Transcription Persists in the Brain of People With HIV and Viral Suppression
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