Journal article
Gene expression and chromatin conformation of microglia in virally suppressed people with HIV
Life science alliance, v 7(10)
01 Oct 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.
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Details
- Title
- Gene expression and chromatin conformation of microglia in virally suppressed people with HIV
- Creators
- Johannes Cm Schlachetzki - University of California, San DiegoSara Gianella - University of California SystemZhengyu Ouyang - University of California, San DiegoAddison J Lana - University of California, San DiegoXiaoxu Yang - University of UtahSydney O'Brien - University of California, San DiegoJean F Challacombe - University of California, San DiegoPeter J Gaskill - Drexel UniversityKelly L Jordan-SciuttoAntoine Chaillon - University of California SystemDavid Moore - University of California, San DiegoCristian L Achim - University of California, San DiegoRonald J Ellis - University of California, San DiegoDavey M Smith - University of California SystemChristopher K Glass - University of California, San Diego
- Publication Details
- Life science alliance, v 7(10)
- Publisher
- Life Science Alliance
- Number of pages
- 13
- Grant note
- National Institutes of Health: AI036214, AI169609, DA055491, MH062512, UL1TR001442, AI164559, U24 MH100928, P30 AI036214, 1RF1AG061060-01, 1R21MH134401-01, K99HD111686, R01AI164559
We would like to thank the participants of the Last Gift study for their tissue donation and support. This study was supported by NIH grants 1RF1AG061060-01 (CK Glass) , 1R21MH134401-01 (JCM Schlachetzki and X Yang) , K99HD111686 (X Yang) , and R01AI164559 (HOPE Delaney Collaboratory) . This work was also supported by the Department of Veterans Affairs, the James B Pendleton Charitable Trust, the NIH-funded San Diego Center for AIDS Research (P30 AI036214) , and grants from the National Institutes of Health AI036214 (DM Smith-CFAR) , AI169609 (BEAT Delaney Collaboratory) , DA055491 (A Chaillon) , MH062512 (HNRC) , UL1TR001442 (ACTRI) , AI164559 (HOPE Delaney Collaboratory) , and U24 MH100928 (California NeuroAIDS Tissue Network) .
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001280066700001
- Scopus ID
- 2-s2.0-85199933974
- Other Identifier
- 991021894713404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biology