@article{17054430f9cd4ce49ded96f70526eed3,
title = "Intact HIV Proviruses Persist in the Brain Despite Viral Suppression with ART",
abstract = "Objective: Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure and possible cause of comorbid disease. However, the size and replication competent nature of the central nervous system (CNS) reservoir is unclear. Here, we used the intact proviral DNA assay (IPDA) to provide the first quantitative assessment of the intact and defective HIV reservoir in the brain of people with HIV (PWH). Methods: Total, intact, and defective HIV proviruses were measured in autopsy frontal lobe tissue from viremic (n = 18) or virologically suppressed (n = 12) PWH. Total or intact/defective proviruses were measured by detection of HIV pol or the IPDA, respectively, through use of droplet digital polymerase chain reaction (ddPCR). HIV-seronegative individuals were included as controls (n = 6). Results: Total HIV DNA was present at similar levels in brain tissues from untreated viremic and antiretroviral (ART)-suppressed individuals (median = 22.3 vs 26.2 HIV pol copies/106 cells), reflecting a stable CNS reservoir of HIV that persists despite therapy. Furthermore, 8 of 10 viremic and 6 of 9 virally suppressed PWH also harbored intact proviruses in the CNS (4.63 vs 12.7 intact copies/106 cells). Viral reservoirs in CNS and matched lymphoid tissue were similar in the composition of intact and/or defective proviruses, albeit at lower levels in the brain. Importantly, CNS resident CD68+ myeloid cells in virally suppressed individuals harbored HIV DNA, directly showing the presence of a CNS resident HIV reservoir. Interpretation: Our results demonstrate the first evidence for an intact, potentially replication competent HIV reservoir in the CNS of virally suppressed PWH. ANN NEUROL 2022;92:532–544.",
author = "Cochrane, {Catherine R.} and Angelovich, {Thomas A.} and Byrnes, {Sarah J.} and Emily Waring and Guanizo, {Aleks C.} and Trollope, {Gemma S.} and Jingling Zhou and Judith Vue and Lachlan Senior and Emma Wanicek and Eddine, {Janna Jamal} and Gartner, {Matthew J.} and Jenkins, {Trisha A.} and Gorry, {Paul R.} and Brew, {Bruce J.} and Lewin, {Sharon R.} and Estes, {Jacob D.} and Michael Roche and Churchill, {Melissa J.}",
note = "Funding Information: This work was supported by the National Health and Medical Research Council, Australia 1183032 (to M.J.C., J.D.E., M.R., and P.R.G.), The Jack Brockhoff Foundation JBF Grant number 4501 - 2018 (to T.A.A. and M.J.C.), and the Melbourne HIV Cure Consortium (to M.R. and C.R.C.). Research reported in this publication was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number R21DA055489 (to M.J.C., M.R., and T.A.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.R.L. is supported by a National Health and Medical Research Council, Australia Practitioner Fellowship (S.R.L.). All authors gratefully acknowledge the support from the NNTC and this publication was made possible from NIH funding through the NIMH and NINDS Institutes by the following grants: Texas NeuroAIDS Research Center: U24MH100930, California NeuroAIDS Tissue Network: U24MH100928, National Neurological AIDS Bank: U24MH100929, Manhattan HIV Brain Bank: U24MH100931, and Data Coordinating Center: U24MH100925. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NNTC or NIH. The authors thank Dr Anna Hearps and Dr Michelle Wong (Burnet Institute, Australia) for providing reagents. Open access publishing facilitated by RMIT University, as part of the Wiley - RMIT University agreement via the Council of Australian University Librarians. Funding Information: This work was supported by the National Health and Medical Research Council, Australia 1183032 (to M.J.C., J.D.E., M.R., and P.R.G.), The Jack Brockhoff Foundation JBF Grant number 4501 ‐ 2018 (to T.A.A. and M.J.C.), and the Melbourne HIV Cure Consortium (to M.R. and C.R.C.). Research reported in this publication was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number R21DA055489 (to M.J.C., M.R., and T.A.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.R.L. is supported by a National Health and Medical Research Council, Australia Practitioner Fellowship (S.R.L.). All authors gratefully acknowledge the support from the NNTC and this publication was made possible from NIH funding through the NIMH and NINDS Institutes by the following grants: Texas NeuroAIDS Research Center: U24MH100930, California NeuroAIDS Tissue Network: U24MH100928, National Neurological AIDS Bank: U24MH100929, Manhattan HIV Brain Bank: U24MH100931, and Data Coordinating Center: U24MH100925. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NNTC or NIH. The authors thank Dr Anna Hearps and Dr Michelle Wong (Burnet Institute, Australia) for providing reagents. Open access publishing facilitated by RMIT University, as part of the Wiley ‐ RMIT University agreement via the Council of Australian University Librarians. Funding Information: S.R.L. has received investigator‐initiated grant funding from Gilead, Merck, and ViiV Healthcare. She has provided paid scientific advice to Abivax, Abbvie, and Gilead. P.R.G. previously received investigator‐initiated grant funding from ViiV Healthcare. Publisher Copyright: {\textcopyright} 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",
year = "2022",
month = oct,
doi = "10.1002/ana.26456",
language = "English (US)",
volume = "92",
pages = "532--544",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "4",
}