Catherine R Cochrane1,2, Thomas A Angelovich1,3,4, Michael Roche1,4, Melissa J Churchill1,3,5, Sarah J Byrnes1, Emily Waring1,2, Aleks C Guanizo1, Gemma S Trollope1,2, Jingling Zhou1, Judith Vue1, Lachlan Senior1, Emma Wanicek1, Janna Jamal Eddine1, Matthew J Gartner4, Trisha A Jenkins1, Paul R Gorry1,6,7, Bruce J Brew8, Sharon R Lewin4,6,9, Jacob D Estes10. 1. Emerging Infections Program, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia. 2. Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia. 3. Life Sciences, Burnet Institute, Melbourne, VIC, Australia. 4. Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. 5. Departments of Microbiology and Medicine, Monash University, Melbourne, VIC, Australia. 6. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia. 7. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. 8. Peter Duncan Neurosciences Unit, Departments of Neurology and Immunology St Vincent's Hospital, Sydney, University of New South Wales and University of Notre Dame, Sydney, New South Wales, Australia. 9. Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. 10. Vaccine and Gene Therapy Institute, Oregon National Primate Research Centre, Oregon Health & Science University, Portland, OR, USA.
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.
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.
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