Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy
HIV establishes a persistent viral reservoir in the brain despite viral suppression in blood to undetectable levels on antiretroviral therapy (ART). The brain viral reservoir in virally suppressed HIV+ individuals is not well-characterized. In this study, intact, defective, and total HIV proviral ge...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/15/4/1009 |
| _version_ | 1797603153935335424 |
|---|---|
| author | Dana Gabuzda Jun Yin Vikas Misra Sukrutha Chettimada Benjamin B. Gelman |
| author_facet | Dana Gabuzda Jun Yin Vikas Misra Sukrutha Chettimada Benjamin B. Gelman |
| author_sort | Dana Gabuzda |
| collection | DOAJ |
| description | HIV establishes a persistent viral reservoir in the brain despite viral suppression in blood to undetectable levels on antiretroviral therapy (ART). The brain viral reservoir in virally suppressed HIV+ individuals is not well-characterized. In this study, intact, defective, and total HIV proviral genomes were measured in frontal lobe white matter from 28 virally suppressed individuals on ART using the intact proviral DNA assay (IPDA). HIV gag DNA/RNA levels were measured using single-copy assays and expression of 78 genes related to inflammation and white matter integrity was measured using the NanoString platform. Intact proviral DNA was detected in brain tissues of 18 of 28 (64%) individuals on suppressive ART. The median proviral genome copy numbers in brain tissue as measured by the IPDA were: intact, 10 (IQR 1–92); 3′ defective, 509 (225–858); 5′ defective, 519 (273–906); and total proviruses, 1063 (501–2074) copies/10<sup>6</sup> cells. Intact proviral genomes accounted for less than 10% (median 8.3%) of total proviral genomes in the brain, while 3′ and 5′ defective genomes accounted for 44% and 49%, respectively. There was no significant difference in median copy number of intact, defective, or total proviruses between groups stratified by neurocognitive impairment (NCI) vs. no NCI. In contrast, there was an increasing trend in intact proviruses in brains with vs. without neuroinflammatory pathology (56 vs. 5 copies/10<sup>6</sup> cells, <i>p</i> = 0.1), but no significant differences in defective or total proviruses. Genes related to inflammation, stress responses, and white matter integrity were differentially expressed in brain tissues with >5 vs. +5 intact proviruses/10<sup>6</sup> cells. These findings suggest that intact HIV proviral genomes persist in the brain at levels comparable to those reported in blood and lymphoid tissues and increase CNS inflammation/immune activation despite suppressive ART, indicating the importance of targeting the CNS reservoir to achieve HIV cure. |
| first_indexed | 2024-03-11T04:26:24Z |
| format | Article |
| id | doaj.art-ad536478c62e45e19775144bd6da6e2e |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T04:26:24Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-ad536478c62e45e19775144bd6da6e2e2023-11-17T21:46:54ZengMDPI AGViruses1999-49152023-04-01154100910.3390/v15041009Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral TherapyDana Gabuzda0Jun Yin1Vikas Misra2Sukrutha Chettimada3Benjamin B. Gelman4Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USAHIV establishes a persistent viral reservoir in the brain despite viral suppression in blood to undetectable levels on antiretroviral therapy (ART). The brain viral reservoir in virally suppressed HIV+ individuals is not well-characterized. In this study, intact, defective, and total HIV proviral genomes were measured in frontal lobe white matter from 28 virally suppressed individuals on ART using the intact proviral DNA assay (IPDA). HIV gag DNA/RNA levels were measured using single-copy assays and expression of 78 genes related to inflammation and white matter integrity was measured using the NanoString platform. Intact proviral DNA was detected in brain tissues of 18 of 28 (64%) individuals on suppressive ART. The median proviral genome copy numbers in brain tissue as measured by the IPDA were: intact, 10 (IQR 1–92); 3′ defective, 509 (225–858); 5′ defective, 519 (273–906); and total proviruses, 1063 (501–2074) copies/10<sup>6</sup> cells. Intact proviral genomes accounted for less than 10% (median 8.3%) of total proviral genomes in the brain, while 3′ and 5′ defective genomes accounted for 44% and 49%, respectively. There was no significant difference in median copy number of intact, defective, or total proviruses between groups stratified by neurocognitive impairment (NCI) vs. no NCI. In contrast, there was an increasing trend in intact proviruses in brains with vs. without neuroinflammatory pathology (56 vs. 5 copies/10<sup>6</sup> cells, <i>p</i> = 0.1), but no significant differences in defective or total proviruses. Genes related to inflammation, stress responses, and white matter integrity were differentially expressed in brain tissues with >5 vs. +5 intact proviruses/10<sup>6</sup> cells. These findings suggest that intact HIV proviral genomes persist in the brain at levels comparable to those reported in blood and lymphoid tissues and increase CNS inflammation/immune activation despite suppressive ART, indicating the importance of targeting the CNS reservoir to achieve HIV cure.https://www.mdpi.com/1999-4915/15/4/1009HIV reservoirsintact proviral DNA assayintact proviral genomesHIV-associated neurocognitive disordersneuroinflammation |
| spellingShingle | Dana Gabuzda Jun Yin Vikas Misra Sukrutha Chettimada Benjamin B. Gelman Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy Viruses HIV reservoirs intact proviral DNA assay intact proviral genomes HIV-associated neurocognitive disorders neuroinflammation |
| title | Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy |
| title_full | Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy |
| title_fullStr | Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy |
| title_full_unstemmed | Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy |
| title_short | Intact Proviral DNA Analysis of the Brain Viral Reservoir and Relationship to Neuroinflammation in People with HIV on Suppressive Antiretroviral Therapy |
| title_sort | intact proviral dna analysis of the brain viral reservoir and relationship to neuroinflammation in people with hiv on suppressive antiretroviral therapy |
| topic | HIV reservoirs intact proviral DNA assay intact proviral genomes HIV-associated neurocognitive disorders neuroinflammation |
| url | https://www.mdpi.com/1999-4915/15/4/1009 |
| work_keys_str_mv | AT danagabuzda intactproviraldnaanalysisofthebrainviralreservoirandrelationshiptoneuroinflammationinpeoplewithhivonsuppressiveantiretroviraltherapy AT junyin intactproviraldnaanalysisofthebrainviralreservoirandrelationshiptoneuroinflammationinpeoplewithhivonsuppressiveantiretroviraltherapy AT vikasmisra intactproviraldnaanalysisofthebrainviralreservoirandrelationshiptoneuroinflammationinpeoplewithhivonsuppressiveantiretroviraltherapy AT sukruthachettimada intactproviraldnaanalysisofthebrainviralreservoirandrelationshiptoneuroinflammationinpeoplewithhivonsuppressiveantiretroviraltherapy AT benjaminbgelman intactproviraldnaanalysisofthebrainviralreservoirandrelationshiptoneuroinflammationinpeoplewithhivonsuppressiveantiretroviraltherapy |