Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV

Thomas A Angelovich^{1

2

3}, Catherine R Cochrane^{1

4}, Jingling Zhou¹, Carolin Tumpach³, Sarah J Byrnes¹, Janna Jamal Eddine¹, Emily Waring¹, Kathleen Busman-Sahay⁵, Claire Deleage⁶, Trisha A Jenkins¹, Anna C Hearps^{2

7}, Stuart Turville⁸, Paul R Gorry¹, Sharon R Lewin^{3

9

10}, Bruce J Brew^{11

12}, Jacob D Estes^{1

5}, Michael Roche^{1

3}, Melissa J Churchill^{1

2

13}

Affiliations

¹ Infectious and Inflammatory Diseases, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia.
² Life Sciences Discipline, Burnet Institute, Melbourne, Victoria, Australia.
³ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁴ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁵ Vaccine and Gene Therapy Institute, Oregon Health & Science University, Hillsboro, Oregon, USA.
⁶ AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
⁷ Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ The Kirby Institute, University of New South Wales, Kensington, New South Wales, Australia.
⁹ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
¹⁰ Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹¹ Peter Duncan Neurosciences Unit, Departments of Neurology and Immunology St. Vincent's Hospital, University of New South Wales, Sydney, New South Wales, Australia.
¹² University of Notre Dame, Sydney, New South Wales, Australia.
¹³ Departments of Microbiology and Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 37493435
PMCID: PMC10914117
DOI: 10.1002/ana.26750

Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV

Thomas A Angelovich et al. Ann Neurol. 2023 Oct.

. 2023 Oct;94(4):798-802.

doi: 10.1002/ana.26750. Epub 2023 Aug 12.

Authors

Affiliations

¹ Infectious and Inflammatory Diseases, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia.
² Life Sciences Discipline, Burnet Institute, Melbourne, Victoria, Australia.
³ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁴ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁵ Vaccine and Gene Therapy Institute, Oregon Health & Science University, Hillsboro, Oregon, USA.
⁶ AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
⁷ Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ The Kirby Institute, University of New South Wales, Kensington, New South Wales, Australia.
⁹ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
¹⁰ Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹¹ Peter Duncan Neurosciences Unit, Departments of Neurology and Immunology St. Vincent's Hospital, University of New South Wales, Sydney, New South Wales, Australia.
¹² University of Notre Dame, Sydney, New South Wales, Australia.
¹³ Departments of Microbiology and Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 37493435
PMCID: PMC10914117
DOI: 10.1002/ana.26750

Abstract

Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023;94:798-802.

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Conflict of interest statement

Potential Conflicts of Interest

She has participated as a paid member of scientific advisory boards to Abivax, Immunocore, Efsam, AbbVie, and Gilead. C.R.C. is currently employed by ViiV Healthcare. C.R.C.’s contribution to this project was completed while at RMIT University.

Figures

**FIGURE 1:**
Quantification of HIV *pol* DNA in human brain regions. HIV *pol* DNA was quantified in fresh frozen FWM (*blue*), BG (*red*), and CBM ( *purple*) tissue from VS (n = 16) and untreated PWH (viremic; n = 21) or HIV-seronegative controls (HIV-; n = 2) by ddPCR. HIV *pol* DNA copies standardized to 10⁶ cell equivalents. Median and IQRs shown. Comparisons made using non-parametric Mann–Whitney U tests. *p < 0.05. BG = basal ganglia; CBM = cerebellum; ddPCR = droplet digital polymerase chain reaction; FWM = frontal white matter; IQR = interquartile range; PWH = people with HIV; VS = virally suppressed.

**FIGURE 2:**
Intact and defective proviral landscape across multiple brain regions in PWH. (A) Intact (Ψ⁺*env*⁺), 3′ defective (Ψ⁺*env*⁻), and 5′ defective (Ψ⁻*env*⁺) HIV proviruses were quantified in matched frozen human FWM (*blue*; n = 8), BG (*red*; n = 6), or CBM ( *purple*; n = 8) from viremic PWH by IPDA. Proviral copy number was standardized to 10⁶ cells. (B) Proviral copy number of intact, 3′ defective, and 5′ defective proviral HIV DNA in FWM (n = 8), BG (n = 8), and CBM (n = 8) from virally suppressed PWH. Symbols represent individuals. Comparisons made using nonparametric paired Wilcoxon tests. *p < 0.05, **p < 0.01. BG = basal ganglia; CBM = cerebellum; FWM = frontal white matter; IPDA = intact proviral DNA assay; PWH = people with HIV; VS = virally suppressed.

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References

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Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV

Affiliations

Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV

Authors

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Abstract

Conflict of interest statement

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References

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LinkOut - more resources

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Medical