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March 2022; 9 (2) EditorialOpen Access

Is HIV Brain Disease Preventable?

View ORCID ProfileBruce J. Brew
First published February 9, 2022, DOI: https://doi.org/10.1212/NXI.0000000000001145
Bruce J. Brew
From the Faculty of Medicine (B.J.B.), University of New South Wales, and University of Notre Dame Sydney; and Departments of Neurology and HIV Medicine (B.J.B.), St Vincent's Hospital, and Peter Duncan Neurosciences Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia.
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Is HIV Brain Disease Preventable?
Bruce J. Brew
Neurol Neuroimmunol Neuroinflamm Mar 2022, 9 (2) e1145; DOI: 10.1212/NXI.0000000000001145

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There are 2 major issues in the field of neuro-HIV. Is HIV present in the brain in most if not all patients? This is important to facilitate eradication strategies given the difficulties of delivering therapies across the blood-brain barrier. Second, what is the mechanism of brain damage when HIV is suppressed by antiretroviral drugs (the therapeutic paradox)? This too is significant as the field is divided as to possibilities: residual brain damage occurring before adequate antiretroviral drugs—the so-called legacy effect, ongoing HIV replication at levels below what are currently detectable, the effect of comorbidities such as vascular disease, or antiretroviral toxicity.

In this issue of Neurology® Neuroimmunology and Neuroinflammation, Sari et al.1 used advanced brain imaging (a PET/MRI scanner with a second-generation TSPO ligand that identifies glial/macrophage activation) in 14 aviremic patients (HIV RNA <50 copies/mL; CD4 count 708 ± 260 cells/μL) on combination antiretroviral therapy (cART), 6 elite controllers (ECs) (HIV RNA <50 copies/mL; CD4 count 692 ± 188 cells/μL), and 16 healthy controls (HCs) focusing on the thalamus, putamen, amygdala, hippocampus, parietal operculum cortex, superior temporal white matter, and brainstem. Neuropsychologic assessment was performed though limited. ECs and HCs were not different in the degree of binding and therefore glial activation, whereas cART patients had significantly more binding implying neuroinflammation.

There are some limitations to the study. It is predicated on brain inflammation as a signal for ongoing infection in the context of HIV disease. There is possibly an alternate cause, namely cART neurotoxicity. The number of patients was small, neuropsychologic testing was not comprehensive, CSF was not assessed for HIV, and the frontal white matter was not studied, although it is known to be a site of HIV replication and inflammation.

Nonetheless, the study findings are important and advance the field. Why are ECs no different from HCs? ECs likely suppress brain infection given that replication was suppressed in the blood. Why are ECs different from cART-treated patients who show increased inflammation despite viral suppression? This suggests that ECs may prevent seeding of the brain by HIV and that ultra-early cART (around seroconversion) may mirror this. Why are cART-treated patients still showing neuroinflammation? cART may not fully control HIV brain replication, or it may cause neuroinflammation without there being any HIV replication—cART-related neurotoxicity the evidence for which is both in vitro and observational in vivo studies2,3 but counterbalanced by long-term pediatric studies into adulthood generally showing cognitive improvement and stability.4 It is well known that cART at least in some cases has limited ability to effectively suppress brain infection likely because of difficulties in brain entry, intrinsic brain cell efficacy (microglia, astrocytes, and pericytes as opposed to T cells), and lack of effect on early transcription.5,-,8

How do these findings address the 2 main questions in the neuro-HIV field? Eradication from the brain may not be necessary if cART is commenced at the earliest time, namely seroconversion. Second, brain disease may be prevented by such ultra-early treatment. However, existing data do not support these suggestions,9,10 possibly because cART was commenced early but not ultra-early, a very difficult practical issue. In addition, existing cART only partially treats brain disease—better drugs possibly of a new class such as transcription inhibitors should be considered. Further studies are needed.

The findings of Sari et al. have relevance beyond neuro-HIV. Very early intervention possibly in the presymptomatic disease phase is pertinent to many neurologic diseases but perhaps especially in Alzheimer and possibly in multiple sclerosis. Nonetheless, this has to be counterbalanced by consideration of the potential for long-term neurotoxicity of therapies that have to be administered for years. Finally, the significance of brain inflammation in relation to particular diseases needs cautious interpretation, not necessarily reflecting the pathophysiologic process under investigation.

Study Funding

No targeted funding reported.

Disclosure

B.J. Brew has received speaker fees from and served as an advisory board member for Biogen, ViiV, and Johnson and Johnson; serves as an editorial member for International Journal for Tryptophan Research, Faculty of 1000 Medicine, Journal of Neurovirology, AIDS, and Lancet HIV; has received research support from NHMRC, Biogen, St Vincent's Clinic Foundation, and Peter Duncan Foundation; receives royalties from Oxford University Press and Cambridge University Press; and holds the patent for a monoclonal antibody for Quinolinic acid as part of test kit for monitoring MS severity and progression (PCT/IB2013/055902). Go to Neurology.org/NN for full disclosures.

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the author.

  • See page e1144

  • Received December 9, 2021.
  • Accepted in final form December 13, 2021.
  • Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

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    . Multimodal investigation of neuroinflammation in aviremic patients with HIV on antiretroviral therapy and HIV elite controllers. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1144.
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    . CNS neurotoxicity of antiretrovirals. J Neuroimmune Pharmacol. 2021;16(1):130-143.
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    1. Bertrand L,
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    ; International Maternal Pediatric Adolescent AIDS Clinical Trials 219/219C Study Team. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009;23(14):1893-1901.
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    1. Asahchop EL,
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    . The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes. PLoS One. 2013;8(4):e62196.
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    . Blood-brain barrier pericytes as a target for HIV-1 infection. Brain. 2019;142(3):502-511.
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    1. Henderson LJ,
    2. Johnson TP,
    3. Smith BR, et al
    . Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy. AIDS. 2019;33(suppl 2):S145-S157.
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    1. Wright EJ,
    2. Grund B,
    3. Robertson KR, et al
    ; INSIGHT START Neurology Substudy Group. No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts. AIDS. 2018;32(8):985-997.
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    1. Chan P,
    2. Kerr SJ,
    3. Kroon E, et al
    . Cognitive trajectories after treatment in acute HIV infection. AIDS. 2021;35(6):883-888.
    OpenUrl

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