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April 09, 2013; 80 (15) Article

Molecular and pathologic insights from latent HIV-1 infection in the human brain

Paula Desplats, Wilmar Dumaop, David Smith, Anthony Adame, Ian Everall, Scott Letendre, Ronald Ellis, Mariana Cherner, Igor Grant, Eliezer Masliah
First published March 13, 2013, DOI: https://doi.org/10.1212/WNL.0b013e31828c2e9e
Paula Desplats
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Wilmar Dumaop
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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David Smith
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Anthony Adame
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Ian Everall
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Scott Letendre
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Ronald Ellis
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Mariana Cherner
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Igor Grant
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Eliezer Masliah
From the Departments of Neurosciences (P.D., A.A., R.E., E.M.), Pathology (W.D., E.M.), Medicine (D.S., S.L.), and Psychiatry (I.E., M.C., I.G.), University of California San Diego, La Jolla. Dr. Everall is currently affiliated with the Department of Psychiatry, University of Melbourne, Melbourne, Australia.
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Citation
Molecular and pathologic insights from latent HIV-1 infection in the human brain
Paula Desplats, Wilmar Dumaop, David Smith, Anthony Adame, Ian Everall, Scott Letendre, Ronald Ellis, Mariana Cherner, Igor Grant, Eliezer Masliah
Neurology Apr 2013, 80 (15) 1415-1423; DOI: 10.1212/WNL.0b013e31828c2e9e

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Abstract

Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.

Methods: This was a case-control comparison of HIV-1 seropositive (HIV+) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.

Results: HIV+ controls (n = 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV+ cases (n = 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n = 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV+ controls, the HIV+ latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV+ latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor–α, and CD74.

Conclusion: Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.

GLOSSARY

GFAP=
glial fibrillary acidic protein;
HAART=
highly active antiretroviral therapy;
HAD=
HIV-associated dementia;
HAND=
HIV-associated neurocognitive disorders;
HIVE=
HIV encephalitis;
HNRC=
HIV Neurobehavioral Research Center;
IL=
interleukin;
TNF=
tumor necrosis factor;
UCSD=
University of California, San Diego

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at www.neurology.org

  • Editorial, page 1363

  • Received March 14, 2012.
  • Accepted in final form November 29, 2012.
  • © 2013 American Academy of Neurology
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