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Smaller Limbic Structures Are Associated with Immunosuppression and Viral Load in Over 1000 HIV-Infected Adults Across Five Continents: Findings from the ENIGMA-HIV Working Group

38 Pages Posted: 7 Sep 2019

See all articles by Talia M. Nir

Talia M. Nir

University of Southern California - Imaging Genetics Center

Jean-Paul Fouche

University of Cape Town (UCT) - Department of Psychiatry

Jintanat Ananworanich

Government of the United States of America - Henry M. Jackson Foundation for the Advancement of Military Medicine

Beau M. Ances

Washington University in St. Louis

Jasmina Boban

University of Novi Sad

Bruce J. Brew

University of New South Wales (UNSW) - St Vincent’s Hospital

Joga R. Chaganti

University of New South Wales (UNSW)

Linda Chang

University of Maryland

Christopher R.K. Ching

University of Southern California

Lucette A. Cysique

University of New South Wales (UNSW)

Thomas Ernst

University of Maryland

Joshua Faskowitz

University of Southern California - Imaging Genetics Center

Vikash Gupta

University of Southern California - Imaging Genetics Center

Jaroslaw Harezlak

Indiana University Bloomington

Jodi M. Heaps-Woodruff

University of Missouri at Saint Louis

Charles H. Hinkin

University of California, Los Angeles (UCLA)

Jacqueline Hoare

University of Cape Town (UCT)

John A. Joska

University of Cape Town (UCT)

Kalpana J. Kallianpur

University of Hawaii

Taylor Kuhn

University of California, Los Angeles (UCLA)

Hei Y. Lam

University of Southern California - Imaging Genetics Center

Meng Law

Monash University

Christine Lebrun-Frenay

Université d'Amiens - Centre Hospitalier Universitaire

Andrew J. Levine

Université d'Amiens - Centre Hospitalier Universitaire

Lydiane Mondot

Université d'Amiens - Centre Hospitalier Universitaire

Beau K. Nakamoto

University of Hawaii

Bradford A. Navia

Tufts University

Xavier Pennec

Université Côte d'Azur

Eric C. Porges

University of Florida

Cecilia M. Shikuma

University of Hawaii

April D. Thames

University of California, Los Angeles (UCLA)

Victor Valcour

University of California, San Francisco (UCSF)

Matteo Vassallo

Centre Hospitalier de Cannes

Adam J. Woods

University of Florida

Paul M. Thompson

University of Southern California - Imaging Genetics Center

Ronald A. Cohen

University of Florida

Robert Paul

University of Missouri at Saint Louis

Dan J Stein

University of Cape Town (UCT) - SAMRC Unit on Risk & Resilience in Mental Disorders; University of Cape Town (UCT) - Department of Psychiatry

Neda Jahanshad

University of Southern California - Imaging Genetics Center

ENIGMA-HIV Working Group

Independent

More...

Abstract

Background: Despite more widely accessible combination antiretroviral therapy (cART), the human immunodeficiency virus type-1 (HIV) infection remains a global public health challenge. Even in treated and chronically HIV-infected (HIV+) individuals, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in-vivo may delineate the neuropathological processes underlying these deficits. However, to date, neuroimaging findings are inconsistent.

Methods: We established the ENIGMA-HIV Working Group to retrospectively pool and harmonize heterogeneous data from 12 HIV neuroimaging studies across Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1- weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72·4% on cART; 70·3% male; 41·6% with detectable viral load; dVL), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell counts) or dVL. Follow-up analyses stratified data by cART status and sex.

Findings: After Bonferroni correction, lower current CD4+ counts were associated with smaller hippocampal (β=20·3 mm3 per 100 cells/mm3; p=0·0001) and thalamic volumes (β=29.3; p=0·003); in participants not on cART, they were associated with smaller putamen volumes (β=65·1; p=0·0009). dVLs were associated with smaller hippocampi (Cohen's d=0·24; p=0·0003) and amygdala (d=0·18; p=0·0058).

Interpretation: In a globally representative population of HIV+ individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Deficits in these regions may represent a generalizable brain signature of HIV-infection in the cART era. Our findings support the role of viral suppression and immune restoration in maintaining brain health.

Funding Statement: Funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided by the NIH Big Data to Knowledge Program (BD2K; U54 EB020403). Additional funding for this work was provided by NIH grants R01AG059874 (NJ), R01MH117601 (NJ), T32AG058507 (TMN and CRKC), 5T32MH073526 (CRKC), MH083553 (CHH), MH19535 (CHH), R01HL095135 (KJK), MH095661 (TK), UL1RR033176 (TK), UL1TR000124 (TK), MH19535 (TK), NS080655 (BAN), K01AA025306 (ECP), R01HL095135 (CMS), U54MD007584 (CMS), K23MH095661 (ADT), K23AG032872 (VV), R01NS061696 (VV), K24MH098759 (VV), K01AG050707 (AJW), P01AA019072 (RAC), R01MH074368 (RAC), P30 AI042853 (RAC), and by R01MH085604 (RP). This study was also supported by the SA Medical Research Council (DJS), NHMRC APP568746 and APP1045400 (LAC), and the European Research Council Advanced Grant MedYMA 2011- 291080 (XP).

Declaration of Interests: PMT, TMN, NJ, and CRKC received partial research support from Biogen, Inc., for work unrelated to the topic of this manuscript. BKN has received an honorarium from MedLink Neurology. VV has served as a consultant for Merck and ViiV Healthcare in the past 3 years, not related to this work. JA has received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche and AbbVie. The remaining authors all declare no conflicts of interest.

Ethics Approval Statement: Each study obtained approval from their local ethics committee or institutional review board; participants signed an informed consent form at each participating site.

Keywords: HIV, Brain Volume, Subcortical, MRI, CD4+ Count, Detecable Viral Load, Multi-site, Global Consortium, cART era

Suggested Citation

Nir, Talia M. and Fouche, Jean-Paul and Ananworanich, Jintanat and Ances, Beau M. and Boban, Jasmina and Brew, Bruce J. and Chaganti, Joga R. and Chang, Linda and Ching, Christopher R.K. and Cysique, Lucette A. and Ernst, Thomas and Faskowitz, Joshua and Gupta, Vikash and Harezlak, Jaroslaw and Heaps-Woodruff, Jodi M. and Hinkin, Charles H. and Hoare, Jacqueline and Joska, John A. and Kallianpur, Kalpana J. and Kuhn, Taylor and Lam, Hei Y. and Law, Meng and Lebrun-Frenay, Christine and Levine, Andrew J. and Mondot, Lydiane and Nakamoto, Beau K. and Navia, Bradford A. and Pennec, Xavier and Porges, Eric C. and Shikuma, Cecilia M. and Thames, April D. and Valcour, Victor and Vassallo, Matteo and Woods, Adam J. and Thompson, Paul M. and Cohen, Ronald A. and Paul, Robert and Stein, Dan J and Jahanshad, Neda and Group, ENIGMA-HIV Working, Smaller Limbic Structures Are Associated with Immunosuppression and Viral Load in Over 1000 HIV-Infected Adults Across Five Continents: Findings from the ENIGMA-HIV Working Group (08/24/2019 01:34:06). Available at SSRN: https://ssrn.com/abstract=3444420 or http://dx.doi.org/10.2139/ssrn.3444420

Talia M. Nir

University of Southern California - Imaging Genetics Center

Marina del Rey, CA
United States

Jean-Paul Fouche

University of Cape Town (UCT) - Department of Psychiatry

United States

Jintanat Ananworanich

Government of the United States of America - Henry M. Jackson Foundation for the Advancement of Military Medicine

6720-A Rockledge Drive, Suite 100
Bethesda, MD 20817
United States

Beau M. Ances

Washington University in St. Louis

One Brookings Drive
Campus Box 1208
Saint Louis, MO MO 63130-4899
United States

Jasmina Boban

University of Novi Sad

Trg Dositeja Obradovica 3
Novi Sad, 21000
Serbia

Bruce J. Brew

University of New South Wales (UNSW) - St Vincent’s Hospital ( email )

Victoria Street
Darlinghurst, Sydney 2100
Australia

Joga R. Chaganti

University of New South Wales (UNSW)

Kensington
High St
Sydney, NSW 2052
Australia

Linda Chang

University of Maryland

College Park
College Park, MD 20742
United States

Christopher R.K. Ching

University of Southern California

2250 Alcazar Street
Los Angeles, CA 90089
United States

Lucette A. Cysique

University of New South Wales (UNSW)

Kensington
High St
Sydney, NSW 2052
Australia

Thomas Ernst

University of Maryland

College Park
College Park, MD 20742
United States

Joshua Faskowitz

University of Southern California - Imaging Genetics Center

Marina del Rey, CA
United States

Vikash Gupta

University of Southern California - Imaging Genetics Center

Marina del Rey, CA
United States

Jaroslaw Harezlak

Indiana University Bloomington

Dept of Biology
100 South Indiana Ave.
Bloomington, IN 47405
United States

Jodi M. Heaps-Woodruff

University of Missouri at Saint Louis

1 University Blvd.
St Louis, MO 63121
United States

Charles H. Hinkin

University of California, Los Angeles (UCLA)

405 Hilgard Avenue
Box 951361
Los Angeles, CA 90095
United States

Jacqueline Hoare

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

John A. Joska

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

Kalpana J. Kallianpur

University of Hawaii

Honolulu, HI 96822
United States

Taylor Kuhn

University of California, Los Angeles (UCLA)

405 Hilgard Avenue
Box 951361
Los Angeles, CA 90095
United States

Hei Y. Lam

University of Southern California - Imaging Genetics Center

Marina del Rey, CA
United States

Meng Law

Monash University

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Christine Lebrun-Frenay

Université d'Amiens - Centre Hospitalier Universitaire

Amiens
France

Andrew J. Levine

Université d'Amiens - Centre Hospitalier Universitaire

Amiens
France

Lydiane Mondot

Université d'Amiens - Centre Hospitalier Universitaire

Amiens
France

Beau K. Nakamoto

University of Hawaii

Honolulu, HI 96822
United States

Bradford A. Navia

Tufts University

Medford, MA 02155
United States

Xavier Pennec

Université Côte d'Azur

France

Eric C. Porges

University of Florida

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Cecilia M. Shikuma

University of Hawaii

Honolulu, HI 96822
United States

April D. Thames

University of California, Los Angeles (UCLA)

405 Hilgard Avenue
Box 951361
Los Angeles, CA 90095
United States

Victor Valcour

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Matteo Vassallo

Centre Hospitalier de Cannes

France

Adam J. Woods

University of Florida

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Paul M. Thompson

University of Southern California - Imaging Genetics Center

Marina del Rey, CA
United States

Ronald A. Cohen

University of Florida

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Robert Paul

University of Missouri at Saint Louis

1 University Blvd.
St Louis, MO 63121
United States

Dan J Stein

University of Cape Town (UCT) - SAMRC Unit on Risk & Resilience in Mental Disorders

Cape Town
South Africa

University of Cape Town (UCT) - Department of Psychiatry

United States

Neda Jahanshad (Contact Author)

University of Southern California - Imaging Genetics Center ( email )

Marina del Rey, CA
United States

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