title: Neuroimaging abnormalities in clade C HIV are independent of Tat genetic diversity.
abstract: Controversy remains regarding the neurotoxicity of clade C human immunodeficiency virus (HIV-C). When examined in preclinical studies, a cysteine to serine substitution in the C31 dicysteine motif of the HIV-C Tat protein (C31S) results in less severe brain injury compared to other viral clades. By contrast, patient cohort studies identify significant neuropsychological impairment among HIV-C individuals independent of Tat variability. The present study clarified this discrepancy by examining neuroimaging markers of brain integrity among HIV-C individuals with and without the Tat substitution. Thirty-seven HIV-C individuals with the Tat C31S substitution, 109 HIV-C individuals without the Tat substitution (C31C), and 34 HIV- controls underwent 3T structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Volumes were determined for the caudate, putamen, thalamus, corpus callosum, total gray matter, and total white matter. DTI metrics included fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). Tracts of interest included the anterior thalamic radiation (ATR), cingulum bundle (CING), uncinate fasciculus (UNC), and corpus callosum (CC). HIV+ individuals exhibited smaller volumes in subcortical gray matter, total gray matter and total white matter compared to HIV- controls. HIV+ individuals also exhibited DTI abnormalities across multiple tracts compared to HIV- controls. By contrast, neither volumetric nor diffusion indices differed significantly between the Tat C31S and C31C groups. Tat C31S status is not a sufficient biomarker of HIV-related brain integrity in patient populations. Clinical attention directed at brain health is warranted for all HIV+ individuals, independent of Tat C31S or clade C status.
authors.affiliation: Missouri Institute of Mental Health, University of Missouri, St. Louis, MO, USA. paulro@umsl.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Paul
authors.affiliation: Missouri Institute of Mental Health, University of Missouri, St. Louis, MO, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Phillips
authors.affiliation: Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, 7700, South Africa.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hoare
authors.affiliation: Department of Computer Science, Brown University, Providence, RI, 02912, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Laidlaw
authors.affiliation: Department of Computer Science, Brown University, Providence, RI, 02912, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cabeen
authors.affiliation: Department of Mathematics and Statistics, Missouri University of Science and Technology, Rolla, MO, 65409, USA.
authors.forename: Gayla R
authors.initials: GR
authors.lastname: Olbricht
authors.affiliation: Department of Mathematics and Statistics, Missouri University of Science and Technology, Rolla, MO, 65409, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, 7700, South Africa.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Stein
authors.affiliation: Division of Medical Virology, Stellenbosch University and National Health Laboratory Services (NHLS), Cape Town, South Africa.
authors.forename: Susan
authors.initials: S
authors.lastname: Engelbrecht
authors.affiliation: MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, Stellenbosch, 7599, South Africa.
authors.forename: Soraya
authors.initials: S
authors.lastname: Seedat
authors.affiliation: Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, 90007, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Salminen
authors.affiliation: Missouri Institute of Mental Health, University of Missouri, St. Louis, MO, USA.
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Baker
authors.affiliation: Missouri Institute of Mental Health, University of Missouri, St. Louis, MO, USA.
authors.forename: Jodi
authors.initials: J
authors.lastname: Heaps
authors.affiliation: Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, 7700, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Joska
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001931:Brain Mapping; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D056324:Diffusion Tensor Imaging / Q000295:instrumentation / Q000379:methods*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D006678:HIV / Q000235:genetics* / Q000472:pathogenicity; D015658:HIV Infections / Q000000981:diagnostic imaging* / Q000473:pathology / Q000821:virology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D011699:Putamen / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D013788:Thalamus / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: C30C31 dicysteine motif; Clade C; HIV; Neuroimaging; Tat C31S