Abstract
The human immunodeficiency virus (HIV) has multiple genetic clades with varying prevalence throughout the world. Both HIV clade C (HIV-C) and HIV clade B (HIV-B) can cause cognitive impairment, but it is unclear if these clades are characterized by similar patterns of brain dysfunction. We examined brain volumetrics and neuropsychological performance among highly active antiretroviral therapy (HAART)-naïve HIV-B and HIV-C participants. Thirty-four HAART-naïve HIV-infected (HIV+) participants [17 HIV-B (USA); 17 HIV-C (South Africa)] and 34 age- and education-matched HIV-uninfected (HIV−) participants were evaluated. All participants underwent similar laboratory, neuropsychological, and neuroimaging studies. Brain volume measures were assessed within the caudate, putamen, amygdala, thalamus, hippocampus, corpus callosum, and cortical (gray and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics. HIV− and HIV+ individuals were similar in age. On laboratory examination, HIV-C participants had lower CD4 cell counts and higher plasma HIV viral loads than HIV-B individuals. In general, HIV+ participants performed significantly worse on neuropsychological measures of processing speed and memory and had significantly smaller relative volumetrics within the thalamus, hippocampus, corpus callosum, and cortical gray and white matter compared to the respective HIV− controls. Both HIV-B and HIV-C are associated with similar volumetric declines when compared to matched HIV− controls. HIV-B and HIV-C were associated with significant reductions in brain volumetrics and poorer neuropsychological performance; however, no specific effect of HIV clade subtype was evident. These findings suggest that HIV-B and HIV-C both detrimentally affect brain integrity.
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References
Ances BM, Sisti D, Vaida F, Liang CL, Leontiev O, Perthen JE, Buxton RB et al (2009) Resting cerebral blood flow: a potential biomarker of the effects of HIV in the brain. Neurology 73(9):702–708. doi:10.1212/WNL.0b013e3181b59a97. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2734291&tool=pmcentrez&rendertype=abstract
Ances BM, Ortega M, Vaida F, Heaps J, Paul R (2012) Independent effects of HIV, aging, and HAART on brain volumetric measures. Journal of Acquired Immune Deficiency Syndromes 59(5):469–477. doi:10.1097/QAI.0b013e318249db17. Available at http://www.ncbi.nlm.nih.gov/pubmed/22269799
Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, McCutchan JA, Ellis RJ (2010) HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. The Journal of Infectious Diseases 201(3):336–340. doi:10.1086/649899. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2804778&tool=pmcentrez&rendertype=abstract
Anthony IC, Bell JE (2008) The neuropathology of HIV/AIDS. International Review of Psychiatry (Abingdon, England) 20(1): 15–24. doi:10.1080/09540260701862037. Available at http://www.ncbi.nlm.nih.gov/pubmed/18240059
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799. doi:10.1212/01.WNL.0000287431.88658.8b. Available at http://www.ncbi.nlm.nih.gov/pubmed/17914061
Archibald SL, Masliah E, Fennema-Notestine C, Marcotte TD, Ellis RJ, McCutchan JA, Heaton RK et al (2004) Correlation of in vivo neuroimaging abnormalities with postmortem human immunodeficiency virus encephalitis and dendritic loss. Archives of Neurology 61(3):369–376. doi:10.1001/archneur.61.3.369. Available at http://www.ncbi.nlm.nih.gov/pubmed/15023814
Arendt G, Hefter H, Elsing C, Strohmeyer G, Freund HJ (1990) Motor dysfunction in HIV-infected patients without clinically detectable central-nervous deficit. J Neurol 237(6):362–368. Available at http://www.springerlink.com/index/K76465858137QW16.pdf
Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Greenberg RN, Berger JR (2004) Neuroimaging correlates of HIV-associated BBB compromise. Journal of Neuroimmunology 157(1–2):140–146. doi:10.1016/j.jneuroim.2004.08.025. Available at http://www.ncbi.nlm.nih.gov/pubmed/15579291
Becker JT, Sanders J, Madsen SK, Ragin A, Kingsley L, Maruca V, Cohen B et al (2011) Subcortical brain atrophy persists even in HAART-regulated HIV disease. Brain Imaging Behav 5(2):77–85. doi:10.1007/s11682-011-9113-8
Campbell GR, Watkins JD, Loret EP, Spector SA (2011) Differential induction of rat neuronal excitotoxic cell death by human immunodeficiency virus. AIDS Res Hum Retroviruses 27(6):647–654. doi:10.1089/aid.2010.0192
Cardenas VA, Meyerhoff DJ, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J et al (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. Journal of Neurovirology 15(4):324–333. doi:10.1080/13550280902973960. Available at http://informahealthcare.com/doi/abs/10.1080/13550280902973960
Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. Journal of Clinical and Experimental Neuropsychology 26(3):307–319. doi:10.1080/13803390490510031. Available at http://www.ncbi.nlm.nih.gov/pubmed/15512922
Chang L, Andres M, Sadino J, Jiang CS, Nakama H, Miller E, Ernst T (2011) Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. NeuroImage 58(4):1017–1027. doi:10.1016/j.neuroimage.2011.07.010. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3171637&tool=pmcentrez&rendertype=abstract
Clark US, Cohen RA, Sweet LH, Gongvatana A, Devlin KN, Hana GN, Westbrook ML et al (2012) Effects of HIV and early life stress on amygdala morphometry and neurocognitive function. Journal of the International Neuropsychological Society: JINS 18(4):657–668. doi:10.1017/S1355617712000434. Available at http://www.ncbi.nlm.nih.gov/pubmed/22621973
Cohen RA, Harezlak J, Gongvatana A, Buchthal S, Schifitto G, Clark U, Paul R et al (2010) Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. Journal of Neurovirology 16(6): 435–444. doi:10.3109/13550284.2010.520817
Constantino AA, Huang Y, Zhang H, Wood C, Zheng JC (2011) HIV-1 clade B and C isolates exhibit differential replication: relevance to macrophage-mediated neurotoxicity. Neurotoxicity Research 20(3):277–288. doi:10.1007/s12640-011-9241-3. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3407549&tool=pmcentrez&rendertype=abstract
Crum-Cianflone NF, Roediger MP, Moore DJ, Hale B, Weintrob A, Ganesan A, Eberly LE, Johnson E, Agan BK, Letendre S (2012) Prevalence and factors associated with sleep disturbances among early-treated HIV-infected persons. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America 54(10):1485–1494. doi:10.1093/cid/cis192. Available at http://www.ncbi.nlm.nih.gov/pubmed/22431801
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL et al (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage 31(3):968–980. doi:10.1016/j.neuroimage.2006.01.021. Available at http://www.ncbi.nlm.nih.gov/pubmed/16530430
Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, Collier AC et al (2011) CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS (London, England) 25(14):1747–1751. doi:10.1097/QAD.0b013e32834a40cd. Available at http://www.ncbi.nlm.nih.gov/pubmed/21750419
Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proceedings of the National Academy of Sciences of the United States of America 97(20):11050–11055. doi:10.1073/pnas.200033797. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=27146&tool=pmcentrez&rendertype=abstract
Fischl B, David H, Salat EB, Albert M, Dieterich M, Haselgrove C, Van Der Kouwe A et al (2002) Whole brain segmentation: neurotechnique automated labeling of neuroanatomical structures in the human brain. Analysis 33:341–355
Gandhi N, Saiyed Z, Thangavel S, Rodriguez J, Rao KV, Nair MP (2009) Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes. AIDS Research and Human Retroviruses 25(7):691–699. doi:10.1089/aid.2008.0299. Available at http://online.liebertpub.com/doi/abs/10.1089/aid.2008.0299
Gongvatana A, Cohen RA, Correia S, Devlin KN, Miles J, Kang H, Ombao H, Navia B, Laidlaw DH, Tashima KT (2011) Clinical contributors to cerebral white matter integrity in HIV-infected individuals. Journal of Neurovirology 17(5):477–486. doi:10.1007/s13365-011-0055-0. Available at http://www.ncbi.nlm.nih.gov/pubmed/21965122
Gougeon ML, Piacentini M (2009) New insights on the role of apoptosis and autophagy in HIV pathogenesis. Apoptosis: an International Journal on Programmed Cell Death 14(4):501–508. doi:10.1007/s10495-009-0314-1. Available at http://www.ncbi.nlm.nih.gov/pubmed/19199038
Heaps JM, Joska J, Hoare J, Ortega M, Agrawal A, Seedat S, Ances BM, Stein DJ, Paul R (2012) Neuroimaging markers of human immunodeficiency virus infection in South Africa. Journal of Neurovirology 18(3):151–156. doi:10.1007/s13365-012-0090-5. Available at http://www.ncbi.nlm.nih.gov/pubmed/22528474
Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75(23):2087–2096. doi:10.1212/WNL.0b013e318200d727. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2995535&tool=pmcentrez&rendertype=abstract
Hoare J, Westgarth-Taylor J, Fouche JP, Combrinck M, Spottiswoode B, Stein DJ, Joska JA (2013) Relationship between apolipoprotein E4 genotype and white matter integrity in HIV-positive young adults in South Africa. European Archives of Psychiatry and Clinical Neuroscience 263(3):189–195. doi:10.1007/s00406-012-0341-8. Available at http://www.ncbi.nlm.nih.gov/pubmed/22825739
Holt JL, Kraft-Terry SD, Chang L (2012) Neuroimaging studies of the aging HIV-1-infected brain. Journal of Neurovirology 18(4):291–302. doi:10.1007/s13365-012-0114-1. Available at http://www.ncbi.nlm.nih.gov/pubmed/22653528
Jayadev S, Garden GA (2009) Host and viral factors influencing the pathogenesis of HIV-associated neurocognitive disorders. Journal of Neuroimmune Pharmacology 4(2):175–189. doi:10.1007/s11481-009-9154-6.Host. Available at http://www.springerlink.com/index/3067M66N70454864.pdf
Joska JA, Westgarth-Taylor J, Myer L, Hoare J, Thomas KGF, Combrinck M, Paul RH, Stein DJ, Flisher AJ (2011) Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa. AIDS and Behavior 15(6):1197–1203. doi:10.1007/s10461-010-9744-6. Available at http://www.ncbi.nlm.nih.gov/pubmed/20614176
Kallianpur KJ, Kirk GR, Sailasuta N, Valcour V, Shiramizu B, Nakamoto BK, Shikuma C (2012) Regional cortical thinning associated with detectable levels of HIV DNA. Cerebral Cortex 22(9):2065–2075. doi:10.1093/cercor/bhr285. Available at http://www.ncbi.nlm.nih.gov/pubmed/22016479
Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994
Kumar AM, Fernandez JB, Singer EJ, Commins D, Waldrop-Valverde D, Ownby RL, Kumar M (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains. Journal of Neurovirology 15(3):257–274. doi:10.1080/13550280902973952. Available at http://www.ncbi.nlm.nih.gov/pubmed/19499455
Mattson MP, Haughey NJ, Nath A (2005) Cell death in HIV dementia. Cell Death and Differentiation 12(Suppl 1): 893–904. doi:10.1038/sj.cdd.4401577. Available at http://www.ncbi.nlm.nih.gov/pubmed/15761472
Mishra M, Vetrivel S, Siddappa NB, Ranga U, Seth P (2008) Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif. Annals of Neurology 63(3):366–376. doi:10.1002/ana.21292. Available at http://www.ncbi.nlm.nih.gov/pubmed/18074388
Modi G, Hari K, Modi M, Mochan A (2007) The frequency and profile of neurology in Black South African HIV infected (clade C) patients—a hospital-based prospective audit. Journal of the Neurological Sciences 254(1–2):60–64. doi:10.1016/j.jns.2007.01.001. Available at http://www.ncbi.nlm.nih.gov/pubmed/17291536
Pfefferbaum A, Rosenbloom MJ, Rohlfing T, Kemper CA, Deresinski S, Sullivan EV (2009) Frontostriatal fiber bundle compromise in HIV infection without dementia. AIDS (London, England) 23(15):1977–1985. doi:10.1097/QAD.0b013e32832e77fe. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2864007&tool=pmcentrez&rendertype=abstract
Pfefferbaum A, Rosenbloom MJ, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Sullivan EV (2012) Regional brain structural dysmorphology in human immunodeficiency virus infection: effects of acquired immune deficiency syndrome, alcoholism, and age. Biological Psychiatry 72(5):361–370. doi:10.1016/j.biopsych.2012.02.018. Available at http://www.ncbi.nlm.nih.gov/pubmed/22458948
Rambaut A, Posada D, Crandall KA, Holmes EC (2004) The causes and consequences of HIV evolution. Nature Reviews. Genetics 5(1):52–61. doi:10.1038/nrg1246. Available at http://www.ncbi.nlm.nih.gov/pubmed/14708016
Rao VR, Neogi U, Talboom JS, Padilla L, Rahman M, Fritz-French C, Gonzalez-Ramirez S et al (2013) Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence. Retrovirology 10(1):61. doi:10.1186/1742-4690-10-61. Available at http://www.ncbi.nlm.nih.gov/pubmed/23758766
Rao VR, Sas AR, Eugenin EA, Siddappa NB, Bimonte-Nelson H, Berman JW, Ranga U, Tyor WR, Prasad VR (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 28(40):10010–10016. doi:10.1523/JNEUROSCI.2955-08.2008. Available at http://www.jneurosci.org/content/28/40/10010.short
Samikkannu T, Agudelo M, Gandhi N, Reddy P, Saiyed Z, Nwankwo D, Nair M (2011) Human immunodeficiency virus type 1 clade B and C Gp120 differentially induce neurotoxin arachidonic acid in human astrocytes: implications for neuroAIDS. Journal of NeuroVirology 17(3):230–238. doi:10.1007/s13365-011-0026-5. Available at http://dx.doi.org/10.1007/s13365-011-0026-5
Shapshak P, Kangueane P, Fujimura RK, Commins D, Chiappelli F, Singer E, Levine AJ et al (2011) Editorial neuroAIDS review. AIDS (London, England) 25(2):123–141. doi:10.1097/QAD.0b013e328340fd42. Available at http://www.ncbi.nlm.nih.gov/pubmed/21076277
Stout JC, Ellis RJ, Jernigan TL, Archibald SL, Abramson I, Wolfson T, McCutchan JA, Wallace MR, Atkinson JH, Grant I (1998) Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group. Archives of Neurology 55(2):161–168. Available at http://www.ncbi.nlm.nih.gov/pubmed/9482357
Thompson PM, Dutton RA, Hayashi KM, Toga AW, Lopez OL, Aizenstein HJ, Becker JT (2005) Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline. Proc Natl Acad Sci U S A 102:15647–15652
Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Kumar A, Soni S, Sibtain NA et al (2012) Mapping the brain in younger and older asymptomatic HIV-1 men: frontal volume changes in the absence of other cortical or diffusion tensor abnormalities. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior 48(2):230–241. doi:10.1016/j.cortex.2011.03.006. Available at http://www.ncbi.nlm.nih.gov/pubmed/21481856
Wadia RS, Pujari SN, Kothari S et al (2001) Neurological manifestations of HIV disease. J Assoc Phys India 49:343–348. Available at http://ukpmc.ac.uk/abstract/MED/11291974
Wainberg MA (2004) HIV-1 subtype distribution and the problem of drug resistance. AIDS 18(Suppl 3):S63–S68. doi:10.1097/01.aids.0000131319.67773.8e. Available at http://journals.lww.com/aidsonline/Abstract/2004/06003/HIV_1_subtype_distribution_and_the_problem_of_drug.12.aspx
Wang X, Foryt P, Ochs R, Chung JH, Wu Y, Parrish T, Ragin AB (2011) Abnormalities in resting-state functional connectivity in early human immunodeficiency virus infection. Brain Connectivity 1(3):207–217. doi:10.1089/brain.2011.0016. Available at http://www.ncbi.nlm.nih.gov/pubmed/22433049
Wiley CA, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann SA, Dailey P, Achim CL (1998) Distribution of brain HIV load in AIDS. Brain Pathology (Zurich, Switzerland) 8(2):277–284. Available at http://www.ncbi.nlm.nih.gov/pubmed/9804386
Yepthomi T, Paul R, Vallabhaneni S, Kumarasamy N, Tate DF, Solomon S, Flanigan T (2006) Neurocognitive consequences of HIV in Southern India: a preliminary study of clade C virus. Journal of the International Neuropsychological Society: JINS 12(3):424–430. Available at http://www.ncbi.nlm.nih.gov/pubmed/16903135
Acknowledgments
This study was financially supported by the National Institute of Mental Health (K23MH081786 to B.M.A., R01MH22005 to F.V., and R01MH085604 to R.P.), National Institute of Nursing Research (R01NR012907, R01NR012657, and R01NR014449 to B.M.A.), National Institute of Allergy and Infectious Disease (R01AI47033 to F.V.), National Institute of Health (MH065857 to R.P., J.J., and J.M.H.), Grossman Chancellor’s Fellowship (to M.O.), and National Science Foundation IGERT (0548890 to M.O.)
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Ortega, M., Heaps, J.M., Joska, J. et al. HIV clades B and C are associated with reduced brain volumetrics. J. Neurovirol. 19, 479–487 (2013). https://doi.org/10.1007/s13365-013-0202-x
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DOI: https://doi.org/10.1007/s13365-013-0202-x