Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection
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MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.
KeywordsAntiretroviral therapy Brain CD4+ T cell Immune recovery/reconstitution Inflammation MRI
This work was supported by awards from the National Institutes of Health for the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) [N01 MH2205 and HHSN271201000027C] and NIH grants R01 MH079752, NIH P30 MH0625, and R21 NS069355. The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Government. The authors report no conflict of interest. Preliminary aspects of this work were presented at the Society for Neuroscience 2010 Meeting, November 2010, San Diego, CA [Program No. 764.4], and at the Fourth International Meeting on HIV Infection and the Central Nervous System: Treating the Brain in the HAART Era, July 2011, Frascati (Rome), Italy [Poster P2].
The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego; University of Texas, Galveston; University of Washington, Seattle; Washington University, St. Louis; and is headquartered at the University of California, San Diego, and includes: Director: Igor Grant, M.D.; Co-Directors: J. Allen McCutchan, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Terry Alexander, R.N.; Laboratory, Pharmacology and Immunology Component: Scott Letendre, M.D. (P.I.), Edmund Capparelli, Pharm.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Steven Paul Woods, Psy.D., Matthew Dawson; Virology Component: David Smith, M.D. (P.I.); Imaging Component: Christine Fennema-Notestine, Ph.D. (P.I.), Terry L. Jernigan, Ph.D., Michael J. Taylor, Ph.D., Rebecca J. Theilmann, Ph.D., John Hesselink, M.D.; Data Management Unit: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman; Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Protocol Coordinating Component: Thomas D. Marcotte, Ph.D. (P.I.); Johns Hopkins University Site: Justin McArthur (P.I.), Mary Smith; Mount Sinai School of Medicine Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P., Cheuk Tang, Ph.D., and Thomas Naidich, M.D.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.), Will Toperoff, N.P.; University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Kenneth Maravilla, MD, KC Stegbauer, Ph.D., Trudy Jones, M.N., A.R.N.P.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N., Gregory Chaljub, M.D.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.
- Becker JT, Maruca V, Kingsley LA, Sanders JM, Alger JR, Barker PB, Goodkin K, Martin E, Miller EN, Ragin A, Sacktor N, Selnes O (2011a) Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology 54(2):113–121. doi: 10.1007/s00234-011-0854-2 PubMedCrossRefGoogle Scholar
- Becker JT, Sanders J, Madsen SK, Ragin A, Kingsley L, Maruca V, Cohen B, Goodkin K, Martin E, Miller EN, Sacktor N, Alger JR, Barker PB, Saharan P, Carmichael OT, Thompson PM (2011b) Subcortical brain atrophy persists even in HAART-regulated HIV disease. Brain Imaging Behav 5:77–85PubMedCrossRefGoogle Scholar
- Binquet C, Chene G, Jacqmin-Gadda H, Journot V, Saves M, Lacoste D, Dabis F (2001) Modeling changes in CD4-positive T-lymphocyte counts after the start of highly active antiretroviral therapy and the relation with risk of opportunistic infections: the Aquitaine Cohort, 1996–1997. Am J Epidemiol 153:386–393PubMedCrossRefGoogle Scholar
- Cardenas VA, Meyerhoff DJ, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J, Grant RM, Chao LL, Truran D, Weiner MW (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15:324–333PubMedCrossRefGoogle Scholar
- Cohen RA, Harezlak J, Gongvatana A, Buchthal S, Schifitto G, Clark U, Paul R, Taylor M, Thompson P, Tate D, Alger J, Brown M, Zhong J, Campbell T, Singer E, Daar E, McMahon D, Tso Y, Yiannoutsos CT, Navia B (2010a) Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. J Neurovirol 16:435–444PubMedGoogle Scholar
- Cohen RA, Harezlak J, Schifitto G, Hana G, Clark U, Gongvatana A, Paul R, Taylor M, Thompson P, Alger J, Brown M, Zhong J, Campbell T, Singer E, Daar E, McMahon D, Tso Y, Yiannoutsos CT, Navia B (2010b) Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era. J Neurovirol 16:25–32PubMedCrossRefGoogle Scholar
- Fennema-Notestine C, Gamst AC, Quinn BT, Pacheco J, Jernigan TL, Thal L, Buckner R, Killiany R, Blacker D, Dale AM, Fischl B, Dickerson B, Gollub RL (2007) Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data. Neuroinformatics 5:235–245PubMedCrossRefGoogle Scholar
- Goicoechea M, Smith DM, Liu L, May S, Tenorio AR, Ignacio CC, Landay A, Haubrich R (2006) Determinants of CD4+ T cell recovery during suppressive antiretroviral therapy: association of immune activation, T cell maturation markers, and cellular HIV-1 DNA. J Infect Dis 194:29–37PubMedCrossRefGoogle Scholar
- Jernigan TL, Archibald SL, Fennema-Notestine C, Taylor MJ, Theilmann RJ, Julaton MD, Notestine RJ, Wolfson T, Letendre SL, Ellis RJ, Heaton RK, Gamst AC, Franklin DR Jr, Clifford DB, Collier AC, Gelman BB, Marra C, McArthur JC, McCutchan JA, Morgello S, Simpson DM, Grant I (2011) Clinical factors related to brain structure in HIV: the CHARTER study. J Neurovirol 17:248–257PubMedCrossRefGoogle Scholar
- Moore DM, Harris R, Lima V, Hogg B, May M, Yip B, Justice A, Mocroft A, Reiss P, Lampe F, Chene G, Costagliola D, Elzi L, Mugavero MJ, Monforte AD, Sabin C, Podzamczer D, Fatkenheuer G, Staszewski S, Gill J, Sterne JA (2009) Effect of baseline CD4 cell counts on the clinical significance of short-term immunologic response to antiretroviral therapy in individuals with virologic suppression. J Acquir Immune Defic Syndr 52:357–363PubMedCrossRefGoogle Scholar
- 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. Arch Neurol 55:161–168PubMedCrossRefGoogle Scholar
- Tan R, Westfall AO, Willig JH, Mugavero MJ, Saag MS, Kaslow RA, Kempf MC (2008) Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 47:553–558PubMedCrossRefGoogle Scholar