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Dual-mixed HIV-1 coreceptor tropism and HIV-associated neurocognitive deficits

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Abstract

HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described. This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to four sequential neurocognitive assessments over a median of 160 days (IQR, 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count, and problematic methamphetamine use. Six subjects (8.3 %) had DM at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR, 7.2–12.2). There were 44 (61.1 %) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio, 4.4; 95 % CI, 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier; 95 % CI, 1.0–1.2). This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together, these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.

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Acknowledgments

The Translational Methamphetamine AIDS Research Center (TMARC) group is affiliated with the University of California, San Diego (UCSD) and the Sanford-Burnham Medical Research Institute. The TMARC is comprised of: Director: Igor Grant, M.D.; Co-Directors: Ronald J. Ellis, M.D., Ph.D., Cristian Achim, M.D., Ph.D., and Scott Letendre, M.D.; Center Manager: Steven Paul Woods, Psy.D.; Aaron Carr (Assistant Center Manager); Clinical Assessment and Laboratory Core: Scott Letendre, M.D. (P.I.), Ronald J. Ellis, M.D., Ph.D., Rachel Schrier, Ph.D.; Neuropsychiatric Core: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Mariana Cherner, Ph.D., Thomas Marcotte, Ph.D., Erin E. Morgan, Ph.D.; Neuroimaging Core: Gregory Brown, Ph.D. (P.I.), Terry Jernigan, Ph.D., Anders Dale, Ph.D., Thomas Liu, Ph.D., Miriam Scadeng, Ph.D., Christine Fennema-Notestine, Ph.D., Sarah L. Archibald, M.A.; Neurosciences and Animal Models Core: Cristian Achim, M.D., Ph.D., Eliezer Masliah, M.D., Stuart Lipton, M.D., Ph.D.; Participant Unit: J. Hampton Atkinson, M.D., Rodney von Jaeger, M.P.H. (Unit Manager); Data Management and Information Systems Unit: Anthony C. Gamst, Ph.D., Clint Cushman (Unit Manager); Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D., Reena Deutsch, Ph.D., Anya Umlauf, M.S.; Project 1: Arpi Minassian, Ph.D. (P.I.), William Perry, Ph.D., Mark Geyer, Ph.D., Brook Henry, Ph.D.; Project 2: Amanda B. Grethe, Ph.D. (P.I.), Martin Paulus, M.D., Ronald J. Ellis, M.D., Ph.D.; Project 3: Sheldon Morris, M.D., M.P.H. (P.I.), David M. Smith, M.D., M.A.S., Igor Grant, M.D.; Project 4: Svetlana Semenova, Ph.D. (P.I.), Athina Markou, Ph.D.; Project 5: Marcus Kaul, Ph.D. (P.I.). The authors report no conflicts of interest. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. We are grateful to all the participants in the San Diego Primary Infection Cohort, CHARTER and TMARC. Phenotypic tropism assays in this study were performed at Monogram Biosciences Clinical Reference Laboratory.

Author contributions

SRM participated in the study design, arranged samples for testing, performed statistical analysis and wrote the primary version of the manuscript; RD performed statistical analysis and participated in writing; SPW was involved in the analysis plan and participated in writing the primary version; EEM was involved in the psychological battery analysis and participated in review of manuscript; DMS participated in study design, enrolled participants, analyzed data and writing of the manuscript, MVV performed the laboratory experiments; SJL and enrolled participants, RKH, SJL, SLL, and IG designed the overarching studies that enrolled the subjects and revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the US National Institutes of Health (NIH) awards AI69432, AI043638, MH062512, MH083552, AI100665, AI077304, AI36214, AI047745, AI074621, GM093939, DA026306, AI080353, AI306214 (CFAR), AI27670 (ACTU), AI43638, DA12065, and the California HIV Research Program grant RN07-SD-702.

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Authors and Affiliations

  1. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Sheldon R. Morris, Susan J. Little, Gabriel Wagner, Scott L. Letendre & Davey M. Smith

  2. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Steven Paul Woods, Reena Deutsch, Erin E. Morgan, Robert K. Heaton & Igor Grant

  3. Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    Davey M. Smith

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  1. Sheldon R. Morris
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  2. Steven Paul Woods
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  3. Reena Deutsch
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Correspondence to Sheldon R. Morris.

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Morris, S.R., Woods, S.P., Deutsch, R. et al. Dual-mixed HIV-1 coreceptor tropism and HIV-associated neurocognitive deficits. J. Neurovirol. 19, 488–494 (2013). https://doi.org/10.1007/s13365-013-0203-9

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