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The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning

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Abstract

Both human immunodeficiency virus (HIV)-1 infection and illicit stimulant use can adversely impact neurocognitive functioning, and these effects can be additive. However, significant variability exists such that as-of-yet unidentified exogenous and endogenous factors affect one’s risk for neurocognitive impairment. Literature on both HIV and stimulant use indicates that host genetic variants in immunologic and dopamine-related genes are one such factor. In this study, the individual and interactive effects of HIV status, stimulant use, and genotype upon neurocognitive functioning were examined longitudinally over a 10-year period. Nine hundred fifty-two Caucasian HIV+ and HIV− cases from the Multicenter AIDS Cohort Study were included. All cases had at least two comprehensive neurocognitive evaluations between 1985 and 1995. Pre-highly active antiretroviral therapy (HAART) data were examined in order to avoid the confounding effect of variable drug regimens. Linear mixed models were used, with neurocognitive domain scores as the outcome variables. No four-way interactions were found, indicating that HIV and stimulant use do not interact over time to affect neurocognitive functioning as a function of genotype. Multiple three-way interactions were found that involved genotype and HIV status. All immunologically related genes found to interact with HIV status affected neurocognitive functioning in the expected direction; however, only C-C chemokine ligand 2 (CCL2) and CCL3 affected HIV+ individuals specifically. Dopamine-related genetic variants generally affected HIV-negative individuals only. Neurocognitive functioning among HIV+ individuals who also used stimulants was not significantly different from those who did not use stimulants. The findings support the role of immunologically related genetic differences in CCL2 and CCL3 in neurocognitive functioning among HIV+ individuals; however, their impact is minor. Being consistent with findings from another cohort, dopamine (DA)-related genetic differences do not appear to impact the longitudinal neurocognitive functioning of HIV+ individuals.

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Acknowledgments

Our deepest gratitude to the volunteers enrolled in the Multicenter AIDS Cohort Study (MACS). This study was funded through the National Institute for Drug Abuse grant R03DA026099 (Levine) and UCLA-AIDS Institute/Center for AIDS Research grant AI28697 (Freimer). Susan Service and Nelson Freimer (UCLA) assisted with data acquisition and analysis.

Data in this manuscript were collected by the volunteers in MACS with centers at Baltimore (U01-AI35042), The Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick (PI), Barbara Crain, Adrian Dobs, Homayoon Farzadegan, Joel Gallant, Lisette Johnson-Hill, Michael W. Plankey, Ned Sacktor, Ola Selnes, James Shepard, and Chloe Thio); Chicago (U01-AI35039), Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services (Steven M. Wolinsky (PI), John P. Phair, Sheila Badri, Maurice O’Gorman, David Ostrow, Frank Palella, and Ann Ragin); Los Angeles (U01-AI35040), University of California, UCLA Schools of Public Health and Medicine (Roger Detels (PI), Otoniel Martínez-Maza (Co-PI), Aaron Aronow, Robert Bolan, Elizabeth Breen, Anthony Butch, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, and Zuo Feng Zhang); Pittsburgh (U01-AI35041), University of Pittsburgh, Graduate School of Public Health (Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Ross D. Cranston, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, and Ronald D. Stall); and the Data Coordinating Center (UM1-AI35043), The Johns Hopkins University Bloomberg School of Public Health (Lisa P. Jacobson (PI), Alvaro Munoz (Co-PI), Alison Abraham, Keri Althoff, Christopher Cox, Jennifer Deal, Gypsyamber D’Souza, Priya Duggal, Janet Schollenberger, Eric C. Seaberg, Sol Su, and Pamela Surkan). The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR000424 (JHU CTSA). Website located at http://www.statepi.jhsph.edu/macs/macs.html. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH).

We also wish to thank the following individuals and their teams for providing genotyping data: by Jacques Fellay, M.D.; Stephen O’Brien, Ph.D.; and James I. Mullins, Ph.D.

Conflict of interest

This study was funded through a grant awarded to Andrew J. Levine by NIDA.

Dr. Miller is the author of the CalCAP Reaction Time Program and has a financial interest in this software. His work with the Multicenter AIDS Cohort Study is funded by NIAID. He has no financial relationship with NIDA or the UCLA AIDS Institute.

Sandra Reynolds does not have any financial relationship with the sponsor of this research.

Christopher Cox does not have any financial relationship with the sponsor of this research.

Janet S. Sinsheimer does not have any financial relationship with the sponsor of this research.

James T. Becker does not have any financial relationship with the sponsor of this research.

Eileen Martin does not have any financial relationship with the sponsor of this research.

Ned Sacktor does not have any financial relationship with the sponsor of this research.

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Authors and Affiliations

  1. Department of Neurology, National Neurological AIDS Bank, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Andrew J. Levine

  2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Sandra Reynolds & Christopher Cox

  3. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Eric N. Miller

  4. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Janet S. Sinsheimer

  5. Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Janet S. Sinsheimer

  6. Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA

    Janet S. Sinsheimer

  7. Departments of Psychiatry and Neurology and Psychology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    James T. Becker

  8. Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA

    Eileen Martin

  9. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ned Sacktor

  10. 11645 Wilshire Blvd., Ste 770, Los Angeles, CA, 90025, USA

    Andrew J. Levine

Authors
  1. Andrew J. Levine
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  2. Sandra Reynolds
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  3. Christopher Cox
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  4. Eric N. Miller
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  5. Janet S. Sinsheimer
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  6. James T. Becker
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  7. Eileen Martin
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  8. Ned Sacktor
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for the Neuropsychology Working Group of the Multicenter AIDS Cohort Study

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Correspondence to Andrew J. Levine.

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Levine, A.J., Reynolds, S., Cox, C. et al. The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning. J. Neurovirol. 20, 243–257 (2014). https://doi.org/10.1007/s13365-014-0241-y

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  • DOI: https://doi.org/10.1007/s13365-014-0241-y

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