Abstract Details

Title A common (GT)n repeat polymorphism in the heme oxygenase-1 promoter associates with neuroinflammation and cognitive impairment in HIV infection

Topic Infectious Disease

Presentation(s) S29 - NeuroHIV: Pathophysiology and Clinical Phenotypes (3:41 PM-3:52 PM)

Poster/Presentation
Number 002

Background Inducible expression of HO-1, an anti-oxidative, anti-inflammatory enzyme, is modulated by a dinucleotide (GT)n repeat of varying length in the HO-1 promoter. Brain HO-1 expression is decreased in HIV+ subjects and this correlates with neuroimmune activation and neurocognitive impairment. We previously showed (autopsied HIV cohort (n=551)) that subjects having least one “short” (GT)n repeat (length <27) allele had reduced brain neuroimmune activation and risk for HIV-encephalitis. We have now determined the relationship between this HO-1 polymorphism and neurocognitive impairment in a living HIV cohort (n=600).

Objective

Determine association between (GT)n repeat length in the promoter of the antioxidant gene, heme oxygenase-1 (HO-1), and neurocognitive impairment in HIV+ subjects.

Design/Methods

We determined HO-1 (GT)n repeat allele lengths in DNA collected from 600 subjects in the CNS HIV Antiretroviral Therapy Effects Research/CHARTER study. We defined ‘short’ (<27 repeats), ‘middle’ (28-34 repeats), and ‘long’ (>34 repeats) alleles. Patients were assigned a neurocognitive diagnosis based upon the Frascati criteria for HIV-associated neurocognitive disorders/HAND {Antinori A,2007}.

Results

HO-1 (GT)n repeats ranged from 13 to 44 with a trimodal distribution at 23, 30, and 39 (GT)n repeats. HIV+ subjects with at least one ‘short’ allele had a lower risk of functional impairment (HAND diagnosis: mild neurocognitive disorder/MND) (p=0.047, OR=0.63). The statistical significance was greatest in subjects without other co-morbidity risks besides HIV (p=0.01, OR=0.54). Presence of a “short” allele did not correlate with plasma/CSF HIV levels or CD4+ T-cell counts.

Conclusions Our data suggest that the presence of a ‘short’ HO-1 (GT)n repeat allele reduces risk for developing neurocognitive impairment in HIV infection. Because ‘short’ HO-1 (GT)n repeat promoters demonstrate greater inducibility in response to stress signals, subjects with short alleles may have a more robust anti-oxidant response. This could decrease neuroimmune activation, neurodegeneration and risk for neurocognitive impairment, and offer a therapeutic target.

Authors/Disclosures
Rolando Garza PRESENTER	No disclosure on file
Alexander J. Gill, MD, PhD (Johns Hopkins University)	Dr. Gill has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medical Logix, LLC. Dr. Gill has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Health Union, LLC . Dr. Gill has received research support from National Multiple Sclerosis Society.
	No disclosure on file
Scott L. Letendre, MD (HNRC, UCSD)	The institution of Dr. Letendre has received research support from National Institutes of Health. The institution of Dr. Letendre has received research support from University at Buffalo. Dr. Letendre has received publishing royalties from a publication relating to health care.
Dennis L. Kolson, MD, PhD (University of Pennsylvania)	The institution of Dr. Kolson has received research support from NIH--R01 research grant.

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