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Title
The identification of intact HIV proviral DNA in human cerebrospinal fluid
Presenter
Sebastian Roa
Authors
Z. Zhang1,2,3, M. Reece2, S. Roa2, W. Tyor1,3, C. Gavegnano2,3,4,5,6, A. Anderson7
Institutions
1Emory University, Neurology, Atlanta, United States, 2Emory University, Pathology and Laboratory Medicine, Atlanta, United States, 3Atlanta Veterans Affairs Medical Center, Decatur, United States, 4Emory University, Pharmacology and Chemical Biology, Atlanta, United States, 5Emory University, Center for Human Health, Atlanta, United States, 6Harvard Medical School, Center for Bioethics, Boston, United States, 7Emory University, Medicine, Atlanta, United States

BACKGROUND: The Central Nervous System (CNS) provides a sanctuary site for HIV-1 persistence, and HI-1 RNA remains detectable in the cerebrospinal fluid (CSF) and brain tissues from people living with HIV-1 (PWH) despite peripheral virologic suppression with ART. Neurocognitive impairment (HIV-associated neurocognitive disorders;HAND), develops in roughly 45% of PWH. We sought to better understand the relationship between reservoir size of replication competent virus in CNS and the periphery and their relationship to severity of neurocognitive deficits in PWH.
METHODS: Exclusion criteria: ART regimen, continuously virologically suppressed; no history of any neurologic disease known to affect memory (including stroke, malignancy involving the brain, traumatic brain injury, schizophrenia, and AIDS-related opportunistic infection of the CNS). A neuropsychological (NP) testing battery was administered that included nine tests used commonly in studies of cognition and HIV acquisition. Intact proviral DNA assay (IPDA) was performed to predict the frequency of replication competent virus in CSF and peripheral blood mononuclear cells (PBMC) from PWH (n=11).
RESULTS: Intact proviral DNA (mean=6.31x103 copies per million cells) persists in the CSF despite ART intervention (8/11 individual PWH were detected intact proviral DNA). We further compared the frequency of intact and defective proviruses in CSF versus PBMC. CSF contains significantly higher frequency of both intact (mean 2.69x103 vs 2.76x102) and defective (5’ defective proviral copy numbers per million cells: mean 1.44x106 vs 4.36x103, p = 0.0228] [3’ defective proviral copy numbers per million cells: mean 4.07x106 vs 7.96x103, p = 0.0228]) proviruses throughout all individuals. Due to small sample size in this study, there was no strong correlation observed between cognitive impairment and viral reservoir in the CSF compartment. Cognition score in this pilot study indicated that both intact and defective reservoir size are associated with poor attention/working memory.
CONCLUSIONS: These data highlight that the CSF is a sanctuary site for the intact HIV-1 reservoir, which persists at significantly higher levels versus the periphery in our cohort.
investigations with a larger sample size are warranted to elucidate potential impact of intact and defective viral sequences on neurocognitive functions in various brain regions.

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