HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: the SEARCH 001 Cohort Study. Neurology

Hawaii AIDS Clinical Research Program, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96816, USA.
Neurology (Impact Factor: 8.29). 04/2009; 72(11):992-8. DOI: 10.1212/01.wnl.0000344404.12759.83
Source: PubMed


The extent to which highly active antiretroviral therapy (HAART) era cognitive disorders are due to active processes, incomplete clearance of reservoirs, or comorbidities is controversial. This study aimed to determine if immunologic and virologic factors influence cognition after first-time HAART in Thai individuals with HIV-associated dementia (HAD) and Thai individuals without HAD (non-HAD).
Variables were captured longitudinally to determine factors predictive of degree of cognitive recovery after first-time HAART. Neuropsychological data were compared to those of 230 HIV-negative Thai controls.
HIV RNA and CD4 lymphocyte counts were not predictive of HAD cross-sectionally or degree of cognitive improvement longitudinally. In contrast, baseline and longitudinal HIV DNA isolated from monocytes correlated to cognitive performance irrespective of plasma HIV RNA and CD4 lymphocyte counts pre-HAART (p < 0.001) and at 48 weeks post HAART (p < 0.001). Levels exceeding 3.5 log(10) copies HIV DNA/10(6) monocyte at baseline distinguished all HAD and non-HAD cases (p < 0.001). At 48 weeks, monocyte HIV DNA was below the level of detection of our assay (10 copies/10(6) cells) in 15/15 non-HAD compared to only 4/12 HAD cases, despite undetectable plasma HIV RNA in 26/27 cases. Baseline monocyte HIV DNA predicted 48-week cognitive performance on a composite score, independently of concurrent monocyte HIV DNA and CD4 count (p < 0.001).
Monocyte HIV DNA level correlates to cognitive performance before highly active antiretroviral therapy (HAART) and 48 weeks after HAART in this cohort and baseline monocyte HIV DNA may predict 48-week cognitive performance. These findings raise the possibility that short-term incomplete cognitive recovery with HAART may represent an active process related to this peripheral reservoir.

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    • "Microglia are less commonly infected than perivascular macrophages and arise from different cell precursors [49, 57–59]. The level of HIV DNA in monocytes, but not plasma viral load or CD4 count, is associated with HAND for HIV-infected persons before and after cART treatment [60], with the association persisting at 3.5 years after cART initiation [61]. It is likely that some of these HIV-infected monocytes harboring HIV DNA could cross the blood brain barrier, contributing to the persistent presence of HIV-infected cells in the brain. "
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    • "Although in a few longitudinal studies, subjects with HAND showed better improvement with initiation of higher CPE regimens, results of cross sectional studies have shown variable results, possibly in part due to initial selection of high-CPE regimens for more medically or neurologically ill patients [73–77]. Since macrophage and microglial cells are the primary cells within the CNS productively infected by HIV, recent investigation has focused on the role of antiretroviral penetration into monocytes, cells which may serve as circulating precursors to these cellular reservoirs within the CNS and which have been found by some investigators to be linked to presence of HAND [78, 79]. Putative ability of individual antiretrovirals to affect HIV replication within monocyte-lineage cells has been quantitated as a monocyte efficacy (ME) score, and one study employing summed ME scores from drug regimens found this to be a closer predictor of neuropsychological performance than CPE [80]. "
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    • "These results are consistent with our unpublished data (Table 2). These results also concur with the findings that monocytes are a critical cellular subset as HIV DNA copies in monocytes correlate with cognitive performance and can be used to predict 48-week cognitive performance [17], although previous studies reported HIV DNA in PBMCs are proportionally correlative to the severity of HAND regardless of HIV RNA levels in the plasma [18]. Furthermore, HIV DNA levels in PBMCs are even associated with individual deficits in neurocognitive domains [18-21]. "
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