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

ABSTRACT 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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Available from: Jerome Hahn Kim, Sep 25, 2015
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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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    ABSTRACT: Combined antiretroviral therapy (cART) extends the lifespan and the quality of life for HIV-infected persons but does not completely eliminate chronic immune activation and inflammation. The low level of chronic immune activation persisting during cART-treated HIV infection is associated with the development of diseases which usually occur in the elderly. Although T-cell activation has been extensively examined in the context of cART-treated HIV infection, monocyte activation is only beginning to be recognized as an important source of inflammation in this context. Here we examine markers and sources of monocyte activation during cART-treated HIV infection and discuss the role of monocytes during cardiovascular disease, HIV-associated neurocognitive disorder, and innate immune aging.
    Research Journal of Immunology 06/2014; 2014:569819. DOI:10.1155/2014/569819
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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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    ABSTRACT: The spectrum of HIV-associated neurocognitive disorder (HAND) has been dramatically altered in the setting of widely available effective antiretroviral therapy (ART). Once culminating in dementia in many individuals infected with HIV, HAND now typically manifests as more subtle, though still morbid, forms of cognitive impairment in persons surviving long-term with treated HIV infection. Despite the substantial improvement in severity of this disorder, the fact that neurologic injury persists despite ART remains a challenge to the community of patients, providers and investigators aiming to optimize quality of life for those living with HIV. Cognitive dysfunction in treated HIV may reflect early irreversible CNS injury accrued before ART is typically initiated, ongoing low-level CNS infection and progressive injury in the setting of ART, or comborbidities including effects of treatment which may confound the beneficial reduction in viral replication and immune activation effected by ART.
    Current HIV/AIDS Reports 07/2013; 10(3). DOI:10.1007/s11904-013-0171-y · 3.80 Impact Factor
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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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    ABSTRACT: We demonstrate for the first time that the genome-wide profiling of HIV-infected peripheral blood mononuclear cells (PBMCs) from HIV-patients free of neurologic disease show overrepresentation of neurodegenerative pathways (Alzheimer's, Parkinson's, ALS, Huntington's and Prion Disease, etc.) in genome-wide microarray analysis, which suggests that this genome-wide representation of neurodegenerative diseases-related pathways in PBMCs could possibly be a subcellular manifestation of neurologic interference by HIV. Further, the cell-tagging analysis attested this belief showing the large majority of genes tagged with cells of monocyte and macrophage lineage, which are implicated in neuronal dysfunction in both viral and non-viral neurodegenerative diseases. Together, these findings suggest that the genomic interference of HIV with neurodegenerative pathways is not by chance, but may be an early sign of HIV-mediated sub-genomic and sub-cellular manifestation of neurologic disease. Moreover, these findings signify the utility of PBMC and genome-wide mapping of the host gene expression as a powerful tool in predicting possible early events in neurologic deterioration in HIV patients.
    Virology Journal 12/2012; 9(1):308. DOI:10.1186/1743-422X-9-308 · 2.18 Impact Factor
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