Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV

Hawaii Center for AIDS, Department of Medicine, University of Hawaii, Honolulu, HI, USA. .
Antiviral therapy (Impact Factor: 3.02). 09/2012; 17(7). DOI: 10.3851/IMP2411
Source: PubMed


Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir.

Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment.

Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (β=0.003, P=0.02), CD4(+) T-cell nadir (β=0.001, P<0.01) and gender (β=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5-433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01).

ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.

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    • "cART regimens with higher monocyte efficacy scores more effectively inhibited the in vitro infection of monocytes and macrophages as compared to treatments with lower scores. HIV seropositive people receiving antiretroviral regimens with lower monocyte efficacy scores had a significantly higher likelihood of cognitive impairment [152]. This occurred even in individuals who had undetectable plasma viral loads. "
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    ABSTRACT: HIV infected people are living longer due to the success of combined antiretroviral therapy (cART).However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14+CD16+ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14+CD16+ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14+CD16+ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.
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    • "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]. Ideally, randomized clinical trials of higher as compared to lower CPE and ME regimens would provide the best data to indicate whether such indices should be taken into account in treatment of HIV infected individuals and specifically those meeting criteria for HAND. "
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