Biomarkers of HIV related central nervous system disease

Brew, Bruce J.; Letendre, Scott

doi:10.1080/09540260701878082

Cited by 55 publications

(27 citation statements)

References 137 publications

(145 reference statements)

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“…38 Both studies suggested that immune activation may actually provide a neuroprotective effect in the pediatric population. This is in stark contrast to the data in the adult population that shows deleterious effects of immune activation on the CNS 39–41 . Both pediatric studies evaluated relatively young children (median age 6–7 years) with perinatal HIV who had only been on cART for a relatively short period of time or who were not on therapy.…”

Section: Discussioncontrasting

confidence: 99%

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

et al. 2016

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Background HIV-infected individuals are at increased risk of neurocognitive impairment compared to the general population. Studies suggest that, despite combination antiretroviral therapy (cART), HIV infection causes immune activation which results in neural damage; however, few data exist in HIV-infected youth. Methods HIV-infected youth 8–26 years old on cART with virologic suppression were prospectively enrolled along with healthy controls. Neurocognitive performance was assessed by age-appropriate Wechsler Intelligence Scales. Soluble and cellular markers of T-lymphocyte and monocyte activation were measured by ELISA and flow cytometry, respectively. Results 45 HIV-infected subjects and 21 controls were enrolled. Markers of T-cell and monocyte activation were higher in the HIV-infected subjects compared to controls, but proportions of inflammatory and patrolling monocytes were similar. Although there was no significant differences in neurocognitive scores between the HIV-infected and control groups, scores were low-average for 4 of 5 testing domains for the HIV-infected subjects and average for all 5 in the controls, and % of HIV-infected subjects with scores classified as “low average” or below was higher than in the controls. Variables most associated with neurocognitive performance among HIV-infected subjects included activated CD4+ T-cells (% CD4+CD38+HLA-DR), monocyte activation (soluble CD14), HIV duration, age and sex. Conclusions HIV-infected youth on cART with virologic suppression show subtle evidence of neurocognitive impairment compared to healthy controls, and increased immune activation appears to play a role. Additional studies are needed to develop strategic interventions beyond cART to potentially improve neurocognitive performance and/or minimize further impairment in this vulnerable population.

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Section: Discussioncontrasting

confidence: 99%

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

et al. 2016

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“…While no biomarker as of yet has proven to be clinically useful at predicting or diagnosing HIV-associated neurological disease, CSF levels of QUIN, MCP-1, and IL-6 are frequently cited as top biomarker candidates (Brew and Letendre 2008). QUIN in particular has been shown to differentiate between HIV-infected individuals with or without dementia (Heyes et al 1991), with or without functional impairments in motor-skill learning and reaction time (Martin et al 1993), as well as SIV-infected macaques with or without encephalitis (Heyes et al 1992a).…”

Section: Discussionmentioning

confidence: 99%

Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART

et al. 2015

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Activation of the kynurenine pathway (KP) of tryptophan catabolism likely contributes to HIV-associated neurological disorders. However, KP activation in brain tissue during HIV infection has been understudied, and the effect of combination anti-retroviral therapy (cART) on KP induction in the brain is unknown. To examine these questions, tryptophan, kynurenine, 3-hydroxykynurenine, quinolinic acid, and serotonin levels were measured longitudinally during SIV infection in striatum and CSF from untreated and cART-treated pigtailed macaques. mRNA levels of KP enzymes also were measured in striatum. In untreated macaques, elevations in KP metabolites coincided with transcriptional induction of upstream enzymes in the KP. Striatal KP induction was also temporally associated - but did not directly correlate - with serotonin losses in the brain. CSF quinolinic acid/tryptophan ratios were found to be the earliest predictor of neurological disease in untreated SIV-infected macaques, outperforming other KP metabolites as well as the putative biomarkers Interleukin-6 (IL-6) and Monocyte chemoattractant protein-1 (MCP-1). Finally, cART did not restore KP metabolites to control levels in striatum despite control of virus, though CSF metabolite levels were normalized in most animals. Overall these results demonstrate that cerebral KP activation is only partially resolved with cART, and that CSF QUIN/TRP ratios are an early, predictive biomarker of CNS disease.

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“…In addition, HIV transmission and incident infections are increasing among older adults, who in turn have a greater risk to develop cognitive impairment. 1,2 The Centers for Disease Control (CDC; Atlanta, GA) estimates that by 2015, half of all people living with HIV infection in the United States will be 50 years of age or older (www.cdc.gov/hiv/topics/over50) and in many localities this threshold has already been exceeded. Therefore, there is an urgent clinical need to better delineate neurologic complications and treatment in HIV+ individuals who are living longer, including those with sustained virologic suppression and immune reconstitution on cART.…”

Section: Aging With Hiv: a Rapidly Growing Populationmentioning

confidence: 99%

HIV and Aging: Effects on the Central Nervous System

2014

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With the introduction of combination antiretroviral therapy, many human immunodeficiency virus-positive (HIV+) individuals are reaching advanced age. The proportion of people living with HIV older than 50 years already exceeds 50% in many communities, and is expected to reach this level nationally by 2015. HIV and aging are independently associated with neuropathological changes, but their concurrence may have a more deleterious effect on the central nervous system (CNS). Published data about neurocognitive and neuroimaging markers of HIV and aging are reviewed. Putative factors contributing to neurocognitive impairment and neuroimaging changes in the aging HIV+ brain, such as metabolic disturbances, cardiovascular risk factors, immune senescence, and neuroinflammation, are described. The possible relationship between HIV and some markers of Alzheimer’s disease is presented. Current research findings emphasize multiple mechanisms related to HIV and combination antiretroviral therapy that compromise CNS structure and function with advancing age.

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Biomarkers of HIV related central nervous system disease

Cited by 55 publications

References 137 publications

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART

HIV and Aging: Effects on the Central Nervous System

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