Paving the path to HIV neurotherapy: Predicting SIV CNS disease

Beck, Sarah E.; Queen, Suzanne E.; Witwer, Kenneth W.; Pate, Kelly A. Metcalf; Mangus, Lisa M.; Gama, Lúcio; Adams, Robert J.; Clements, Janice E.; Zink, M. Christine; Mankowski, Joseph L.

doi:10.1016/j.ejphar.2015.03.018

Cited by 25 publications

(38 citation statements)

References 96 publications

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“…SIV-infected macaque models are of great value for studying the pathogenesis of HAND, including attempts to discover neuroprotective host genes and predictive plasma and CSF biomarkers 153 . SIV-induced neuropathology closely resembles HIV-induced alterations, including multifocal perivascular aggregates in the brain that are composed of macrophages and multi-nucleate giant cells that contain replicating virus 154 .…”

Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

et al. 2016

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In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies -treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism -are needed to reverse or improve HAND-related neurological dysfunction. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Neurol. Author manuscript; available in PMC 2016 July 08. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript chronic infection that can be managed, is associated with a near-normal lifespan and in which opportunistic infections are rare 1 .The first major advancement was an understanding of the direct relationship between HIV replication and subsequent immunological and clinical progression. This finding emphasized the need to completely suppress HIV replication in order to control disease progression.The second major advancement was the development and deployment of combination antiretroviral therapy (CART), which can provide effective systemic suppression of HIV replication. The introduction of CART in the mid-1990s resulted in a 50% decline in the rate of death from AIDS, substantial decreases in rates of maternal-infant transmission, reduced incidence of opportunistic infections, and a 40-50% decrease in the incidence of HIVassociated dementia (HAD), which was previously common and is the most severe form of cognitive impairment associated with the infection 2 .The third major change in the care of HIV+ patients was the ability to monitor the efficacy of CART through the reliable and widespread measurement of CD4 + helper T cells, plasma HIV RNA levels and antiretroviral resistance profiles, all of which are now fully integrated into routine clinical care in the developed world and used to optimize treatment for individual patients. Plasma viral l...

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Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

et al. 2016

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“…Previous studies have only detected YKL-40 expression in macrophages/microglia, but not in neurons and astrocytes in the context of HIV infection (Bonneh-Barkay et al , 2008). Nevertheless, differential up-regulation of CSF YKL-40 has been reported in SIV-infected pigtailed macaques that had developed encephalitis, and have been correlated with increases in the CSF viral load (Beck et al , 2015). These studies have attributed the elevated YKL-40 expression to productive HIV and SIV infections of microglia (Kolson, 2008).…”

Section: Csf Biomarkers For Hiv/neuroaidsmentioning

confidence: 99%

“…sCD163 has been used as a biomarker for systemic monocyte activation in coronary artery disease, rheumatoid arthritis, Gaucher lysosomal storage disease, and cancer (Onofre et al , 2009). In SIV-infected pigtailed macaques, plasma sCD163 is significantly higher in individuals with encephalitis compared to those without encephalitis (Beck et al , 2015). In humans, plasma levels of sCD163 but not CSF levels are shown to be elevated in both early and chronic infection with HIV.…”

Section: Csf Biomarkers For Hiv/neuroaidsmentioning

confidence: 99%

HIV/neuroAIDS biomarkers

Rahimian

2017

Progress in Neurobiology

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HIV infection often causes neurological symptoms including cognitive and motor dysfunction, which have been collectively termed HIV/neuroAIDS. Neuropsychological assessment and clinical symptoms have been the primary diagnostic criteria for HIV/neuroAIDS, even for the mild cognitive and motor disorder, the most prevalent form of HIV/neuroAIDS in the era of combination antiretroviral therapy. Those performance-based assessments and symptoms are generally descriptive and do not have the sensitivity and specificity to monitor the diagnosis, progression, and treatment response of the disease when compared to objective and quantitative laboratory-based biological markers, or biomarkers. In addition, effects of demographics and comorbidities such as substance abuse, psychiatric disease, nutritional deficiencies, and co-infection on HIV/neuroAIDS could be more readily determined using biomarkers than using neuropsychological assessment and clinical symptoms. Thus, there have been great efforts in identification of HIV/neuroAIDS biomarkers over the past two decades. The need for reliable biomarkers of HIV/neuroAIDS is expected to increase as the HIV-infected population ages and their vulnerability to neurodegenerative diseases, particularly Alzheimer’s disease increases. Currently, three classes of HIV/neuroAIDS biomarkers are being pursued to establish objective laboratory-based definitions of HIV-associated neurologic injury: cerebrospinal fluid biomarkers, blood biomarkers, and neuroimaging biomarkers. In this review, we will focus on the current knowledge in the field of HIV/neuroAIDS biomarker discovery.

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“…Interestingly, and perhaps not surprisingly, the markers consistently are linked to immune activation and often tied specifically to innate immune responses and monocyte/macrophage activation and or expansion. Predictive hematologic markers include elevated hemoglobin levels and platelet counts[28] both of which are related to bone marrow dysregulation and acute phase protein responses. Elevation of absolute numbers of monocytes, and/or the percentage of activated CD14+CD16+ monocytes also are predictive of CNS disease in humans and monkeys [3,12].…”

Section: Biomarkers Of Neuroaidsmentioning

confidence: 99%

“…They also underscore the utility of NHP models, in this case CD8 lymphocyte depletion as a valuable tool to understand CNS pathogenesis with HIV. In addition to plasma and hematologic markers of SIV associated disease, chemokines and cytokines including CCL2 and IL-6, and neopterin are found in the CSF that correlate with monocyte and macrophage inflammation [28]. Human cartilage glycoprotein 39 (YKL-40) and neurofilament light chain (NF-L) are markers of neuronal damage that are also found in the CSF [28].…”

Section: Biomarkers Of Neuroaidsmentioning

confidence: 99%

Non-human primate models of SIV infection and CNS neuropathology

Williams

Lackner

Mallard

2016

Current Opinion in Virology

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Non-human primate models of AIDS and neuroAIDS are the premiere model of HIV infection of the CNS and neuropathogenesis. This review discusses current SIV infection models of neuroAIDS emphasizing findings in the last two years. Consistent in these findings is the interplay between host factors that regulated immune responses to virus and viral replication. Several rapid models of AIDS with consistent CNS pathogenesis exist, each of which modulates by antibody treatment or viruses that cause rapid immune suppression and replicate well in macrophages. Consistent in all of these models are data underscoring the importance of monocyte and macrophage activation, infection and accumulation in the CNS.

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Paving the path to HIV neurotherapy: Predicting SIV CNS disease

Cited by 25 publications

References 96 publications

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

HIV/neuroAIDS biomarkers

Non-human primate models of SIV infection and CNS neuropathology

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