Neurocognitive Impact of Antiretroviral Treatment: Thinking Long-Term

McPhail, Megan; Robertson, Kevin

doi:10.1007/s11904-011-0091-7

Cited by 14 publications

(12 citation statements)

References 66 publications

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“…The brain, in particular, represents a sanctuary for HIV-1 latency, where the provirus can persist due to the variable and poor penetration of antiretroviral drugs. 22,23 While viral replication was considered necessary for inflammation and neurodegeneration, recent studies showed a high prevalence of HAND even in long-standing aviremic patients. 24 We provide here a novel explanation for brain damage in the absence of viral replication, mediated by deregulation of BCLL1B that contributes to sustain HIV-1 latency and might also alter the expression of inflammationrelated genes.…”

Section: Resultsmentioning

confidence: 99%

Molecular and pathologic insights from latent HIV-1 infection in the human brain

et al. 2013

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Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.Methods: This was a case-control comparison of HIV-1 seropositive (HIV1) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.Results: HIV1 controls (n 5 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV1 cases (n 5 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n 5 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV1 controls, the HIV1 latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV1 latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor-a, and CD74. Conclusion:Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.

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Section: Resultsmentioning

confidence: 99%

Molecular and pathologic insights from latent HIV-1 infection in the human brain

et al. 2013

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“…NCI in the setting of cART is associated with synaptodendritic degeneration [7, 11, 12]. While the brain represents a sanctuary where HIV can persist due to suboptimal penetration of antiretroviral drugs [13], various studies highlighted the occurrence of NCI even in the setting of viral suppression [14, 15]. Chronic neuroinflammation is believed to drive neurodegeneration in cART-era HAND [7, 9, 16, 17].…”

Section: Introductionmentioning

confidence: 99%

Gene expression patterns associated with neurological disease in human HIV infection

et al. 2017

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The pathogenesis and nosology of HIV-associated neurological disease (HAND) remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI) in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE) and control subjects. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb). We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC), which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN), cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV infection and identify better therapeutic targets for NCI.

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“…However, whether direct or indirect the link between inflammation in the CNS and manifestations of cognitive impairment is yet to be determined. The increase in the incidence of milder forms of HAND may be exacerbated due to the effects of aging in the infected population, although this remains controversial (McPhail and Robertson 2011). Additionally, it has been proposed that the brain may act as a tissue sanctuary for HIV due to limited drug penetrance into the CNS allowing for low levels of replication (McPhail and Robertson 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The increase in the incidence of milder forms of HAND may be exacerbated due to the effects of aging in the infected population, although this remains controversial (McPhail and Robertson 2011). Additionally, it has been proposed that the brain may act as a tissue sanctuary for HIV due to limited drug penetrance into the CNS allowing for low levels of replication (McPhail and Robertson 2011). However, the CNS penetrance of many antiretroviral drugs has since been evaluated, and drugs with improved CNS penetration yield better neurocognitive outcomes, suggesting this problem could be overcome with the proper ART regimen (Letendre et al 2004; Patel et al 2009; Smurzynski et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Humanized mouse models for HIV-1 infection of the CNS

et al. 2014

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Since the onset of the HIV epidemic, there has been a shift from a deadly diagnosis to the management of a chronic disease. This shift is the result of the development of highly effective drugs that are able to suppress viral replication for years. The availability of these regimens has also shifted the neurocognitive pathology associated with infection from potentially devastating to a much milder phenotype. As the disease outcome has changed significantly with the availability of antiretroviral therapy, there is an opportunity to re-evaluate the currently available models to address the neurocognitive pathology seen in suppressed patients. In the following, we seek to summarize the current literature on humanized mouse models and their utility in understanding how HIV infection leads to changes in the central nervous systems (CNS). Also, we identify some of the unanswered questions regarding HIV infection of the CNS as well as the opportunities and limitations of currently existing models to address those questions. Finally, our conclusions indicate that the earlier humanized models used to study HIV infection in the CNS provided an excellent foundation for the type of work currently being performed using novel humanized mouse models. We also indicate the potential of some humanized mouse models that have not been used as of this time for the analysis of HIV infection in the brain.

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Neurocognitive Impact of Antiretroviral Treatment: Thinking Long-Term

Cited by 14 publications

References 66 publications

Molecular and pathologic insights from latent HIV-1 infection in the human brain

Molecular and pathologic insights from latent HIV-1 infection in the human brain

Gene expression patterns associated with neurological disease in human HIV infection

Humanized mouse models for HIV-1 infection of the CNS

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