The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder

Sreeram, Sheetal; Ye, Fengchun; García-Mesa, Yoelvis; Nguyen, Kien; Sayed, Ahmed El; Leskov, Konstantin; Karn, Jonathan

doi:10.1016/j.it.2022.06.003

Cited by 35 publications

(29 citation statements)

References 84 publications

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“…Interestingly, interferon may promote latency in macrophages (Dickey, Martins, Planelles, and Hanley 2022). An important feature of HIV infection of microglia identified in previous in vitro studies has been the rapid induction of viral latency (Alvarez-Carbonell et al 2019; Sreeram et al 2022). Our cerebral organoid model will provide an interesting system to examine the induction of HIV latency, its reactivation, and its effects on both adjacent and more distant neural cells.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Boreland,

Stillitano,

Lin

et al. 2023

Preprint

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Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

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Section: Discussionmentioning

confidence: 99%

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Boreland,

Stillitano,

Lin

et al. 2023

Preprint

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“…Chronic neuroinflammation is widely accepted as a major contributor to HAND as well as other neurodegenerative diseases. 81 In the ART era, the majority of virologically suppressed HAND patients do not display pathological evidence of severe encephalitis, 82 and under physiological conditions, low-level inflammation in the brain is usually asymptomatic. 83 Nevertheless, elements of inflammation in the brain, such as accumulation of mononuclear phagocytes, related microglial activation and astrocytosis, and decreased synaptic and dendritic density, are observed in postmortem samples from HIV patients.…”

Section: Neuroinflammationmentioning

confidence: 99%

“…Chronic neuroinflammation is widely accepted as a major contributor to HAND as well as other neurodegenerative diseases 81 . In the ART era, the majority of virologically suppressed HAND patients do not display pathological evidence of severe encephalitis, 82 and under physiological conditions, low‐level inflammation in the brain is usually asymptomatic 83 .…”

Section: Pathogenesis Of Handmentioning

confidence: 99%

Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

Sviridov,

Bukrinsky

2023

The FASEB Journal

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HIV‐associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV‐induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART‐treated individuals. Here, we propose another factor—impairment of cholesterol homeostasis and lipid rafts by HIV‐1 protein Nef—as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef‐ and cholesterol‐focused mechanism may provide a long‐sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed.

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“…HIV-1 infected microglia cells are the latency reservoir and cause the abnormal inflammatory state for the pathogenesis of HIV-1-associated neurocognitive disorder (HAND), even under the cART control [97]. In order to understand the HIV-1 reactivation mechanism of microglia and develop a therapy targeting HIV-1 reservoirs in the CNS, we used the immortalizing human primary microglia with HIV-1 LTR/Tat-mediated GFP reporter, HC69 cell line [63][64][65] to investigate whether the KDM5 depletion can increase HIV-1 reactivation and cytopathic effect.…”

Section: B)mentioning

confidence: 99%

KDM5A/B promotes HIV-1 latency and KDM5 inhibitors promote HIV-1 lytic reactivation

Zhou

et al. 2022

Preprint

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Combinational antiretroviral therapy (cART) effectively suppresses HIV-1 infection, replication, and pathogenesis in HIV-1 patients. However, the patient's HIV-1 reservoir still cannot be eliminated by current cART or other therapies. One putative HIV-1 eradication strategy is 'shock and kill', which reactivates HIV-1 in latently-infected cells and induces their cytopathic effect or immune clearance to decrease the patients' reservoir size. KDM5A and KDM5B act as the HIV-1 latency-promoting genes, decreasing the HIV-1 viral gene transcription and reactivation in infected cells. Depletion of KDM5 A/B by siRNA knockdown (KD) increases H3K4 trimethylation (H3K4me3) in HIV-1 Tat-mediated transactivation. We also found that the KDM5-specific inhibitor JQKD82 can increase H3K4me3 at the HIV-1 LTR region during HIV-1 reactivation and induce cytopathic effects. We applied the JQKD82 in combination with the non-canonical NF-κB activator AZD5582, which synergistically induced HIV-1 reactivation and cell apoptosis in HIV-1 infected cells. These results suggested that the KDM5 inhibition can be a putative HIV-1 latency-reversing strategy for the HIV-1 'shock and kill' eradication therapy.

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The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder

Cited by 35 publications

References 84 publications

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

KDM5A/B promotes HIV-1 latency and KDM5 inhibitors promote HIV-1 lytic reactivation

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