Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection

Ryan, Sean K.; Gonzalez, Michael; Garifallou, James; Bennett, F. Chris; Williams, Kimberly S.; Sotuyo, Nathaniel; Mironets, Eugene; Cook, Kieona; Hákonarson, Hákon; Anderson, Stewart A.; Jordan‐Sciutto, Kelly L.

doi:10.1016/j.stemcr.2020.02.010

Cited by 48 publications

(48 citation statements)

References 41 publications

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“…We note that primary human microglia derived from human brain infected with the same HIV-1 BaL viral isolate exhibited a pattern of peak virus released followed by a plateau and then decline, a curve that also resembles what we observed [68]. A more recent report of infected iPSC-MG employing a different viral strain also demonstrated a sharp rise in p24 release followed by a plateau, but did not extend the growth curve beyond day 15 of the plateau to assess potential decline [69].…”

Section: Discussionsupporting

confidence: 74%

Comparative analysis of human microglial models for studies of HIV replication and pathogenesis

et al. 2020

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Background HIV associated neurocognitive disorders cause significant morbidity and mortality despite the advent of highly active antiretroviral therapy. A deeper understanding of fundamental mechanisms underlying HIV infection and pathogenesis in the central nervous system is warranted. Microglia are resident myeloid cells of the brain that are readily infected by HIV and may constitute a CNS reservoir. We evaluated two microglial model cell lines (C20, HMC3) and two sources of primary cell-derived microglia (monocyte-derived microglia [MMG] and induced pluripotent stem cell-derived microglia [iPSC-MG]) as potential model systems for studying HIV-microglia interactions. Results All four microglial model cells expressed typical myeloid markers with the exception of low or absent CD45 and CD11b expression by C20 and HMC3, and all four expressed the microglia-specific markers P2RY12 and TMEM119. Marked differences were observed upon gene expression profiling, however, indicating that MMG and iPSC-MG cluster closely together with primary human microglial cells, while C20 and HMC3 were similar to each other but very different from primary microglia. Expression of HIV-relevant genes also revealed important differences, with iPSC-MG and MMG expressing relevant genes at levels more closely resembling primary microglia. iPSC-MG and MMG were readily infected with R5-tropic HIV, while C20 and HMC3 lack CD4 and require pseudotyping for infection. Despite many similarities, HIV replication dynamics and HIV-1 particle capture by Siglec-1 differed markedly between the MMG and iPSC-MG. Conclusions MMG and iPSC-MG appear to be viable microglial models that are susceptible to HIV infection and bear more similarities to authentic microglia than two transformed microglia cell lines. The observed differences in HIV replication and particle capture between MMG and iPSC-MG warrant further study.

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Section: Discussionsupporting

confidence: 74%

Comparative analysis of human microglial models for studies of HIV replication and pathogenesis

et al. 2020

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“…We note that primary human microglia derived from human brain infected with the same HIV-1 BaL viral isolate exhibited a pattern of peak virus released followed by a plateau and then decline, a curve that also resembles what we observed [68]. A more recent report of infected iPSC-MG employing a different viral strain also demonstrated a sharp rise in p24 release followed by a plateau, but did not extend the growth curve beyond day the plateau to assess potential decline [69].…”

Section: Discussionsupporting

confidence: 61%

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

Mohammad

Hammonds

Pujato

et al. 2020

Preprint

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Background: HIV associated neurocognitive disorders cause significant morbidity and mortality despite the advent of highly active antiretroviral therapy. A deeper understanding of fundamental mechanisms underlying HIV infection and pathogenesis in the central nervous system is warranted. Microglia are resident myeloid cells of the brain that are readily infected by HIV and may constitute a CNS reservoir. We evaluated two microglial model cell lines (C20, HMC3) and two sources of primary cell-derived microglia (monocyte-derived microglia [MMG] and induced pluripotent stem cell-derived microglia [iPSC-MG]) as potential model systems for studying HIV-microglia interactions.Results: All four microglial model cells expressed typical myeloid markers with the exception of low or absent CD45 and CD11b expression by C20 and HMC3, and all four expressed the microglia-specific markers P2RY12 and TMEM119. Marked differences were observed upon gene expression profiling, however, indicating that MMG and iPSC-MG cluster closely together with primary human microglial cells, while C20 and HMC3 were similar to each other but very different from primary microglia. Expression of HIV-relevant genes also revealed important differences, with iPSC-MG and MMG expressing relevant genes at levels more closely resembling primary microglia. iPSC-MG and MMG were readily infected with R5-tropic HIV, while C20 and HMC3 lack CD4 and require pseudotyping for infection. Despite many similarities, HIV replication dynamics and HIV-1 particle capture by Siglec-1 differed markedly between the MMG and iPSC-MG.Conclusions: MMG and iPSC-MG appear to be viable microglial models that are susceptible to HIV infection and bear more similarities to authentic microglia than two transformed microglia cell lines. The observed differences in HIV replication and particle capture between MMG and iPSC-MG warrant further study.

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“…In PHIV, this inflammation in the CNS may persist due to the difficulty of common medications being able to cross the blood-brain barrier into the CNS. The HIV-infected monocytes and T cells not only contaminate brain cells, but also release proinflammatory cytokines, viral proteins, and excitotoxins that can activate microglia, perivascular macrophages and astrocyte cells in the CNS and are potential reservoirs for the virus 85 . These are the main contributors to neuroinflammation in HIV infection and these cells release neurotoxic factors such as excitatory amino acids in addition to inflammatory mediators 86 .…”

Section: Discussionmentioning

confidence: 99%

White matter of perinatally HIV infected older youths shows low frequency fluctuations that may reflect glial cycling

Sarma

Pal

Keller

et al. 2021

Sci Rep

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In perinatally HIV-infected (PHIV) children, neurodevelopment occurs in the presence of HIV-infection, and even with combination antiretroviral therapy (cART) the brain can be a reservoir for latent HIV. Consequently, patients often demonstrate long-term cognitive deficits and developmental delay, which may be reflected in altered functional brain activity. Our objective was to examine brain function in PHIV on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo). Further, we studied ALFF and ReHo changes with neuropsychological performance and measures of immune health including CD4 count and viral loads in the HIV-infected youths. We found higher ALFF and ReHo in cerebral white matter in the medial orbital lobe for PHIV (N = 11, age mean ± sd = 22.5 ± 2.9 years) compared to controls (N = 16, age = 22.5 ± 3.0 years), with age and gender as co-variates. Bilateral cerebral white matter showed increased spontaneous regional activity in PHIV compared to healthy controls. No brain regions showed lower ALFF or ReHo in PHIV compared to controls. Higher log10 viral load was associated with higher ALFF and ReHo in PHIV in bilateral cerebral white matter and right cerebral white matter respectively after masking the outcomes intrinsic to the brain regions that showed significantly higher ALFF and ReHo in the PHIV compared to the control. Reductions in social cognition and abstract thinking in PHIV were correlated with higher ALFF at the left cerebral white matter in the left medial orbital gyrus and higher ReHo at the right cerebral white matter in the PHIV patients. Although neuroinflammation and associated neuro repair were not directly measured, the findings support their potential role in PHIV impacting neurodevelopment and cognition.

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Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection

Cited by 48 publications

References 41 publications

Comparative analysis of human microglial models for studies of HIV replication and pathogenesis

Comparative analysis of human microglial models for studies of HIV replication and pathogenesis

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

White matter of perinatally HIV infected older youths shows low frequency fluctuations that may reflect glial cycling

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