Comparative analysis of human microglial models for studies of HIV replication and pathogenesis
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Retrovirology Open Access
RESEARCH
Comparative analysis of human microglial models for studies of HIV replication and pathogenesis Mohammad A. Rai1,4†, Jason Hammonds1,3†, Mario Pujato2,3, Christopher Mayhew5, Krishna Roskin2,3 and Paul Spearman1,3*
Abstract 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. Keywords: Microglia, HIV-associated neurocognitive disorder, Induced pluripotent stem cell, HIV-1, Gene expression profiling
*Correspondence: [email protected] † Mohammad A. Rai and Jason Hammonds made equal contributions to the manuscript 1 Division of Infectious Diseases, Cincinnati Children’s Hospital, 3333 Burnet Avenue, MLC 7017, Cincinnati, OH 45229, USA Full list of author information is available at the end of the article
Background HIV-associated neurocognitive disorder (HAND) encompasses a broad range of neurocognitive dysfunction associated with HIV infection, including HIV-associated asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) [1]. Antiretroviral therapy (ART) has been successful in dramatically reducing the incidence of HIV associated comorbidities,
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