P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model

Soare, Alexandra Y.; Durham, Natasha D.; Gopal, Ramya; Tweel, Benjamin; Hoffman, Kevin W.; Brown, Julia A.; O’Brien, Megan B.; Bhardwaj, Nina; Lim, Jean K.; Chen, Benjamin; Swartz, Talia H.

doi:10.1101/366179

Cited by 4 publications

(4 citation statements)

References 110 publications

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“…Beside ART regimen simplifications, the use of immunomodulators in order to reduce levels of immune activation and inflammation has also been discussed [154]. A very recent study by Soare et al described the effects of the purinergic P2X receptor inhibitors [155]. P2X receptors are known to be expressed on CD4+ T cells, which are targets of HIV-1 infection; in addition, these proteins are known to be involved in the regulation of inflammatory pathways.…”

Section: Novel Art Strategies To Reduce Inflammation: Two-drug Thementioning

confidence: 99%

Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART

Zicari

Sessa

Cotugno

et al. 2019

Viruses

316

243

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Despite effective antiretroviral therapy (ART), people living with HIV (PLWH) still present persistent chronic immune activation and inflammation. This condition is the result of several factors including thymic dysfunction, persistent antigen stimulation due to low residual viremia, microbial translocation and dysbiosis, caused by the disruption of the gut mucosa, co-infections, and cumulative ART toxicity. All of these factors can create a vicious cycle that does not allow the full control of immune activation and inflammation, leading to an increased risk of developing non-AIDS co-morbidities such as metabolic syndrome and cardiovascular diseases. This review aims to provide an overview of the most recent data about HIV-associated inflammation and chronic immune exhaustion in PLWH under effective ART. Furthermore, we discuss new therapy approaches that are currently being tested to reduce the risk of developing inflammation, ART toxicity, and non-AIDS co-morbidities.

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Section: Novel Art Strategies To Reduce Inflammation: Two-drug Thementioning

confidence: 99%

Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART

Zicari

Sessa

Cotugno

et al. 2019

Viruses

316

243

View full text Add to dashboard Cite

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“…The tonsils are an initial site of replication of foot-and-mouth disease virus (FMDV) (26), polyomavirus (27), HIV (28), and Epstein-Barr virus (5,8). Porcine tonsils are primary infection sites for FMDV after simulated natural virus exposure and facilitate replication in the clinical phase, yielding high amounts of viral shedding into the environment due to extensive amplification (26).…”

Section: Introductionmentioning

confidence: 99%

“…Porcine tonsils are primary infection sites for FMDV after simulated natural virus exposure and facilitate replication in the clinical phase, yielding high amounts of viral shedding into the environment due to extensive amplification (26). HIV specifically targets the tonsils because of the interaction with HIV targets in this tissue (28).…”

Section: Introductionmentioning

confidence: 99%

Tropism, susceptibility, infectivity, and cytokine releases of differentiated human tonsillar epithelial cells by different Influenza viruses

Okda

Sakr

Webster

et al. 2021

Preprint

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Human tonsil epithelium cells (HTEC) are a heterogeneous group of actively differentiating cells comprising stratified squamous epithelial and reticulated crypt cells with abundant keratin expression. We hypothesized that the tonsils are a primary site for influenza infection and sustained viral replication. Primary HTEC were grown using an air-liquid culture and infected apically with different influenza viruses (IVs) to measure viral growth kinetics. These cultures were highly differentiated, with subpopulations of heterogenous surface stratified squamous cells rich with both cilia and microvilli; these cells contained more α2,6-linked sialic acids, those preferentially bound by human IVs, than α2,3-linked avian like sialic acids. The stratified squamous cells were interrupted by patches of reticular epithelial cells rich in α2,3-linked sialic acids. The HTEC were permissive for influenza A and B virus replication. Following infection, a subset of cells, mostly ciliated cells, underwent apoptosis while others remained intact despite being positive for IV nucleoprotein. H3N2 virus antigen colocalized with non-ciliated cells while H1N1 virus antigen was mostly associated with ciliated cells. Exposure of HTECs to IVs triggers an early proinflammatory response that fluctuates between viruses. The H3N2 IV induces an early response that persists, whereas pH1N1 induces a primarily late response in HTECs. Our results implicated HTEC as a site for IV replication. The HTEC differentiated system provides a valuable in vitro model for studying cellular tropism, infectivity, cytokine responses and the pathogenesis of IVs.IMPORTANCETo develop an effective intervention against influenza, it is important to identify host factors affecting transmission, pathogenesis, and immune response. Tonsils are lymphoepithelial organs characterized by infiltration of B and T lymphocytes into the squamous epithelium of tonsillar crypts, beneath which germinal centers play key roles in antigen processing and immune response. The heterogenicity of HTECs as well as the sialic acid distributions supports the replication of IVs and may play a role in IV adaptation. Furthermore, Tonsillectomy is a surgical procedure in which tonsils are fully removed from the human throat and may contribute to the diverse outcomes among infected individuals.

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“…The ability of MT-4 to support rapid replication of HIV-1 and gain second-site compensatory mutations unlikely to be acquired in lesspermissive cells has led to the use of this cell line for selection experiments with a wide variety of defective MA and CA mutants (29,48,(52)(53)(54). Uncovering the underlying mechanisms of MT-4 cell line permissivity is important because of the frequent use of this cell line in HIV-1 replication studies (13,(55)(56)(57). In this study, we examined a number of factors involved in viral replication and spread in cells both permissive (i.e., MT-4) and non-permissive (i.e., all other T-cell lines tested) for gp41 CT truncation.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Basis for Permissivity of the MT-4 T-Cell Line to Replication of an HIV-1 Mutant Lacking the gp41 Cytoplasmic Tail

Fernandez

Hoffman

Pezeshkian

et al. 2020

J Virol

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HIV-1 encodes an envelope glycoprotein (Env) that contains a long cytoplasmic tail (CT) harboring trafficking motifs implicated in Env incorporation into virus particles and viral transmission. In most physiologically relevant cell types, the gp41 CT is required for HIV-1 replication, but in the MT-4 T-cell line the gp41 CT is not required for a spreading infection. To help elucidate the role of the gp41 CT in HIV-1 transmission, in this study we investigated the viral and cellular factors that contribute to the permissivity of MT-4 cells to gp41 CT truncation. We found that the kinetics of HIV-1 production and virus release are faster in MT-4 than in the other T-cell lines tested, but MT-4 express equivalent amounts of HIV-1 proteins on a per-cell basis relative to cells not permissive to CT truncation. MT-4 cells express higher levels of plasma-membrane-associated Env than non-permissive cells and Env internalization from the plasma membrane is less efficient compared to another T-cell line, SupT1. Paradoxically, despite the high levels of Env on the surface of MT-4 cells, two-fold less Env is incorporated into virus particles produced from MT-4 compared to SupT1 cells. Contact-dependent transmission between co-cultured 293T and MT-4 cells is higher than in co-cultures of 293T with most other T-cell lines tested, indicating that MT-4 are highly susceptible to cell-to-cell infection. These data help to clarify the long-standing question of how MT-4 cells overcome the requirement for the HIV-1 gp41 CT and support a role for gp41 CT-dependent trafficking in Env incorporation and cell-to-cell transmission in physiologically relevant cell lines. IMPORTANCE The HIV-1 Env cytoplasmic tail (CT) is required for efficient Env incorporation into nascent particles and viral transmission in primary CD4+ T cells. The MT-4 T-cell line has been reported to support multiple rounds of infection of HIV-1 encoding a gp41 CT truncation. Uncovering the underlying mechanism of MT-4 T-cell line permissivity to gp41 CT truncation would provide key insights into the role of the gp41 CT in HIV-1 transmission. This study reveals that multiple factors contribute to the unique ability of a gp41 CT truncation mutant to spread in cultures of MT-4 cells. The lack of a requirement for the gp41 CT in MT-4 cells is associated with the combined effects of rapid HIV-1 protein production, high levels of cell-surface Env expression, and increased susceptibility to cell-to-cell transmission compared to non-permissive cells.

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P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model

Cited by 4 publications

References 110 publications

Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART

Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART

Tropism, susceptibility, infectivity, and cytokine releases of differentiated human tonsillar epithelial cells by different Influenza viruses

Elucidating the Basis for Permissivity of the MT-4 T-Cell Line to Replication of an HIV-1 Mutant Lacking the gp41 Cytoplasmic Tail

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