CD32+CD4+ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice

Adams, Philipp; Fiévez, Virginie; Schober, Rafaela; Amand, Mathieu; Iserentant, Gilles; Rutsaert, Sofie; Dessilly, Géraldine; Vanham, Guido; Hedin, Fanny; Cosma, Antonio; Moutschen, Michel; Vandekerckhove, Linos; Seguin-Devaux, Carole

doi:10.1016/j.isci.2020.101881

Cited by 15 publications

(22 citation statements)

References 96 publications

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“…In line with this, CD32 high CD4 T cells from blood of treated PLH have been described to express higher levels of HLA-DR and CD69 than other subsets ( 22 ). Other studies also suggested that CD32 marks highly activated/exhausted memory CD4 + T-cell subsets ( 74 ). The increased expression of CD32, which is an Fcγ receptor (FcγRIIa), could also make CD4 + T cells more susceptible to activation by IgG immune complexes.…”

Section: Discussionmentioning

confidence: 98%

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

et al. 2021

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CD4 T cell responses constitute an important component of adaptive immunity and are critical regulators of anti-microbial protection. CD4+ T cells expressing CD32a have been identified as a target for HIV. CD32a is an Fcγ receptor known to be expressed on myeloid cells, granulocytes, B cells and NK cells. Little is known about the biology of CD32+CD4+ T cells. Our goal was to understand the dynamics of CD32+CD4+ T cells in tissues. We analyzed these cells in the blood, lymph nodes, spleen, ileum, jejunum and liver of two nonhuman primate models frequently used in biomedical research: African green monkeys (AGM) and macaques. We studied them in healthy animals and during viral (SIV) infection. We performed phenotypic and transcriptomic analysis at different stages of infection. In addition, we compared CD32+CD4+ T cells in tissues with well-controlled (spleen) and not efficiently controlled (jejunum) SIV replication in AGM. The CD32+CD4+ T cells more frequently expressed markers associated with T cell activation and HIV infection (CCR5, PD-1, CXCR5, CXCR3) and had higher levels of actively transcribed SIV RNA than CD32-CD4+T cells. Furthermore, CD32+CD4+ T cells from lymphoid tissues strongly expressed B-cell-related transcriptomic signatures, and displayed B cell markers at the cell surface, including immunoglobulins CD32+CD4+ T cells were rare in healthy animals and blood but increased strongly in tissues with ongoing viral replication. CD32+CD4+ T cell levels in tissues correlated with viremia. Our results suggest that the tissue environment induced by SIV replication drives the accumulation of these unusual cells with enhanced susceptibility to viral infection.

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Section: Discussionmentioning

confidence: 98%

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

et al. 2021

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“…Humanized mice recapitulate key aspects of HIV-1 infection and pathogenesis (48, 49), however whether they recapitulate inflammasome activation upon HIV-1 infection remains undetermined. We first investigated whether inflammasome activation contributes to the early host response during HIV-1 infection in humanized mice.…”

Section: Resultsmentioning

confidence: 99%

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Amand

Adams

Schober

et al. 2022

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Background: HIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1β and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice. Methods: NSG mice were engrafted with human CD34+ hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA. Results: Expression of caspase-1, NLRP3 and IL1-β was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at day 24 in lymph node and bone marrow (FC 1.49 and 1.64, p<0.05) and coincides with increased IL-18 levels in plasma (6.89 vs. 83.19 pg/ml, p=0.004). AIM2 and IFI16 expression correlated with increased viral load in tissues (p<0.005 for the spleen) and loss of CD4+ T cells percentage in blood (p<0.0001 for the spleen). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs. 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4 + T cells (44.3% vs 36,7%, p=0.01) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106 cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice. Discussion: we report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+ T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.

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“…As emphasized in the preceding section, many viral markers are challenging to measure due to the scarcity of the HIV reservoir. Because identification of a cell population enriched in HIV reservoir cells would tremendously facilitate HIV cure research, many elegant studies have been undertaken to identify the major reservoir cell types by the expression of cell surface markers [92][93][94][95][96][97][98][99]. Some promising candidate reservoir markers such as CD32a and CD30 have indeed been identified (reviewed in [100]) but still have to be assessed as potential predictors of viral rebound.…”

Section: Host Biomarkers Of Virological Remission and Posttreatment H...mentioning

confidence: 99%

Towards a molecular profile of antiretroviral therapy-free HIV remission

Adams¹,

Berkhout²,

Pasternak³

2022

Current Opinion in HIV and AIDS

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Purpose of reviewTo summarize the current status and highlight recent findings on predictive biomarkers for posttreatment HIV control (PTC) and virological remission. While historically, many studies focused on virological markers, there is an increasing tendency to enter immune and metabolic factors into the equation. Recent findingsOn the virological side, several groups reported that cell-associated HIV RNA could predict time to viral rebound. Recent data hints at the possible importance of the genic location and chromatin context of the integrated provirus, although these factors still need to be assessed in relation to PTC and virological remission. Evidence from immunological studies highlighted innate and humoral immunity as important factors for prolonged HIV remission. Interestingly, novel metabolic markers have emerged, which offer additional angles to our understanding of latency and viral rebound. SummaryFacilitating PTC and virological remission remain top priorities for the HIV cure research. We advocate for clear and precise definitions for both phenomena in order to avoid misconceptions and to strengthen the conclusions that can be drawn. As no one-size-fits-all marker has emerged yet, more biomarkers are on the horizon, and viral rebound is a complex and heterogeneous process, it is likely that a combination of various biomarkers in cohesion will be necessary for a more accurate prediction of antiretroviral therapyfree HIV remission.

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CD32+CD4+ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice

Cited by 15 publications

References 96 publications

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Towards a molecular profile of antiretroviral therapy-free HIV remission

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CD32+CD4+ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice

Cited by 15 publications

References 96 publications

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Towards a molecular profile of antiretroviral therapy-free HIV remission

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The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice