Flt3L-Mediated Expansion of Plasmacytoid Dendritic Cells Suppresses HIV Infection in Humanized Mice

Pham, Tram N. Q.; Méziane, Oussama; Miah, Mohammad Alam; Volodina, Olga; Colas, Chloé; Béland, Kathie; Li, Yuanyi; Dallaire, Frédéric; Keler, Tibor; Guimond, Jean; Lesage, Sylvie; Cheong, Cheolho; Haddad, Élie; Cohen, Éric A.

doi:10.1016/j.celrep.2019.10.094

Cited by 17 publications

(16 citation statements)

References 51 publications

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“…antivirals drugs, antibodies) and immune-modulatory agents (e.g. pDC modulators [22]) geared towards preventing HIV transmission, controlling HIV replication, and ameliorating CD4+ T cell depletion and chronic immune activation [4]. The HSChumanized mouse model supports HIV transmission via the IV (along with IP) route [18]; however, conflicting reports exist for the mucosal route of transmission [23,24].…”

Section: Hematopoietic Stem Cells (Hsc)-humanized Mouse Modelmentioning

confidence: 99%

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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The development of safe and effective combination antiretroviral therapies for human immunodeficiency virus (HIV) infection over the past several decades has significantly reduced HIV-associated morbidity and mortality. Additionally, antiretroviral drugs have provided an effective means of protection against HIV transmission. Despite these advances, significant limitations exist; namely, the inability to eliminate HIV reservoirs, the inability to reverse lymphoid tissues damage, and the lack of an effective vaccine for preventing HIV transmission. Evaluation of the safety and efficacy of therapeutics and vaccines for eliminating HIV reservoirs and preventing HIV transmission requires robust in vivo models. Since HIV is a human-specific pathogen, that targets hematopoietic lineage cells and lymphoid tissues, in vivo animal models for HIV-host interactions require incorporation of human hematopoietic lineage cells and lymphoid tissues. In this review, we will discuss the construction of mouse models with human lymphoid tissues and/or hematopoietic lineage cells, termed, human immune system (HIS)-humanized mice. These HIS-humanized mouse models can support the development of functional human innate and adaptive immune cells, along with primary (thymus) and secondary (spleen) lymphoid tissues. We will discuss applications of HIS-humanized mouse models in evaluating the safety and efficacy of therapeutics against HIV reservoirs and associated immunopathology, and delineate the human immune response elicited by candidate HIV vaccines. In addition to focusing on how these HIS-humanized mouse models have already furthered our understanding of HIV and contributed to HIV therapeutics development, we discuss how emerging HIS-humanized rat models could address the limitations of HIS-mouse models.

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Section: Hematopoietic Stem Cells (Hsc)-humanized Mouse Modelmentioning

confidence: 99%

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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“…It is unclear whether the pDCs from elite controllers are better equipped to suppress viral replication or if the pDC cell numbers are maintained because the viral load is suppressed by other immune cells, like CTLs or natural killer (NK) cells. Third, expansion of pDCs during acute infection delays onset of viremia and reduces HIV replication in humanized mice (Pham et al, 2019).…”

Section: Would There Be Benefit In Restoring Pdc Cell Numbers With a mentioning

confidence: 99%

Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

Sluis

Egedal

Jakobsen

2020

Front. Cell. Infect. Microbiol.

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Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for acquiring, processing, and presenting antigens to T cells and they express costimulatory or coinhibitory molecules that determine immune activation or anergy. For these reasons, cell-based therapeutic approaches using DCs have been explored in cancer and infectious diseases but with limited success. In humans, DCs are divided into heterogeneous subsets with distinct characteristics. Two major subsets are CD11c + myeloid (m)DCs and CD11c − plasmacytoid (p)DCs. pDCs are different from mDCs and play an essential role in the innate immune system via the production of type I interferons (IFN). However, pDCs are also able to take-up antigens and effectively cross present them. Given the rarity of pDCs in blood and technical difficulties in obtaining them from human blood samples, the understanding of human pDC biology and their potential in immunotherapeutic approaches (e.g. cell-based vaccines) is limited. However, due to the recent advancements in cell culturing systems that allow for the generation of functional pDCs from CD34 + hematopoietic stem and progenitor cells (HSPC), studying pDCs has become easier. In this mini-review, we hypothesize about the use of pDCs as a cell-based therapy to treat HIV by enhancing anti-HIV-immune responses of the adaptive immune system and enhancing the anti-viral responses of the innate immune system. Additionally, we discuss obstacles to overcome before this approach becomes clinically applicable.

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“…Infection and analysis of humanized mice: Humanized bone marrow-liver-thymus (hu-BLT) mice were generated and infected with HIV NL4.3-ADA-GFP, as we previously described (46).…”

Section: Hiv-dna Quantification: Facs-sorted Dn T-cells and Cd4+ T-cementioning

confidence: 99%

“…To assess whether DN T-cells can support viral persistence during ART, a group of mice was treated with ART (raltegravir: 70 mg/ml, emtricitabine: 166 mg/ml and tenofovir: 170 mg/ml), or PBS as control, for three to six weeks (47). In all cases, spleen and lung tissues were harvested; cells from blood and the tissues were on October 29, 2020 by guest http://jvi.asm.org/ Downloaded from isolated as previously described (46). At sacrifice, all ART-treated mice were virally suppressed (<40 HIV-RNA copies/ml of plasma).…”

Section: Hiv-dna Quantification: Facs-sorted Dn T-cells and Cd4+ T-cementioning

confidence: 99%

“…Furthermore, Nef, a viral protein known to efficiently down-regulate CD4 expression, persists in the lungs of aviremic PLWH, causing pulmonary vascular pathologies via the induction of endothelial cell apoptosis (72). In order to better understand the dynamics of HIV-infected pulmonary DN T-cells during different phases of infection, we used a humanized hu-BLT mice model(46), as it is not feasible to performbronchoscopies during acute infection in PLHW. Interestingly, when compared to blood and on October 29, 2020 by guest http://jvi.asm.org/ Downloaded from spleen as a lymphoid tissue, the lungs were enriched in p24 + DN T-cells in both early and late HIV infection stages, suggesting that the lungs are favorable tissues for HIV seeding within DN T-cells during acute infection.…”

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confidence: 99%

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HIV Infection and Persistence in Pulmonary Mucosal Double Negative T Cells In Vivo

Méziane

Salahuddin

Pham

et al. 2020

J Virol

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The lungs are relatively unexplored anatomical HIV reservoirs in the antiretroviral therapy (ART) era. Double negative (DN) T-cells are a subset of T-cells which lack expression of CD4 and CD8 (CD4-CD8-) and may play both regulatory and effector functions during HIV infection. Notably, circulating DN T-cells were previously described as cellular HIV reservoirs. Here, we undertook a thorough analysis of pulmonary versus blood DN T-cells of people living with HIV (PLWH) under ART. Bronchoalveolar lavage (BAL) fluid and matched peripheral blood were collected from n=35 PLWH on ART and n=16 uninfected volunteers without respiratory symptoms. Both PLWH and HIV- adults displayed higher frequencies of DN T-cells in BAL versus blood, and these cells mostly exhibited an effector memory phenotype. In PLWH, pulmonary mucosal DN T-cells expressed higher levels of HLA-DR and several cellular markers associated with HIV persistence (CCR6, CXCR3 and PD-1) compared to blood. We also observed that DN T-cells were less senescent (CD28-CD57+) and expressed less immunosuppressive ectonucleotidase (CD73/CD39), granzyme B and perforin in the BAL compared to the blood of PLWH. Importantly, FACS-sorted DN T-cells from the BAL of PLWH under suppressive ART harbored HIV-DNA. Using the humanized bone marrow-liver-thymus (hu-BLT) mouse model of HIV infection, we observed higher infection frequencies of lung DN T-cells compared to blood and spleen in both early and late HIV infection. Overall, our findings show that HIV is seeded in pulmonary mucosal DN T-cells early following infection and persists in these potential cellular HIV reservoirs even during long-term ART. Importance Reservoirs of HIV during ART are the primary reasons why HIV/AIDS remains an incurable disease. Indeed, HIV remains latent and unreachable by antiretrovirals in cellular and anatomical sanctuaries, preventing its eradication. The lungs have received very little attention compared to other anatomical reservoirs, despite being immunological effector sites exhibiting characteristics ideal for HIV persistence. Furthermore, PLWH suffer from a high burden of pulmonary non-opportunistic infections suggesting impaired pulmonary immunity despite ART. Meanwhile, various immune cell populations have been proposed to be cellular reservoirs in blood, including CD4-CD8- DN T-cells, a subset that may originate from CD4 downregulation by HIV proteins. The present study aims to describe DN T-cells in human and humanized mice lungs in relation to intrapulmonary HIV burden. The characterization of DN T-cells as cellular HIV reservoirs and the lungs as an anatomical HIV reservoir will contribute towards the development of targeted HIV eradication strategies.

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Flt3L-Mediated Expansion of Plasmacytoid Dendritic Cells Suppresses HIV Infection in Humanized Mice

Cited by 17 publications

References 51 publications

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

HIV Infection and Persistence in Pulmonary Mucosal Double Negative T Cells In Vivo

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