Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab

Serra‐Peinado, Carla; Grau-Expósito, Judith; Luque-Ballesteros, Laura; Astorga-Gamaza, Antonio; Navarro, Jordi; Gallego-Rodriguez, Jenny; Martín, Margarita; Curran, Adrían; Burgos, Joaquín; Ribera, Esteban; Raventós, Berta; Willekens, Rein; Torrella, Ariadna; Planas, Bibiana; Badía, Rosa; García, Felipe; Castellví, Josep; Genescà, Meritxell; Falcó, Vicenç; Buzón, María J.

doi:10.1038/s41467-019-11556-4

Cited by 43 publications

(54 citation statements)

References 47 publications

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“…Next, we applied PP-SLIDE to characterize latent cells from HIV-infected individuals, using a CyTOF panel ( Supplementary file 1 ) that is directed at markers of the major subsets and differentiation states of CD4+ T cells and includes receptors and intracellular proteins associated with latency ( Banga et al, 2016 ; Buzon et al, 2014 ; Chomont et al, 2009 ; Descours et al, 2017 ; Fromentin et al, 2016 ; Hogan et al, 2018 ; Iglesias-Ussel et al, 2013 ; Khoury et al, 2016 ; Li et al, 2019 ; Serra-Peinado et al, 2019 ; Sun et al, 2015 ). Since reactivation events are rare and reducing background was key, we conjugated different anti-Gag antibodies to three different metal lanthanides and only considered cells displaying a Gag signal in all three channels as true events.…”

Section: Resultsmentioning

confidence: 99%

Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

Neidleman

Luo

Frouard

et al. 2020

eLife

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The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8–10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.

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Section: Resultsmentioning

confidence: 99%

Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

Neidleman

Luo

Frouard

et al. 2020

eLife

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“…Very recently, Serra-Peinado et al reported a higher percentage of HIV RNA + cells among cells expressing CD20 (96). CD20 is a known B-cell surface marker but is dimly expressed on a small subpopulation of CD4 + T cells.…”

Section: Cd2 Cd30 and Cd20mentioning

confidence: 99%

“…CD20 is a known B-cell surface marker but is dimly expressed on a small subpopulation of CD4 + T cells. Although the contribution of CD20 dim CD4 + T cells to the total pool of HIV RNA + cells was modest (median of 18.6% in ART-treated and 25.0% in viremic HIV-infected individuals), ex vivo treatment of primary peripheral blood mononuclear cells (PBMCs) from ART-suppressed individuals with the anti-CD20 monoclonal antibody Rituximab appeared to reduce the pool of HIV RNA + cells when combined with latency-reversing agents (96). Further studies are needed to elucidate whether Rituximab treatment is also capable of reducing the total or intact HIV DNA reservoir.…”

Section: Cd2 Cd30 and Cd20mentioning

confidence: 99%

The Quest for Cellular Markers of HIV Reservoirs: Any Color You Like

2019

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Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function, but is unable to eradicate the virus. Therefore, development of an HIV cure has become one of the main priorities of the HIV research field. The main obstacle for an HIV cure is the formation of latent viral reservoirs, where the virus is able to “hide” despite decades of therapy, just to reignite active replication once therapy is stopped. Revealing HIV hiding places is thus central to HIV cure research, but the absence of markers of these reservoir cells greatly complicates the search for a cure. Identification of one or several marker(s) of latently infected cells would represent a significant step forward toward a better description of the cell types involved and improved understanding of HIV latency. Moreover, it could provide a “handle” for selective therapeutic targeting of the reservoirs. A number of cellular markers of HIV reservoir have recently been proposed, including immune checkpoint molecules, CD2, and CD30. CD32a is perhaps the most promising of HIV reservoir markers as it is reported to be associated with a very prominent enrichment in HIV DNA, although this finding has been challenged. In this review, we provide an update on the current knowledge about HIV reservoir markers. We specifically highlight studies that characterized markers of persistently infected cells in the lymphoid tissues.

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“…These factors include the immune negative checkpoints PD-1, TIGIT, LAG-3 ( Fromentin et al, 2016 ), and CTLA-4 ( McGary et al, 2017 ), as well as other factors such as CD2 ( Iglesias-Ussel et al, 2013 ), CCR6 ( Gosselin et al, 2017 ), and Survivin ( Kuo et al, 2018 ). Other host factors are shown to be enriched, in particular, in HIV-infected transcriptionally active cells, such as CD30 ( Hogan et al, 2018 ) and CD20 ( Serra-Peinado et al, 2019 ). These factors, especially those that reside on the cell surface, may be useful for targeting these cells and can provide a better understanding of HIV persistence biology.…”

Section: Discussionmentioning

confidence: 99%

Sialyl-LewisX Glycoantigen Is Enriched on Cells with Persistent HIV Transcription during Therapy

et al. 2020

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SUMMARY A comprehensive understanding of the phenotype of persistent HIV-infected cells, transcriptionally active and/or transcriptionally inactive, is imperative for developing a cure. The relevance of cell-surface glycosylation to HIV persistence has never been explored. We characterize the relationship between cell-surface glycomic signatures and persistent HIV transcription in vivo. We find that the cell surface of CD4 + T cells actively transcribing HIV, despite suppressive therapy, harbors high levels of fucosylated carbohydrate ligands, including the cell extravasation mediator Sialyl-Lewis X (SLe X ), compared with HIV-infected transcriptionally inactive cells. These high levels of SLe X are induced by HIV transcription in vitro and are maintained after therapy in vivo. Cells with high-SLe X are enriched with markers associated with HIV susceptibility, signaling pathways that drive HIV transcription, and pathways involved in leukocyte extravasation. We describe a glycomic feature of HIV-infected transcriptionally active cells that not only differentiates them from their transcriptionally inactive counterparts but also may affect their trafficking abilities.

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Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab

Cited by 43 publications

References 47 publications

Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

The Quest for Cellular Markers of HIV Reservoirs: Any Color You Like

Sialyl-LewisX Glycoantigen Is Enriched on Cells with Persistent HIV Transcription during Therapy

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