HIV-1 infection alters CD4+memory T-cell phenotype at the site of disease in extrapulmonary tuberculosis

ABSTRACTThe extreme stability of the latent HIV-1 reservoir in the CD4+memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status.IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4+memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

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CD300a identifies a CD4+ memory T cell subset with a higher susceptibility to HIV-1 infection

AIDS ◽

10.1097/qad.0000000000002544 ◽

2020 ◽

Vol 34 (8) ◽

pp. 1249-1252

Author(s):

Joana Vitallé ◽

Laura Tarancón-Díez ◽

María R. Jiménez-Leon ◽

Iñigo Terrén ◽

Ane Orrantia ◽

...

Keyword(s):

T Cell ◽

Cell Subset ◽

T Cell Subset ◽

Memory T Cell ◽

Hiv 1

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Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity

Scientific Reports ◽

10.1038/s41598-017-06352-3 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 38

Author(s):

Femke Stelma ◽

Annikki de Niet ◽

Marjan J. Sinnige ◽

Karel A. van Dort ◽

Klaas P. J. M. van Gisbergen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Phenotype ◽

Memory T Cell

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β-catenin does not regulate memory T cell phenotype

Nature Medicine ◽

10.1038/nm0510-513 ◽

2010 ◽

Vol 16 (5) ◽

pp. 513-514 ◽

Cited By ~ 23

Author(s):

Gregory Driessens ◽

Yan Zheng ◽

Thomas F Gajewski

Keyword(s):

T Cell ◽

Cell Phenotype ◽

Memory T Cell

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Segregation of R5 and X4 HIV-1 variants to memory T cell subsets differentially expressing CD62L in ex vivo infected human lymphoid tissue

AIDS ◽

10.1097/00002030-200206140-00006 ◽

2002 ◽

Vol 16 (9) ◽

pp. 1245-1249 ◽

Cited By ~ 16

Author(s):

Françoise Gondois-Rey ◽

Jean-Charles Grivel ◽

Angelique Biancotto ◽

Marjorie Pion ◽

Robert Vigne ◽

...

Keyword(s):

T Cell ◽

Lymphoid Tissue ◽

Ex Vivo ◽

T Cell Subsets ◽

Memory T Cell ◽

Human Lymphoid Tissue ◽

Hiv 1

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Quantification of naive and memory T-cell turnover during HIV-1 infection

AIDS ◽

10.1097/qad.0000000000000822 ◽

2015 ◽

Vol 29 (16) ◽

pp. 2071-2080 ◽

Cited By ~ 18

Author(s):

Nienke Vrisekoop ◽

Julia Drylewicz ◽

Rogier Van Gent ◽

Tendai Mugwagwa ◽

Steven F.L. Van Lelyveld ◽

...

Keyword(s):

T Cell ◽

Cell Turnover ◽

Memory T Cell ◽

Hiv 1

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Application of a Standardized Flow Cytometry Panel for Defining and Monitoring the Immunophenotype of CAR-T Cells

Blood ◽

10.1182/blood-2019-128745 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5626-5626

Author(s):

Irene Scarfò ◽

Kathleen Gallagher ◽

Marcela V. Maus ◽

Rebecca Larson ◽

Maegan Sheehan ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Unmet Need ◽

Central Memory ◽

T Cell Subsets ◽

Effector Memory ◽

Cell Phenotype ◽

Memory T Cell ◽

Car T

Chimeric antigen receptor T-cells (CAR-T) have emerged as an extremely promising therapy for hematological malignancies. The immunophenotype of apheresis material and the CAR-T cell product is known to be predictive of the likelihood of response to treatment of certain malignancies. Central memory and stem cell-like memory T cell phenotypes are associated with a more sustained proliferative response and long-term CAR-T persistence (Fraietta et al, Nature Medicine, 2018). There is an unmet need for standardized methods and reagents to reliably profile the memory phenotype of CAR-Ts to better evaluate product quality, and support improvements in CAR-T manufacturing. The BD Biosciences dried memory T-cell panel contains a pre-validated mixture of 7 antibodies for the identification of naïve, stem cell memory, central memory and effector memory CD4+ and CD8+ T cell subsets. The pre-mixed dried antibody tube offers consistency in staining profiles over time and reduces the risk of operator errors. Additional drop-in antibodies can complement the panel and enable more in-depth evaluation of the T cell phenotype. Here we demonstrate the use of this panel with drop-in markers to monitor changes in expression of PD-1, TIM-3, LAG-3, HLA-DR, CD45RO, and CXCR3 on T cells transduced to express our novel anti-CD37 CAR. Cells were stained at day 0 prior to transduction, day 7, and following resting and re-stimulation, and acquired on a 12 color BD FACS Lyric. The use of a standardized memory T-cell panel will allow us to more accurately evaluate how T-cell phenotype impacts on the efficacy and longevity of response in patients receiving CAR-T therapies. Disclosures Maus: INFO PENDING: Other: INFO PENDING. Bornheimer:BD Biosciences: Employment. Hanley:BD Biosciences: Employment. Frigault:Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy.

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