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  1. Article ; Online: Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.

    Clohosey, Matthew L / Mann, Brendan T / Ryan, Paul L / Apanasovich, Tatiyana V / Maggirwar, Sanjay B / Pennington, Daniel J / Soriano-Sarabia, Natalia

    Cells

    2020  Volume 9, Issue 12

    Abstract: Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments ... ...

    Abstract Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of γδ T cell populations is a byproduct of primary Humanimmunodeficiency virus (HIV) infection. This is most pronounced in the depletion and loss of function within cells expressing a Vγ9Vδ2 TCR (Vδ2 cells). Whether or not prolonged viral suppression mediated by antiretroviral therapy (ART) can reverse these effects has yet to be determined. In this study, we present evidence of similar Vδ2 cell functional responses within a cohort of people living with HIV (PLWH) that has been stably suppressed for >1 year and uninfected donors. Through the use of aminobisphosphonate drugs, we were able to generate a comprehensive comparison between ex vivo and expanded Vδ2 cells within each group. Both groups had largely similar compositions of memory and effector phenotypes, post-expansion TCR repertoire diversity, and cytotoxic capabilities. Our findings support the notion that ART promotes the recovery of Vδ2 polyfunctionality and provides insight for strategies aiming to reconstitute the full immune response after infection with HIV.
    MeSH term(s) Adult ; Anti-Retroviral Agents/therapeutic use ; Cell Line, Tumor ; Female ; HIV/drug effects ; HIV/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; Humans ; Immunologic Memory/immunology ; Intraepithelial Lymphocytes/immunology ; Male ; Phenotype ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocyte Subsets/immunology
    Chemical Substances Anti-Retroviral Agents ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2020-12-01
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9122568
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.

    Sanz, Marta / Weideman, Ann Marie K / Ward, Adam R / Clohosey, Matthew L / Garcia-Recio, Susana / Selitsky, Sara R / Mann, Brendan T / Iannone, Marie Anne / Whitworth, Chloe P / Chitrakar, Alisha / Garrido, Carolina / Kirchherr, Jennifer / Coffey, Alisha R / Tsai, Yi-Hsuan / Samir, Shahryar / Xu, Yinyan / Copertino, Dennis / Bosque, Alberto / Jones, Brad R /
    Parker, Joel S / Hudgens, Michael G / Goonetilleke, Nilu / Soriano-Sarabia, Natalia

    Frontiers in immunology

    2023  Volume 14, Page(s) 1219250

    Abstract: Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small ... ...

    Abstract Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in
    MeSH term(s) Humans ; HIV Infections/drug therapy ; HIV-1 ; Virus Activation ; Virus Latency ; Alendronate/therapeutic use ; Alendronate/pharmacology ; HIV Seropositivity
    Chemical Substances Alendronate (X1J18R4W8P)
    Language English
    Publishing date 2023-09-06
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1219250
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.

    Sanz, Marta / Weideman, Ann Marie K / Ward, Adam R / Clohosey, Matthew L / Garcia-Recio, Susana / Selitsky, Sara R / Mann, Brendan T / Iannone, Marie Anne / Whitworth, Chloe P / Chitrakar, Alisha / Garrido, Carolina / Kirchherr, Jennifer / Coffey, Alisha R / Tsai, Yi-Hsuan / Samir, Shahryar / Xu, Yinyan / Copertino, Dennis / Bosque, Alberto / Jones, Brad R /
    Parker, Joel S / Hudgens, Michael G / Goonetilleke, Nilu / Soriano-Sarabia, Natalia

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small ... ...

    Abstract Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in
    Language English
    Publishing date 2023-02-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.07.527421
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: γδ T cells: an immunotherapeutic approach for HIV cure strategies.

    Garrido, Carolina / Clohosey, Matthew L / Whitworth, Chloe P / Hudgens, Michael / Margolis, David M / Soriano-Sarabia, Natalia

    JCI insight

    2018  Volume 3, Issue 12

    Abstract: Current strategies aimed to cure HIV infection are based on combined efforts to reactivate the virus from latency and improve immune effector cell function to clear infected cells. These strategies are primarily focused on CD8+ T cells and approaches are ...

    Abstract Current strategies aimed to cure HIV infection are based on combined efforts to reactivate the virus from latency and improve immune effector cell function to clear infected cells. These strategies are primarily focused on CD8+ T cells and approaches are challenging due to insufficient HIV antigen production from infected cells and poor HIV-specific CD8+ T cells. γδ T cells represent a unique subset of effector T cells that can traffic to tissues, and selectively target cancer or virally infected cells without requiring MHC presentation. We analyzed whether γδ T cells represent a complementary/alternative immunotherapeutic approach towards HIV cure strategies. γδ T cells from HIV-infected virologically suppressed donors were expanded with bisphosphonate pamidronate (PAM) and cells were used in autologous cellular systems ex vivo. These cells (a) are potent cytotoxic effectors able to efficiently inhibit HIV replication ex vivo, (b) degranulate in the presence of autologous infected CD4+ T cells, and (c) specifically clear latently infected cells after latency reversal with vorinostat. This is the first proof of concept to our knowledge showing that γδ T cells target and clear autologous HIV reservoirs upon latency reversal. Our results open potentially new insights into the immunotherapeutic use of γδ T cells for current interventions in HIV eradication strategies.
    MeSH term(s) CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; HIV Antigens/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV-1 ; Humans ; Immunotherapy ; Receptors, Antigen, T-Cell, gamma-delta/immunology
    Chemical Substances HIV Antigens ; Receptors, Antigen, T-Cell, gamma-delta
    Language English
    Publishing date 2018-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.120121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy.

    Tang, Yuyang / Chaillon, Antoine / Gianella, Sara / Wong, Lilly M / Li, Dajiang / Simermeyer, Theresa L / Porrachia, Magali / Ignacio, Caroline / Woodworth, Brendon / Zhong, Daniel / Du, Jiayi / de la Parra Polina, Eduardo / Kirchherr, Jennifer / Allard, Brigitte / Clohosey, Matthew L / Moeser, Matt / Sondgeroth, Amy L / Whitehill, Gregory D / Singh, Vidisha /
    Dashti, Amir / Smith, Davey M / Eron, Joseph J / Bar, Katherine J / Chahroudi, Ann / Joseph, Sarah B / Archin, Nancie M / Margolis, David M / Jiang, Guochun

    The Journal of clinical investigation

    2023  Volume 133, Issue 12

    Abstract: Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain ...

    Abstract Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.
    MeSH term(s) Animals ; Humans ; Microglia ; HIV-1 ; Brain ; Macrophages ; Proviruses/genetics ; HIV Infections/drug therapy
    Language English
    Publishing date 2023-06-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI167417
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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.184: Show issues Location:
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  6. Article ; Online: Measuring the contribution of γδ T cells to the persistent HIV reservoir.

    James, Katherine S / Trumble, Ilana / Clohosey, Matthew L / Moeser, Matthew / Roan, Nadia R / Adimora, Adaora A / Joseph, Sarah B / Archin, Nancie M / Hudgens, Michael / Soriano-Sarabia, Natalia

    AIDS (London, England)

    2019  Volume 34, Issue 3, Page(s) 363–371

    Abstract: Objective: To study the contribution of γδ T cells to the persistent HIV reservoir.: Design: Fifteen HIV-seropositive individuals on suppressive ART were included. We performed parallel quantitative viral outgrowth assays (QVOA) of resting CD4 T ( ... ...

    Abstract Objective: To study the contribution of γδ T cells to the persistent HIV reservoir.
    Design: Fifteen HIV-seropositive individuals on suppressive ART were included. We performed parallel quantitative viral outgrowth assays (QVOA) of resting CD4 T (rCD4) cells in the presence or absence of γδ T cells.
    Methods: Resting αβ+CD4 T cells were magnetically isolated from PBMCs using two different custom cocktails, only one kit contained antibodies to deplete γδ T cells, resulting in two populations: rCD4 cells and rCD4 cells depleted of γδ cells. Frequency of infection was analyzed by QVOA and DNA measurements.
    Results: Recovery of replication-competent HIV from cultures of rCD4 cells was similar in 11 individuals despite the presence of γδ T cells. In four donors, HIV recovery was lower when γδ T cells were present. Expression of the cytotoxic marker CD16 on Vδ2 cells was the only variable associated with the lower HIV recovery. Our results highlight the potency of those responses since a mean of 10 000 γδ T cells were present within 2.5 million rCD4 cells. However, despite the low frequency of γδ T cells, the presence of cytotoxic Vδ2 cells correlated with lower HIV recovery from cultures of rCD4 cells.
    Conclusion: Results of this study show that quantification of the contribution of γδ T cells to the reservoir is challenging because of their low numbers compared with conventional rCD4 cells and highlights the potent antiviral function of γδ T cells and the impact of their presence on the frequency of latent HIV infection.
    MeSH term(s) CD4-Positive T-Lymphocytes ; Disease Reservoirs ; HIV Infections ; Humans
    Language English
    Publishing date 2019-11-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 639076-6
    ISSN 1473-5571 ; 0269-9370 ; 1350-2840
    ISSN (online) 1473-5571
    ISSN 0269-9370 ; 1350-2840
    DOI 10.1097/QAD.0000000000002434
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2228: Show issues Location:
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  7. Article ; Online: HIV-Specific, Ex Vivo Expanded T Cell Therapy: Feasibility, Safety, and Efficacy in ART-Suppressed HIV-Infected Individuals.

    Sung, Julia A / Patel, Shabnum / Clohosey, Matthew L / Roesch, Lauren / Tripic, Tamara / Kuruc, JoAnn D / Archin, Nancie / Hanley, Patrick J / Cruz, C Russell / Goonetilleke, Nilu / Eron, Joseph J / Rooney, Clio M / Gay, Cynthia L / Bollard, Catherine M / Margolis, David M

    Molecular therapy : the journal of the American Society of Gene Therapy

    2018  Volume 26, Issue 10, Page(s) 2496–2506

    Abstract: Adoptive T cell therapy has had dramatic successes in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the ... ...

    Abstract Adoptive T cell therapy has had dramatic successes in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the long-term goal of using HXTCs as part of strategies to clear persistent HIV infection. In this phase 1 proof-of-concept study (NCT02208167), we administered HXTCs to antiretroviral therapy (ART)-suppressed, HIV-infected participants. Participants received two infusions of 2 × 10
    MeSH term(s) Adult ; Aged ; Antiretroviral Therapy, Highly Active/methods ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell- and Tissue-Based Therapy ; Female ; Genetic Therapy ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/therapy ; HIV Infections/virology ; HIV-1/immunology ; HIV-1/pathogenicity ; Humans ; Male ; Middle Aged ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation ; Virus Activation/genetics ; Virus Activation/immunology ; Virus Replication/genetics ; Virus Replication/immunology
    Language English
    Publishing date 2018-09-21
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2018.08.015
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5640: Show issues Location:
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