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  1. Article ; Online: HIV cure: The daunting scale of the problem.

    Siliciano, Janet D / Siliciano, Robert F

    Science (New York, N.Y.)

    2024  Volume 383, Issue 6684, Page(s) 703–705

    Abstract: Cure strategies are confounded by basic reservoir biology. ...

    Abstract Cure strategies are confounded by basic reservoir biology.
    MeSH term(s) Humans ; CD4-Positive T-Lymphocytes/immunology ; HIV Infections/drug therapy ; HIV Infections/virology ; Virus Latency ; Anti-Retroviral Agents/therapeutic use ; Immunologic Memory ; Disease Reservoirs/virology
    Chemical Substances Anti-Retroviral Agents
    Language English
    Publishing date 2024-02-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.adk1831
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  2. Article ; Online: In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure.

    Siliciano, Janet D / Siliciano, Robert F

    Annual review of pathology

    2021  Volume 17, Page(s) 271–294

    Abstract: Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) to lead relatively normal lives, viremia rebounds when treatment is interrupted. Rebound reflects viral persistence in a ... ...

    Abstract Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) to lead relatively normal lives, viremia rebounds when treatment is interrupted. Rebound reflects viral persistence in a stable latent reservoir in resting CD4
    MeSH term(s) CD4-Positive T-Lymphocytes ; HIV Infections/drug therapy ; HIV-1/physiology ; Humans ; Viremia ; Virus Latency/physiology ; Virus Replication
    Language English
    Publishing date 2021-11-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2227429-7
    ISSN 1553-4014 ; 1553-4006
    ISSN (online) 1553-4014
    ISSN 1553-4006
    DOI 10.1146/annurev-pathol-050520-112001
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  3. Article ; Online: Low Inducibility of Latent Human Immunodeficiency Virus Type 1 Proviruses as a Major Barrier to Cure.

    Siliciano, Janet D / Siliciano, Robert F

    The Journal of infectious diseases

    2021  Volume 223, Issue 12 Suppl 2, Page(s) 13–21

    Abstract: The latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting CD4+ T cells is a major barrier to cure. The dimensions of the reservoir problem can be defined with 2 assays. A definitive minimal estimate of the frequency of latently ... ...

    Abstract The latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting CD4+ T cells is a major barrier to cure. The dimensions of the reservoir problem can be defined with 2 assays. A definitive minimal estimate of the frequency of latently infected cells is provided by the quantitative viral outgrowth assay (QVOA), which detects cells that can be induced by T-cell activation to release infectious virus. In contrast, the intact proviral DNA assay (IPDA) detects all genetically intact proviruses and provides a more accurate upper limit on reservoir size than standard single-amplicon polymerase chain reaction assays which mainly detect defective proviruses. The frequency of cells capable of initiating viral rebound on interruption of antiretroviral therapy lies between the values produced by the QVOA and the IPDA. We argue here that the 1-2-log difference between QVOA and IPDA values in part reflects that the fact that many replication-competent proviruses are not readily induced by T-cell activation. Findings of earlier studies suggest that latently infected cells can be activated to proliferate in vivo without expressing viral genes. The proliferating cells nevertheless retain the ability to produce virus on subsequent stimulation. The low inducibility of latent proviruses is a major problem for the shock-and-kill strategy for curing HIV-1 infection, which uses latency-reversing agents to induce viral gene expression and render infected cells susceptible to immune clearance. The latency-reversing agents developed to date are much less effective at reversing latency than T-cell activation. Taken together, these results indicate that HIV-1 eradication will require the discovery of much more effective ways to induce viral gene expression.
    MeSH term(s) Animals ; Anti-HIV Agents/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Lymphocyte Activation ; Proviruses/drug effects ; Proviruses/genetics ; Proviruses/physiology ; Virus Latency ; Virus Replication
    Chemical Substances Anti-HIV Agents
    Language English
    Publishing date 2021-02-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiaa649
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  4. Article ; Online: Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists.

    Siliciano, Janet D / Siliciano, Robert F

    The Journal of clinical investigation

    2020  Volume 130, Issue 11, Page(s) 5665–5667

    Abstract: Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance ... ...

    Abstract Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of the JCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from CD4+ T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected CD4+ T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells.
    MeSH term(s) CD4-Positive T-Lymphocytes ; Clone Cells ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV-1/genetics ; Humans ; Viremia ; Virus Latency ; Virus Replication
    Language English
    Publishing date 2020-10-03
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI141497
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  5. Article: Assays to Measure Latency, Reservoirs, and Reactivation.

    Siliciano, Janet D / Siliciano, Robert F

    Current topics in microbiology and immunology

    2017  Volume 417, Page(s) 23–41

    Abstract: HIV-1 persists even in patients who are successfully treated with combination antiretroviral therapy. The major barrier to cure is a small pool of latently infected resting ... ...

    Abstract HIV-1 persists even in patients who are successfully treated with combination antiretroviral therapy. The major barrier to cure is a small pool of latently infected resting CD4
    MeSH term(s) CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; Genome, Viral/genetics ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/growth & development ; Humans ; Proviruses/genetics ; Proviruses/growth & development ; Viral Load ; Virus Activation ; Virus Latency/genetics
    Language English
    Publishing date 2017-10-25
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 0070-217X
    ISSN 0070-217X
    DOI 10.1007/82_2017_75
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  6. Article ; Online: CD4+ T cells with latent HIV-1 have reduced proliferative responses to T cell receptor stimulation.

    Kufera, Joshua T / Armstrong, Ciara / Wu, Fengting / Singhal, Anushka / Zhang, Hao / Lai, Jun / Wilkins, Hannah N / Simonetti, Francesco R / Siliciano, Janet D / Siliciano, Robert F

    The Journal of experimental medicine

    2024  Volume 221, Issue 3

    Abstract: The latent reservoir for HIV-1 in resting CD4+ T cells persists despite antiretroviral therapy as a barrier to cure. The antigen-driven proliferation of infected cells is a major mechanism of reservoir persistence. However, activation through the T cell ... ...

    Abstract The latent reservoir for HIV-1 in resting CD4+ T cells persists despite antiretroviral therapy as a barrier to cure. The antigen-driven proliferation of infected cells is a major mechanism of reservoir persistence. However, activation through the T cell antigen receptor (TCR) can induce latent proviruses, leading to viral cytopathic effects and immune clearance. In single-cell studies, we show that, relative to uninfected cells or cells with a defective provirus, CD4+ T cells with an intact provirus have a profound proliferative defect in response to TCR stimulation. Virion production was observed in only 16.5% of cultures with an intact provirus, but proliferation was reduced even when no virion production was detected. Proliferation was inversely correlated with in vivo clone size. These results may reflect the effects of previous in vivo proliferation and do not support attempts to reduce the reservoir with antiproliferative agents, which may have greater effects on normal T cell responses.
    MeSH term(s) Humans ; HIV Infections ; HIV-1 ; CD4-Positive T-Lymphocytes ; Virus Latency ; Proviruses ; Receptors, Antigen, T-Cell
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20231511
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  7. Article ; Online: Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells.

    Board, Nathan L / Yuan, Zhe / Wu, Fengting / Moskovljevic, Milica / Ravi, Meghana / Sengupta, Srona / Mun, Sung Soo / Simonetti, Francesco R / Lai, Jun / Tebas, Pablo / Lynn, Kenneth / Hoh, Rebecca / Deeks, Steven G / Siliciano, Janet D / Montaner, Luis J / Siliciano, Robert F

    Nature immunology

    2024  Volume 25, Issue 3, Page(s) 462–470

    Abstract: The persistence of ... ...

    Abstract The persistence of CD4
    MeSH term(s) Animals ; Mice ; Humans ; Antibodies, Bispecific ; HIV-1 ; Killer Cells, Natural ; Cytotoxicity, Immunologic ; Cell Death ; Mice, Transgenic
    Chemical Substances Antibodies, Bispecific
    Language English
    Publishing date 2024-01-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-023-01741-5
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  8. Article ; Online: Engaging innate immunity in HIV-1 cure strategies.

    Board, Nathan L / Moskovljevic, Milica / Wu, Fengting / Siliciano, Robert F / Siliciano, Janet D

    Nature reviews. Immunology

    2021  Volume 22, Issue 8, Page(s) 499–512

    Abstract: Combination antiretroviral therapy (ART) can block multiple stages of the HIV-1 life cycle to prevent progression to AIDS in people living with HIV-1. However, owing to the persistence of a reservoir of latently infected ... ...

    Abstract Combination antiretroviral therapy (ART) can block multiple stages of the HIV-1 life cycle to prevent progression to AIDS in people living with HIV-1. However, owing to the persistence of a reservoir of latently infected CD4
    MeSH term(s) CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; HIV Infections/therapy ; HIV-1 ; Humans ; Immunity, Innate ; Virus Latency
    Language English
    Publishing date 2021-11-25
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-021-00649-1
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  9. Article: Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4

    Sambaturu, Narmada / Fray, Emily J / Wu, Fengting / Zitzmann, Carolin / Simonetti, Francesco R / Barouch, Dan H / Siliciano, Janet D / Siliciano, Robert F / Ribeiro, Ruy M / Perelson, Alan S / Molina-París, Carmen / Leitner, Thomas

    bioRxiv : the preprint server for biology

    2023  

    Abstract: HIV can persist in a latent form as integrated DNA (provirus) in resting ... ...

    Abstract HIV can persist in a latent form as integrated DNA (provirus) in resting CD4
    Language English
    Publishing date 2023-11-03
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.03.565539
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  10. Article ; Online: Recent developments in the effort to cure HIV infection: going beyond N = 1.

    Siliciano, Janet D / Siliciano, Robert F

    The Journal of clinical investigation

    2016  Volume 126, Issue 2, Page(s) 409–414

    Abstract: Combination antiretroviral therapy (ART) can suppress plasma HIV to undetectable levels, allowing HIV-infected individuals who are treated early a nearly normal life span. Despite the clear ability of ART to prevent morbidity and mortality, it is not ... ...

    Abstract Combination antiretroviral therapy (ART) can suppress plasma HIV to undetectable levels, allowing HIV-infected individuals who are treated early a nearly normal life span. Despite the clear ability of ART to prevent morbidity and mortality, it is not curative. Even in individuals who have full suppression of viral replication on ART, there are resting memory CD4+ T cells that harbor stably integrated HIV genomes, which are capable of producing infectious virus upon T cell activation. This latent viral reservoir is considered the primary obstacle to the development of an HIV cure, and recent efforts in multiple areas of HIV research have been brought to bear on the development of strategies to eradicate or develop a functional cure for HIV. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, and animal models for the study HIV latency and therapeutic strategies.
    MeSH term(s) Animals ; Anti-Retroviral Agents/therapeutic use ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV-1/physiology ; Humans ; Immunologic Memory/drug effects ; Virus Latency/drug effects ; Virus Latency/immunology
    Chemical Substances Anti-Retroviral Agents
    Language English
    Publishing date 2016-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI86047
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