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  1. Article ; Online: Intranuclear Positions of HIV-1 Proviruses Are Dynamic and Do Not Correlate with Transcriptional Activity.

    Burdick, Ryan C / Deleage, Claire / Duchon, Alice / Estes, Jacob D / Hu, Wei-Shau / Pathak, Vinay K

    mBio

    2022  Volume 13, Issue 1, Page(s) e0325621

    Abstract: The relationship between spatiotemporal distribution of HIV-1 proviruses and their transcriptional activity is not well understood. To elucidate the intranuclear positions of transcriptionally active HIV-1 proviruses, we utilized an RNA ... ...

    Abstract The relationship between spatiotemporal distribution of HIV-1 proviruses and their transcriptional activity is not well understood. To elucidate the intranuclear positions of transcriptionally active HIV-1 proviruses, we utilized an RNA fluorescence
    MeSH term(s) Humans ; Proviruses/genetics ; HIV-1/genetics ; HeLa Cells ; Virus Integration ; In Situ Hybridization, Fluorescence ; HIV Infections ; HIV Seropositivity ; RNA/metabolism
    Chemical Substances RNA (63231-63-0)
    Language English
    Publishing date 2022-01-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.03256-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: In Situ Multiplexing to Identify, Quantify, and Phenotype the HIV-1/SIV Reservoir Within Lymphoid Tissue.

    Busman-Sahay, Kathleen / Nekorchuk, Michael D / Starke, Carly Elizabeth / Chan, Chi Ngai / Estes, Jacob D

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2407, Page(s) 277–290

    Abstract: Modern combination antiretroviral therapy (ART) regimens provide abiding viral suppression for most individuals infected with human immunodeficiency virus (HIV). However, the persistence of viral reservoirs ensures that eradication of HIV-1 (i.e., cure) ... ...

    Abstract Modern combination antiretroviral therapy (ART) regimens provide abiding viral suppression for most individuals infected with human immunodeficiency virus (HIV). However, the persistence of viral reservoirs ensures that eradication of HIV-1 (i.e., cure) or sustained ART-free remission (i.e., functional cure) remains elusive, necessitating continual, strict ART adherence and contributing to HIV-1-related comorbidities. Eradication of these viral reservoirs, which persist primarily within lymphoid tissue, will require a deeper understanding of the cellular neighborhoods in which latent and active HIV-1-infected cells reside. By pairing highly sensitive in situ hybridization (ISH) with an exceptionally flexible immunofluorescence (IF) approach, we describe a simple, yet highly adaptable multiplex protocol for investigating the quantity, distribution, and characteristics of HIV-1 viral reservoirs.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes ; HIV Infections/drug therapy ; HIV-1/genetics ; Lymphoid Tissue ; Macaca mulatta ; Phenotype ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus/genetics ; Viral Load ; Virus Latency
    Language English
    Publishing date 2022-01-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1871-4_19
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pathobiology of HIV/SIV-associated changes in secondary lymphoid tissues.

    Estes, Jacob D

    Immunological reviews

    2013  Volume 254, Issue 1, Page(s) 65–77

    Abstract: Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4(+) T lymphocyte that primarily resides within organs of the immune ... ...

    Abstract Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4(+) T lymphocyte that primarily resides within organs of the immune system. The impact of HIV infection on secondary LTs, in particular lymph nodes, is critical to delineate, as these immune organs are the principal sites for initiating and facilitating immune responses and are critical for lymphocyte homeostatic maintenance and survival. The underlying structural elements of LTs, fibroblastic reticular cell (FRC) network, not only form the architectural framework for these organs, but also play in integral role in the production and storage of cytokines needed for T-cell survival. There is an interdependent relationship between the FRC stromal network and CD4(+) T lymphocytes for their survival and maintenance that is progressively disrupted during HIV disease. HIV infection results in profound pathological changes to LTs induced by persistent chronic immune activation and inflammation that leads to progressive collagen deposition and fibrosis disrupting and damaging the important FRC network. In this review, I focus on the process, mechanisms, and the implications of pathological damage to important secondary LTs, combining what we have learned from HIV-infected individuals as well as the invaluable knowledge gained from studies in non-human primate simian immunodeficiency virus infection models.
    MeSH term(s) Animals ; Antiretroviral Therapy, Highly Active ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/virology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/pathology ; Humans ; Inflammation/immunology ; Lymph Nodes/anatomy & histology ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Lymphoid Tissue/immunology ; Lymphoid Tissue/pathology ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/pathology
    Language English
    Publishing date 2013-06-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.12070
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Correction: Tracking the Luminal Exposure and Lymphatic Drainage Pathways of Intravaginal and Intrarectal Inocula Used in Nonhuman Primate Models of HIV Transmission.

    Smedley, Jeremy / Turkbey, Baris / Bernardo, Marcelino L / Del Prete, Gregory Q / Estes, Jacob D / Griffiths, Gary L / Kobayashi, Hisataka / Choyke, Peter L / Lifson, Jeffrey D / Keele, Brandon F

    PloS one

    2023  Volume 18, Issue 7, Page(s) e0288566

    Abstract: This corrects the article DOI: 10.1371/journal.pone.0092830.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pone.0092830.].
    Language English
    Publishing date 2023-07-07
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0288566
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Enhancing immune responses to limit chronic immune activation during SIV.

    Estes, Jacob D

    The Journal of clinical investigation

    2012  Volume 122, Issue 5, Page(s) 1611–1614

    Abstract: The persistent immune activation that is typical of HIV-1 and SIV infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death-1 (PD-1). ...

    Abstract The persistent immune activation that is typical of HIV-1 and SIV infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death-1 (PD-1). Targeting this exhaustion pathway could result in improved antiviral immune responses, but there have been concerns that it would also lead to increased inflammation and immunopathology. In this issue of the JCI, Dyavar Shetty et al. demonstrate that blocking PD-1 actually reduced proinflammatory responses and improved immunity in the gut of SIV-infected rhesus macaques, suggesting that this might have therapeutic potential to prevent opportunistic infections in HIV-infected patients.
    MeSH term(s) Animals ; Antibodies, Neutralizing/pharmacology ; Antiviral Agents/pharmacology ; Bacterial Translocation ; Humans ; Interferon Type I/metabolism ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Simian Acquired Immunodeficiency Syndrome/drug therapy
    Chemical Substances Antibodies, Neutralizing ; Antiviral Agents ; Interferon Type I ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2012-04-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI63389
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Eliminating HIV reservoirs for a cure: the issue is in the tissue.

    Busman-Sahay, Kathleen / Starke, Carly E / Nekorchuk, Michael D / Estes, Jacob D

    Current opinion in HIV and AIDS

    2021  Volume 16, Issue 4, Page(s) 200–208

    Abstract: Purpose of review: Advances in antiretroviral therapy have saved numerous lives, converting a diagnosis with human immunodeficiency virus 1 (HIV-1) from a death sentence into the possibility for a (nearly) normal life in many instances. However, the ... ...

    Abstract Purpose of review: Advances in antiretroviral therapy have saved numerous lives, converting a diagnosis with human immunodeficiency virus 1 (HIV-1) from a death sentence into the possibility for a (nearly) normal life in many instances. However, the obligation for lifelong adherence, increased risk of accumulated co-morbidities, and continued lack of uniform availability around the globe underscores the need for an HIV cure. Safe and scalable HIV cure strategies remain elusive, in large part due to the presence of viral reservoirs in which caches of infected cells remain hidden from immune elimination, primarily within tissues. Herein, we summarize some of the most exciting recent advances focused on understanding, quantifying, and ultimately targeting HIV tissue viral reservoirs.
    Recent findings: Current studies have underscored the differences between viral reservoirs in tissue compartments as compared to peripheral blood, in particular, the gastrointestinal (GI) tract. Additionally, several novel or modified techniques are showing promise in targeting the latent viral reservoir, including modifications in drug delivery platforms and techniques such as CRISPR.
    Summary: Elimination of tissue viral reservoirs is likely the key to generation of an effective HIV cure. Exciting studies have come out recently that reveal crucial insights into topics ranging from the basic biology of reservoir seeding to effective drug targeting. However, there are still many outstanding questions in the field about the relative importance of specific reservoirs, such as the GI tract, that may alter the final strategy pursued.
    MeSH term(s) CD4-Positive T-Lymphocytes ; Disease Reservoirs ; HIV Infections/drug therapy ; HIV-1/genetics ; Humans ; Virus Latency
    Language English
    Publishing date 2021-05-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2502511-9
    ISSN 1746-6318 ; 1746-630X
    ISSN (online) 1746-6318
    ISSN 1746-630X
    DOI 10.1097/COH.0000000000000688
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Non-Human Primate Models of HIV Brain Infection and Cognitive Disorders.

    Byrnes, Sarah J / Angelovich, Thomas A / Busman-Sahay, Kathleen / Cochrane, Catherine R / Roche, Michael / Estes, Jacob D / Churchill, Melissa J

    Viruses

    2022  Volume 14, Issue 9

    Abstract: Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions ... ...

    Abstract Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation.
    MeSH term(s) Animals ; Brain ; Cognition ; Cognitive Dysfunction ; HIV Infections/complications ; Inflammation ; Primates ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus ; Viral Load
    Language English
    Publishing date 2022-09-09
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14091997
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  8. Article ; Online: Antiretroviral drug exposure in lymph nodes is heterogeneous and drug dependent.

    Rosen, Elias P / Deleage, Claire / White, Nicole / Sykes, Craig / Brands, Catherine / Adamson, Lourdes / Luciw, Paul / Estes, Jacob D / Kashuba, Angela D M

    Journal of the International AIDS Society

    2022  Volume 25, Issue 4, Page(s) e25895

    Abstract: Introduction: HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as ... ...

    Abstract Introduction: HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4
    Methods: Between December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4
    Results: Through MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4
    Conclusions: Our investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.
    MeSH term(s) Animals ; Anti-Retroviral Agents/therapeutic use ; Collagen/therapeutic use ; HIV Infections/drug therapy ; Humans ; Lymph Nodes/metabolism ; Macaca mulatta/genetics ; Macaca mulatta/metabolism ; Male ; RNA, Viral/genetics ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/metabolism
    Chemical Substances Anti-Retroviral Agents ; RNA, Viral ; Collagen (9007-34-5)
    Language English
    Publishing date 2022-04-20
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2467110-1
    ISSN 1758-2652 ; 1758-2652
    ISSN (online) 1758-2652
    ISSN 1758-2652
    DOI 10.1002/jia2.25895
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  9. Article ; Online: Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4

    Dubé, Mathieu / Tastet, Olivier / Dufour, Caroline / Sannier, Gérémy / Brassard, Nathalie / Delgado, Gloria-Gabrielle / Pagliuzza, Amélie / Richard, Corentin / Nayrac, Manon / Routy, Jean-Pierre / Prat, Alexandre / Estes, Jacob D / Fromentin, Rémi / Chomont, Nicolas / Kaufmann, Daniel E

    Cell host & microbe

    2023  Volume 31, Issue 9, Page(s) 1507–1522.e5

    Abstract: Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow- ...

    Abstract Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization (FISH), we detect active HIV transcription in 14/18 people with HIV on suppressive ART, with a median of 28/million CD4
    MeSH term(s) Humans ; CD8-Positive T-Lymphocytes ; In Situ Hybridization, Fluorescence ; Phenotype ; Proviruses ; CD4-Positive T-Lymphocytes
    Language English
    Publishing date 2023-09-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2278004-X
    ISSN 1934-6069 ; 1931-3128
    ISSN (online) 1934-6069
    ISSN 1931-3128
    DOI 10.1016/j.chom.2023.08.006
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  10. Article: Visualizing the Immune System: Providing Key Insights into HIV/SIV Infections.

    Estes, Jacob D / LeGrand, Roger / Petrovas, Constantinos

    Frontiers in immunology

    2018  Volume 9, Page(s) 423

    Abstract: Immunological inductive tissues, such as secondary lymphoid organs, are composed of distinct anatomical microenvironments for the generation of immune responses to pathogens and immunogens. These microenvironments are characterized by the ... ...

    Abstract Immunological inductive tissues, such as secondary lymphoid organs, are composed of distinct anatomical microenvironments for the generation of immune responses to pathogens and immunogens. These microenvironments are characterized by the compartmentalization of highly specialized immune and stromal cell populations, as well as the presence of a complex network of soluble factors and chemokines that direct the intra-tissue trafficking of naïve and effector cell populations. Imaging platforms have provided critical contextual information regarding the molecular and cellular interactions that orchestrate the spatial microanatomy of relevant cells and the development of immune responses against pathogens. Particularly in HIV/SIV disease, imaging technologies are of great importance in the investigation of the local interplay between the virus and host cells, with respect to understanding viral dynamics and persistence, immune responses (i.e., adaptive and innate inflammatory responses), tissue structure and pathologies, and changes to the surrounding milieu and function of immune cells. Merging imaging platforms with other cutting-edge technologies could lead to novel findings regarding the phenotype, function, and molecular signatures of particular immune cell targets, further promoting the development of new antiviral treatments and vaccination strategies.
    MeSH term(s) Animals ; Cell Communication ; HIV/immunology ; HIV Infections/immunology ; Humans ; Immune System ; Macaca mulatta ; Phantoms, Imaging ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/immunology
    Language English
    Publishing date 2018-03-02
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.00423
    Database MEDical Literature Analysis and Retrieval System OnLINE

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