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  1. Article ; Online: D614G and SARS-CoV-2 replication fitness.

    Engelman, Kathleen D / Engelman, Alan N

    Signal transduction and targeted therapy

    2021  Volume 6, Issue 1, Page(s) 99

    MeSH term(s) COVID-19 ; Humans ; Mutation ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics
    Chemical Substances Spike Glycoprotein, Coronavirus
    Language English
    Publishing date 2021-03-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2886872-9
    ISSN 2059-3635 ; 2095-9907
    ISSN (online) 2059-3635
    ISSN 2095-9907
    DOI 10.1038/s41392-021-00498-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Long-Acting Cabotegravir for HIV/AIDS Prophylaxis.

    Engelman, Kathleen D / Engelman, Alan N

    Biochemistry

    2021  Volume 60, Issue 22, Page(s) 1731–1740

    Abstract: The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for ... ...

    Abstract The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for HIV-1. By contrast, small molecule inhibitors of the HIV-1 enzymes reverse transcriptase, integrase, and protease have been developed that effectively block virus replication. Three different drug compounds are commonly prescribed for people living with HIV as once-daily oral tablets. Once-daily pills composed of two different reverse transcriptase inhibitors are moreover approved as preexposure prophylaxis (PrEP) treatment for virus naïve individuals who may partake in behaviors associated with increased risk of HIV-1 acquisition such as unprotected sex or injection drug use. Long-acting (LA) injectable HIV-1 enzyme inhibitors are at the same time being developed to sidestep adherence noncompliance issues that can arise from self-administered once-daily oral dosing regimens. Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors. In this Perspective, we examine bench to bedside aspects of CAB-LA treatment and development, starting from the biochemical basis of HIV-1 integration and pharmacological inhibition of integrase catalysis. We also review the results of recent clinical trials that evaluated CAB-LA, as well as the promises and challenges that surround its use for HIV/AIDS PrEP.
    MeSH term(s) Acquired Immunodeficiency Syndrome/drug therapy ; Acquired Immunodeficiency Syndrome/prevention & control ; Anti-HIV Agents/pharmacology ; HIV Infections/drug therapy ; HIV Infections/prevention & control ; HIV Integrase/drug effects ; HIV Integrase/metabolism ; HIV-1/drug effects ; HIV-1/pathogenicity ; Humans ; Pre-Exposure Prophylaxis/methods ; Pyridones/metabolism ; Pyridones/therapeutic use ; Reverse Transcriptase Inhibitors/pharmacology
    Chemical Substances Anti-HIV Agents ; Pyridones ; Reverse Transcriptase Inhibitors ; HIV Integrase (EC 2.7.7.-) ; cabotegravir (HMH0132Z1Q) ; p31 integrase protein, Human immunodeficiency virus 1 (YY6481J2FF)
    Language English
    Publishing date 2021-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.1c00157
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Long-Acting Cabotegravir for HIV/AIDS Prophylaxis

    Engelman, Kathleen D / Engelman, Alan N

    Biochemistry. 2021 May 24, v. 60, no. 22

    2021  

    Abstract: The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for ... ...

    Abstract The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for HIV-1. By contrast, small molecule inhibitors of the HIV-1 enzymes reverse transcriptase, integrase, and protease have been developed that effectively block virus replication. Three different drug compounds are commonly prescribed for people living with HIV as once-daily oral tablets. Once-daily pills composed of two different reverse transcriptase inhibitors are moreover approved as preexposure prophylaxis (PrEP) treatment for virus naïve individuals who may partake in behaviors associated with increased risk of HIV-1 acquisition such as unprotected sex or injection drug use. Long-acting (LA) injectable HIV-1 enzyme inhibitors are at the same time being developed to sidestep adherence noncompliance issues that can arise from self-administered once-daily oral dosing regimens. Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors. In this Perspective, we examine bench to bedside aspects of CAB-LA treatment and development, starting from the biochemical basis of HIV-1 integration and pharmacological inhibition of integrase catalysis. We also review the results of recent clinical trials that evaluated CAB-LA, as well as the promises and challenges that surround its use for HIV/AIDS PrEP.
    Keywords RNA-directed DNA polymerase ; catalytic activity ; disease prevention ; drugs ; etiological agents ; integrases ; pandemic ; people ; proteinases ; risk ; vaccination ; virus replication ; viruses
    Language English
    Dates of publication 2021-0524
    Size p. 1731-1740.
    Publishing place American Chemical Society
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.1c00157
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Neutralizing antibodies against Epstein-Barr virus infection of B cells can protect from oral viral challenge in the rhesus macaque animal model.

    Mühe, Janine / Aye, Pyone Pyone / Quink, Carol / Eng, Jing Ying / Engelman, Kathleen / Reimann, Keith A / Wang, Fred

    Cell reports. Medicine

    2021  Volume 2, Issue 7, Page(s) 100352

    Abstract: Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCVs) from nonhuman primates are transmitted through oral secretions, penetrate the mucosal epithelium, and establish persistent infection in B cells. To determine whether neutralizing antibodies ... ...

    Abstract Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCVs) from nonhuman primates are transmitted through oral secretions, penetrate the mucosal epithelium, and establish persistent infection in B cells. To determine whether neutralizing antibodies against epithelial or B cell infection could block oral transmission and persistent LCV infection, we use rhesus macaques, the most accurate animal model for EBV infection by faithfully reproducing acute and persistent infection in humans. Naive animals are infused with monoclonal antibodies neutralizing epithelial cell infection or B cell infection and then challenged orally with recombinant rhesus LCV. Our data show that high-titer B cell-neutralizing antibodies alone, but not epithelial cell-neutralizing antibodies, can provide complete protection of rhesus macaques from oral LCV challenge, but not in all hosts. Thus, neutralizing antibodies against B cell infection are important targets for EBV vaccine development, but they may not be sufficient.
    MeSH term(s) Administration, Oral ; Animals ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; Disease Models, Animal ; Epstein-Barr Virus Infections/blood ; Epstein-Barr Virus Infections/immunology ; Epstein-Barr Virus Infections/prevention & control ; Herpesvirus 4, Human/immunology ; Lymphocryptovirus/immunology ; Macaca mulatta
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral
    Language English
    Publishing date 2021-07-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2666-3791
    ISSN (online) 2666-3791
    DOI 10.1016/j.xcrm.2021.100352
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Anti-CD40 antibody 2C10 binds to a conformational epitope at the CD40-CD154 interface that is conserved among primate species.

    Michaels, Anthony J / Stoppato, Matteo / Flores, Walter J / Reimann, Keith A / Engelman, Kathleen D

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

    2019  Volume 20, Issue 1, Page(s) 298–305

    Abstract: The antagonistic anti-CD40 antibody, 2C10, and its recombinant primate derivative, 2C10R4, are potent immunosuppressive antibodies whose utility in allo- and xenotransplantation have been demonstrated in nonhuman primate studies. In this study, we ... ...

    Abstract The antagonistic anti-CD40 antibody, 2C10, and its recombinant primate derivative, 2C10R4, are potent immunosuppressive antibodies whose utility in allo- and xenotransplantation have been demonstrated in nonhuman primate studies. In this study, we defined the 2C10 binding epitope and found only slight differences in affinity of 2C10 for CD40 derived from four primate species. Staining of truncation mutants mapped the 2C10 binding epitope to the N-terminal portion of CD40. Alanine scanning mutagenesis of the first 60 residues in the CD40 ectodomain highlighted key amino acids important for binding of 2C10 and for binding of the noncross-blocking anti-CD40 antibodies 3A8 and 5D12. All four 2C10-binding residues defined by mutagenesis clustered near the membrane-distal tip of CD40 and partially overlap the CD154 binding surface. In contrast, the overlapping 3A8 and 5D12 epitopes map to an opposing surface away from the CD154 binding domain. This biochemical characterization of 2C10 confirms the validity of nonhuman primate studies in the translation of this therapeutic antibody and provides insight its mechanism of action.
    MeSH term(s) Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/metabolism ; CD40 Antigens/chemistry ; CD40 Antigens/genetics ; CD40 Antigens/immunology ; CD40 Antigens/metabolism ; CD40 Ligand/chemistry ; CD40 Ligand/genetics ; CD40 Ligand/immunology ; CD40 Ligand/metabolism ; Epitopes/chemistry ; Epitopes/genetics ; Epitopes/immunology ; Epitopes/metabolism ; Humans ; Macaca mulatta ; Mutation ; Protein Conformation ; Sequence Homology, Amino Acid
    Chemical Substances Antibodies, Monoclonal ; CD40 Antigens ; Epitopes ; CD40 Ligand (147205-72-9)
    Language English
    Publishing date 2019-09-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2060594-8
    ISSN 1600-6143 ; 1600-6135
    ISSN (online) 1600-6143
    ISSN 1600-6135
    DOI 10.1111/ajt.15574
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5542: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  6. Article: SIV clearance from neonatal macaques following transient CCR5 depletion.

    Deere, Jesse D / Merriam, David / Leggat, Kawthar Machmach / Chang, Wen-Lan William / Méndez-Lagares, Gema / Kieu, Hung / Dutra, Joseph / Fontaine, Justin / Lu, Wenze / Chin, Ning / Chen, Connie / Tran, Bryant Chi-Thien / Salinas, Jessica / Miller, Corey N / Deeks, Steven G / Lifson, Jeffrey D / Engelman, Kathleen / Magnani, Diogo / Reimann, Keith /
    Stevenson, Mario / Hartigan-O'Connor, Dennis J

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral ... ...

    Abstract Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4
    Language English
    Publishing date 2023-05-01
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.01.533682
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy.

    Varco-Merth, Benjamin D / Brantley, William / Marenco, Alejandra / Duell, Derick D / Fachko, Devin N / Richardson, Brian / Busman-Sahay, Kathleen / Shao, Danica / Flores, Walter / Engelman, Kathleen / Fukazawa, Yoshinori / Wong, Scott W / Skalsky, Rebecca L / Smedley, Jeremy / Axthelm, Michael K / Lifson, Jeffrey D / Estes, Jacob D / Edlefsen, Paul T / Picker, Louis J /
    Cameron, Cheryl Ma / Henrich, Timothy J / Okoye, Afam A

    The Journal of clinical investigation

    2022  Volume 132, Issue 10

    Abstract: Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, ... ...

    Abstract Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.
    MeSH term(s) Animals ; Anti-Retroviral Agents/pharmacology ; Anti-Retroviral Agents/therapeutic use ; CD4-Positive T-Lymphocytes ; Cell Proliferation ; HIV Infections/drug therapy ; Macaca mulatta/genetics ; RNA ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/pharmacology ; Viral Load ; Virus Replication
    Chemical Substances Anti-Retroviral Agents ; RNA (63231-63-0) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2022-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI156063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.184: Show issues Location:
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  8. Article ; Online: IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early

    Wong, Eileen A / Evans, Stephanie / Kraus, Carolyn R / Engelman, Kathleen D / Maiello, Pauline / Flores, Walter J / Cadena, Anthony M / Klein, Edwin / Thomas, Kayla / White, Alexander G / Causgrove, Chelsea / Stein, Brianne / Tomko, Jaime / Mattila, Joshua T / Gideon, Hannah / Lin, P Ling / Reimann, Keith A / Kirschner, Denise E / Flynn, JoAnne L

    Journal of immunology (Baltimore, Md. : 1950)

    2019  Volume 204, Issue 3, Page(s) 644–659

    Abstract: Tuberculosis (TB), caused ... ...

    Abstract Tuberculosis (TB), caused by
    MeSH term(s) Animals ; Antibodies, Neutralizing/metabolism ; Cells, Cultured ; Disease Models, Animal ; Granuloma/immunology ; Humans ; Immunity ; Inflammation/immunology ; Interleukin-10/metabolism ; Lung/immunology ; Lung/pathology ; Lymph Nodes/immunology ; Macaca fascicularis ; Mycobacterium tuberculosis/physiology ; Pulmonary Fibrosis ; Tuberculosis/immunology
    Chemical Substances Antibodies, Neutralizing ; Interleukin-10 (130068-27-8)
    Language English
    Publishing date 2019-12-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1901211
    Database MEDical Literature Analysis and Retrieval System OnLINE

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