333 results on '"Sacha, Jonah B."'
Search Results
2. KDM5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells
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Li, Tai-Wei, Park, Youngmin, Watters, Emily G., Wang, Xu, Zhou, Dawei, Fiches, Guillaume N., Wu, Zhenyu, Badley, Andrew D., Sacha, Jonah B., Ho, Wen-Zhe, Santoso, Netty G., Qi, Jun, and Zhu, Jian
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- 2024
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3. Identification and Characterization of Antigen-Specific CD8+ T Cells Using Surface-Trapped TNF-α and Single-Cell Sequencing.
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Abdulhaqq, Shaheed, Ventura, Abigail B, Reed, Jason S, Bashirova, Arman A, Bateman, Katherine B, McDonald, Eric, Wu, Helen L, Greene, Justin M, Schell, John B, Morrow, David, Wisskirchen, Karin, Martin, Jeffrey N, Deeks, Steven G, Carrington, Mary, Protzer, Ulrike, Früh, Klaus, Hansen, Scott G, Picker, Louis J, Sacha, Jonah B, and Bimber, Benjamin N
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Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,Sexually Transmitted Infections ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Animals ,CD8-Positive T-Lymphocytes ,Epitopes ,Epitopes ,T-Lymphocyte ,HIV Infections ,Macaca mulatta ,Receptors ,Antigen ,T-Cell ,Tumor Necrosis Factor-alpha ,Biochemistry and cell biology - Abstract
CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and β-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.
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- 2021
4. Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Patients Who Received Compassionate-Use Leronlimab
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Yang, Bryant, Fulcher, Jennifer A, Ahn, Jenny, Berro, Marlene, Goodman-Meza, David, Dhody, Kush, Sacha, Jonah B, Naeim, Arash, and Yang, Otto O
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Clinical Research ,Inflammatory and immune system ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,COVID-19 ,HIV Antibodies ,Humans ,Immunization ,Passive ,Middle Aged ,SARS-CoV-2 ,Treatment Outcome ,COVID-19 Serotherapy ,leronlimab ,immunomodulatory therapy ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Clinical sciences - Abstract
BackgroundLeronlimab, a monoclonal antibody blocker of C-C chemokine receptor type 5 originally developed to treat human immunodeficiency virus infection, was administered as an open-label compassionate-use therapeutic for coronavirus disease 2019 (COVID-19).MethodsTwenty-three hospitalized severe/critical COVID-19 patients received 700 mg leronlimab subcutaneously, repeated after 7 days in 17 of 23 patients still hospitalized. Eighteen of 23 received other experimental treatments, including convalescent plasma, hydroxychloroquine, steroids, and/or tocilizumab. Five of 23 received leronlimab after blinded, placebo-controlled trials of remdesivir, sarilumab, selinexor, or tocilizumab. Outcomes and results were extracted from medical records.ResultsMean age was 69.5 ± 14.9 years; 20 had significant comorbidities. At baseline, 22 were receiving supplemental oxygen (3 high flow, 7 mechanical ventilation). Blood showed markedly elevated inflammatory markers (ferritin, D-dimer, C-reactive protein) and an elevated neutrophil-to-lymphocyte ratio. By day 30 after initial dosing, 17 were recovered, 2 were still hospitalized, and 4 had died. Of the 7 intubated at baseline, 4 were fully recovered off oxygen, 2 were still hospitalized, and 1 had died.ConclusionsLeronlimab appeared safe and well tolerated. The high recovery rate suggested benefit, and those with lower inflammatory markers had better outcomes. Some, but not all, patients appeared to have dramatic clinical responses, indicating that unknown factors may determine responsiveness to leronlimab. Routine inflammatory and cell prognostic markers did not markedly change immediately after treatment, although interleukin-6 tended to fall. In some persons, C-reactive protein clearly dropped only after the second leronlimab dose, suggesting that a higher loading dose might be more effective. Future controlled trials will be informative.
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- 2021
5. Improving rigor and reproducibility in nonhuman primate research.
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Bliss-Moreau, Eliza, Amara, Rama R, Buffalo, Elizabeth A, Colman, Ricki J, Embers, Monica E, Morrison, John H, Quillen, Ellen E, Sacha, Jonah B, Roberts, Charles T, and National Primate Research Center Consortium Rigor and Reproducibility Working Group
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National Primate Research Center Consortium Rigor and Reproducibility Working Group ,Animals ,Primates ,Disease Models ,Animal ,Reproducibility of Results ,Biomedical Research ,biomedical research ,data sharing ,nonhuman primates ,preregistration ,quality assurance ,Infectious Diseases ,Good Health and Well Being ,Zoology ,Anthropology ,Behavioral Science & Comparative Psychology - Abstract
Nonhuman primates (NHPs) are a critical component of translational/preclinical biomedical research due to the strong similarities between NHP and human physiology and disease pathology. In some cases, NHPs represent the most appropriate, or even the only, animal model for complex metabolic, neurological, and infectious diseases. The increased demand for and limited availability of these valuable research subjects requires that rigor and reproducibility be a prime consideration to ensure the maximal utility of this scarce resource. Here, we discuss a number of approaches that collectively can contribute to enhanced rigor and reproducibility in NHP research.
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- 2021
6. Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques
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Wu, Helen L., Busman-Sahay, Kathleen, Weber, Whitney C., Waytashek, Courtney M., Boyle, Carla D., Bateman, Katherine B., Reed, Jason S., Hwang, Joseph M., Shriver-Munsch, Christine, Swanson, Tonya, Northrup, Mina, Armantrout, Kimberly, Price, Heidi, Robertson-LeVay, Mitch, Uttke, Samantha, Kumar, Mithra R., Fray, Emily J., Taylor-Brill, Sol, Bondoc, Stephen, Agnor, Rebecca, Junell, Stephanie L., Legasse, Alfred W., Moats, Cassandra, Bochart, Rachele M., Sciurba, Joseph, Bimber, Benjamin N., Sullivan, Michelle N., Dozier, Brandy, MacAllister, Rhonda P., Hobbs, Theodore R., Martin, Lauren D., Panoskaltsis-Mortari, Angela, Colgin, Lois M.A., Siliciano, Robert F., Siliciano, Janet D., Estes, Jacob D., Smedley, Jeremy V., Axthelm, Michael K., Meyers, Gabrielle, Maziarz, Richard T., Burwitz, Benjamin J., Stanton, Jeffrey J., and Sacha, Jonah B.
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- 2023
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7. Clinical Characteristics and Outcomes of COVID-19 Patients Receiving Compassionate Use Leronlimab.
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Yang, Bryant, Fulcher, Jennifer A, Ahn, Jenny, Berro, Marlene, Goodman-Meza, David, Dhody, Kush, Sacha, Jonah B, Naeim, Arash, and Yang, Otto O
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COVID-19 ,SARS-CoV-2 ,immunomodulatory therapy ,leronlimab ,Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Inflammatory and immune system ,Microbiology ,Biological Sciences ,Medical and Health Sciences - Abstract
BackgroundLeronlimab, a monoclonal antibody blocker of CCR5 originally developed to treat HIV-1 infection, was administered as an open label compassionate use therapeutic for COVID-19.Methods23 hospitalized severe/critical COVID-19 patients received 700mg leronlimab subcutaneously, repeated after seven days in 17/23 patients still hospitalized. 18/23 received other experimental treatments, including convalescent plasma, hydroxychloroquine, steroids, and/or tocilizumab. 5/23 received leronlimab after blinded placebo-controlled trials of remdesivir, sarilumab, selinexor, or tocilizumab. Outcomes and results were extracted from medical records.ResultsMean age was 69.5±14.9 years. 20/23 had significant co-morbidities. At baseline, 22/23 were receiving supplemental oxygen (3/23 high flow, 7/23 mechanical ventilation). Blood showed markedly elevated inflammatory markers (ferritin, D-dimer, C-reactive protein) and elevated neutrophil:lymphocyte ratio. By day 30 after initial dosing, 17/23 were recovered, 2/23 were still hospitalized, and 4/23 had died. Of the 7 intubated at baseline, 4/7 were fully recovered off oxygen, 2/7 were still hospitalized, and 1/7 had died.ConclusionsLeronlimab appeared safe and well tolerated. The high recovery rate suggested benefit, and those with lower inflammatory markers had better outcomes. Some but not all patients appeared to have dramatic clinical responses, indicating that unknown factors may determine responsiveness to leronlimab. Routine inflammatory and cell prognostic markers did not markedly change immediately after treatment, although IL-6 tended to fall. In some persons C-reactive protein clearly dropped only after the second leronlimab dose, suggesting that a higher loading dose might be more effective. Future controlled trials will be informative.
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- 2020
8. Immune restoration by TIGIT blockade is insufficient to control chronic SIV infection
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Webb, Gabriela M., primary, Pessoa, Cleiton T., additional, McCullen, Allyson J., additional, Hwang, Joseph M., additional, Humkey, Matthew C., additional, Thormin-Odum, Raymond, additional, Kukula, Kaitlyn A., additional, Smedley, Jeremy, additional, Fischer, Miranda, additional, Sciurba, Joseph, additional, Bochart, Rachele M., additional, Shriver-Munsch, Christine, additional, Ndhlovu, Lishomwa C., additional, and Sacha, Jonah B., additional
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- 2024
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9. Long-term hepatitis B virus infection of rhesus macaques requires suppression of host immunity
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Biswas, Sreya, Rust, Lauren N., Wettengel, Jochen M., Yusova, Sofiya, Fischer, Miranda, Carson, Julien N., Johnson, Josie, Wei, Lei, Thode, Trason, Kaadige, Mohan R., Sharma, Sunil, Agbaria, Majd, Bimber, Benjamin N., Tu, Thomas, Protzer, Ulrike, Ploss, Alexander, Smedley, Jeremy V., Golomb, Gershon, Sacha, Jonah B., and Burwitz, Benjamin J.
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- 2022
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10. Viral escape mutations do not account for non-protection from SIVmac239 challenge in RhCMV/SIV vaccinated rhesus macaques.
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Bimber, Benjamin N., Sunshine, Justine, McElfresh, G. W., Reed, Jason S., Pathak, Reese, Bateman, Katherine B., Hughes, Colette M., Gilbride, Roxanne M., Ford, Julia C., Morrow, David, Lifson, Jeffrey D., Sacha, Jonah B., Hansen, Scott G., and Picker, Louis J.
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VIRAL mutation ,SIMIAN immunodeficiency virus ,RHESUS monkeys ,VACCINATION status ,T cells - Abstract
Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Combination Adenovirus and Protein Vaccines Prevent Infection or Reduce Viral Burden after Heterologous Clade C Simian-Human Immunodeficiency Virus Mucosal Challenge
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Malherbe, Delphine C, Mendy, Jason, Vang, Lo, Barnette, Philip T, Reed, Jason, Lakhashe, Samir K, Owuor, Joshua, Gach, Johannes S, Legasse, Alfred W, Axthelm, Michael K, LaBranche, Celia C, Montefiori, David, Forthal, Donald N, Park, Byung, Wilson, James M, McLinden, James H, Xiang, Jinhua, Stapleton, Jack T, Sacha, Jonah B, Haynes, Barton F, Liao, Hua-Xin, Ruprecht, Ruth M, Smith, Jonathan, Gurwith, Marc, Haigwood, Nancy L, and Alexander, Jeff
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Vaccine Related ,Prevention ,HIV/AIDS ,Infectious Diseases ,Immunization ,Vaccine Related (AIDS) ,Biotechnology ,3.4 Vaccines ,Prevention of disease and conditions ,and promotion of well-being ,Infection ,Good Health and Well Being ,Adenoviridae ,Animals ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Antibody Specificity ,CD4 Lymphocyte Count ,Cell Line ,Genetic Vectors ,Genotype ,HIV ,Humans ,Immunity ,Humoral ,Kaplan-Meier Estimate ,Macaca mulatta ,Male ,Protein Binding ,SAIDS Vaccines ,Simian Acquired Immunodeficiency Syndrome ,Simian Immunodeficiency Virus ,T-Lymphocytes ,Vaccines ,Synthetic ,Viral Envelope Proteins ,Viral Load ,HIV vaccine ,adenovirus vector ,V1V2-specific antibody ,SHIV challenge ,correlate of protection ,rhesus macaque ,simian human immunodeficiency virus ,adenovirus ,neutralizing antibody ,vaccine ,Simian immunodeficiency virus ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology - Abstract
HIV vaccine development is focused on designing immunogens and delivery methods that elicit protective immunity. We evaluated a combination of adenovirus (Ad) vectors expressing HIV 1086.C (clade C) envelope glycoprotein (Env), SIV Gag p55, and human pegivirus GBV-C E2 glycoprotein. We compared replicating simian (SAd7) with nonreplicating human (Ad4) adenovirus-vectored vaccines paired with recombinant proteins in a novel prime-boost regimen in rhesus macaques, with the goal of eliciting protective immunity against SHIV challenge. In both vaccine groups, plasma and buccal Env-specific IgG, tier 1 heterologous neutralizing antibodies, and antibody-dependent cell-mediated viral inhibition were readily generated. High Env-specific T cell responses elicited in all vaccinees were significantly greater than responses targeting Gag. After three intrarectal exposures to heterologous tier 1 clade C SHIV, all 10 sham-vaccinated controls were infected, whereas 4/10 SAd7- and 3/10 Ad4-vaccinated macaques remained uninfected or maintained tightly controlled plasma viremia. Time to infection was significantly delayed in SAd7-vaccinated macaques compared to the controls. Cell-associated and plasma virus levels were significantly lower in each group of vaccinated macaques compared to controls; the lowest plasma viral burden was found in animals vaccinated with the SAd7 vectors, suggesting superior immunity conferred by the replicating simian vectors. Furthermore, higher V1V2-specific binding antibody titers correlated with viral control in the SAd7 vaccine group. Thus, recombinant Ad plus protein vaccines generated humoral and cellular immunity that was effective in either protecting from SHIV acquisition or significantly reducing viremia in animals that became infected, consequently supporting additional development of replicating Ad vectors as HIV vaccines.IMPORTANCE There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV infection and limits in vivo viral replication and associated pathogenesis. Although replicating virus vectors have been advanced as HIV vaccine platforms, there have not been any direct comparisons of the replicating to the nonreplicating format. The present study directly compared the replicating SAd7 to nonreplicating Ad4 vectors in macaques and demonstrated that in the SAd7 vaccine group, the time to infection was significantly delayed compared to the control group, and V1V2 Env-specific binding antibodies correlated with viral outcomes. Viral control was significantly enhanced in vaccinated macaques compared to controls, and in infected SAd7-vaccinated macaques compared to Ad4-vaccinated macaques, suggesting that this vector may have conferred more effective immunity. Because blocking infection is so difficult with current vaccines, development of a vaccine that can limit viremia if infection occurs would be valuable. These data support further development of replicating adenovirus vectors.
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- 2018
12. Anti-HERV-K (HML-2) capsid antibody responses in HIV elite controllers
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de Mulder, Miguel, SenGupta, Devi, Deeks, Steven G, Martin, Jeffrey N, Pilcher, Christopher D, Hecht, Frederick M, Sacha, Jonah B, Nixon, Douglas F, and Michaud, Henri-Alexandre
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Microbiology ,Biological Sciences ,Clinical Research ,Biotechnology ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,Infection ,Good Health and Well Being ,Capsid Proteins ,Cells ,Cultured ,Endogenous Retroviruses ,Epitopes ,Gene Products ,gag ,HIV Antibodies ,HIV Infections ,HIV-1 ,Humans ,Peptide Fragments ,Recombinant Proteins ,Viral Proteins ,HIV ,HERV-K ,Antibodies ,Gag ,Elite Controllers ,Viremic non-controllers ,Clinical Sciences ,Virology - Abstract
BackgroundHuman endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and while the majority are transcriptionally silent, the most recently integrated HERV, HERV-K (HML-2), remains active. During HIV infection, HERV-K (HML-2) specific mRNA transcripts and viral proteins can be detected. In this study, we aimed to understand the antibody response against HERV-K (HML-2) Gag in the context of HIV-1 infection.ResultsWe developed an ELISA assay using either recombinant protein or 164 redundant "15mer" HERV-K (HML-2) Gag peptides to test sera for antibody reactivity. We identified a total of eight potential HERV-K (HML-2) Gag immunogenic domains: two on the matrix (peptides 16 and 31), one on p15 (peptide 85), three on the capsid (peptides 81, 97 and 117), one on the nucleocapsid (peptide 137) and one on the QP1 protein (peptide 157). Four epitopes (peptides 16, 31, 85 and 137) were highly immunogenic. No significant differences in antibody responses were found between HIV infected participants (n = 40) and uninfected donors (n = 40) for 6 out of the 8 epitopes tested. The antibody response against nucleocapsid (peptide 137) was significantly lower (p
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- 2017
13. CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14
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Patterson, Bruce K., Seethamraju, Harish, Dhody, Kush, Corley, Michael J., Kazempour, Kazem, Lalezari, Jay, Pang, Alina P.S., Sugai, Christopher, Mahyari, Eisa, Francisco, Edgar B., Pise, Amruta, Rodrigues, Hallison, Wu, Helen L., Webb, Gabriela M., Park, Byung S., Kelly, Scott, Pourhassan, Nader, Lelic, Alina, Kdouh, Lama, Herrera, Monica, Hall, Eric, Bimber, Benjamin N., Plassmeyer, Matthew, Gupta, Raavi, Alpan, Oral, O’Halloran, Jane A., Mudd, Philip A., Akalin, Enver, Ndhlovu, Lishomwa C., and Sacha, Jonah B.
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- 2021
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14. Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.
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Abdel-Mohsen, Mohamed, Chavez, Leonard, Tandon, Ravi, Chew, Glen M, Deng, Xutao, Danesh, Ali, Keating, Sheila, Lanteri, Marion, Samuels, Michael L, Hoh, Rebecca, Sacha, Jonah B, Norris, Philip J, Niki, Toshiro, Shikuma, Cecilia M, Hirashima, Mitsuomi, Deeks, Steven G, Ndhlovu, Lishomwa C, and Pillai, Satish K
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CD4-Positive T-Lymphocytes ,Humans ,HIV-1 ,HIV Infections ,Galectins ,Anti-HIV Agents ,Blotting ,Western ,Enzyme-Linked Immunosorbent Assay ,Flow Cytometry ,Gene Expression Profiling ,Polymerase Chain Reaction ,Virus Latency ,Virus Activation ,Transcription ,Genetic ,Transcriptome ,Blotting ,Western ,Transcription ,Genetic ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p
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- 2016
15. TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.
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Chew, Glen M, Fujita, Tsuyoshi, Webb, Gabriela M, Burwitz, Benjamin J, Wu, Helen L, Reed, Jason S, Hammond, Katherine B, Clayton, Kiera L, Ishii, Naoto, Abdel-Mohsen, Mohamed, Liegler, Teri, Mitchell, Brooks I, Hecht, Frederick M, Ostrowski, Mario, Shikuma, Cecilia M, Hansen, Scott G, Maurer, Mark, Korman, Alan J, Deeks, Steven G, Sacha, Jonah B, and Ndhlovu, Lishomwa C
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CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Animals ,Macaca mulatta ,Humans ,HIV Infections ,Simian Acquired Immunodeficiency Syndrome ,Disease Progression ,Receptors ,Immunologic ,DNA ,Viral ,RNA ,Viral ,Flow Cytometry ,Cell Separation ,Lymphocyte Activation ,B7-H1 Antigen ,Receptors ,Immunologic ,DNA ,Viral ,RNA ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.
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- 2016
16. Vector-Mediated Delivery of Human Major Histocompatibility Complex-I into Hepatocytes Enables Investigation of T Cell Receptor-Redirected Hepatitis B Virus-Specific T Cells in Mice, and in Macaque Cell Cultures
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Festag, Julia, primary, Festag, Marvin M., additional, Asen, Theresa, additional, Wettengel, Jochen M., additional, Mück-Häusl, Martin A., additional, Abdulhaqq, Shaheed, additional, Stahl-Hennig, Christiane, additional, Sacha, Jonah B., additional, Burwitz, Benjamin J., additional, Protzer, Ulrike, additional, and Wisskirchen, Karin, additional
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- 2023
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17. Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission
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Chang, Xiao L., Webb, Gabriela M., Wu, Helen L., Greene, Justin M., Abdulhaqq, Shaheed, Bateman, Katherine B., Reed, Jason S., Pessoa, Cleiton, Weber, Whitney C., Maier, Nicholas, Chew, Glen M., Gilbride, Roxanne M., Gao, Lina, Agnor, Rebecca, Giobbi, Travis, Torgerson, Jeffrey, Siess, Don, Burnett, Nicole, Fischer, Miranda, Shiel, Oriene, Moats, Cassandra, Patterson, Bruce, Dhody, Kush, Kelly, Scott, Pourhassan, Nader, Magnani, Diogo M., Smedley, Jeremy, Bimber, Benjamin N., Haigwood, Nancy L., Hansen, Scott G., Brown, Timothy R., Ndhlovu, Lishomwa C., and Sacha, Jonah B.
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- 2021
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18. Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection
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Michaud, Henri-Alexandre, de Mulder, Miguel, SenGupta, Devi, Deeks, Steven G, Martin, Jeffrey N, Pilcher, Christopher D, Hecht, Frederick M, Sacha, Jonah B, and Nixon, Douglas F
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Microbiology ,Biological Sciences ,HIV/AIDS ,Clinical Research ,Infectious Diseases ,Sexually Transmitted Infections ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Adult ,Antibodies ,Viral ,Endogenous Retroviruses ,Female ,Gene Expression ,HIV Infections ,Humans ,Male ,Protein Processing ,Post-Translational ,Viral Envelope Proteins ,Virus Activation ,HIV ,Antibody ,HERV ,Endogenous retroviruses ,Transmembrane ,Envelope ,Elite controllers ,Alternative transcripts ,Clinical Sciences ,Virology - Abstract
BackgroundHuman Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load.ResultsWe found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p
- Published
- 2014
19. Expansion of Dysfunctional Tim-3–Expressing Effector Memory CD8+ T Cells during Simian Immunodeficiency Virus Infection in Rhesus Macaques
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Fujita, Tsuyoshi, Burwitz, Benjamin J, Chew, Glen M, Reed, Jason S, Pathak, Reesab, Seger, Elizabeth, Clayton, Kiera L, Rini, James M, Ostrowski, Mario A, Ishii, Naoto, Kuroda, Marcelo J, Hansen, Scott G, Sacha, Jonah B, and Ndhlovu, Lishomwa C
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,Sexually Transmitted Infections ,Immunotherapy ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Acquired Immunodeficiency Syndrome ,Amino Acid Sequence ,Animals ,CD8-Positive T-Lymphocytes ,Cell Proliferation ,Cells ,Cultured ,Cytotoxicity ,Immunologic ,Disease Models ,Animal ,Gene Expression Regulation ,Hepatitis A Virus Cellular Receptor 2 ,Humans ,Immunologic Memory ,Macaca mulatta ,Membrane Proteins ,Molecular Sequence Data ,Molecular Targeted Therapy ,Programmed Cell Death 1 Receptor ,Simian Acquired Immunodeficiency Syndrome ,Simian Immunodeficiency Virus ,Viral Load ,Virus Replication ,Simian immunodeficiency virus ,Biochemistry and cell biology - Abstract
The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses.
- Published
- 2014
20. Cutting Edge: An Antibody Recognizing Ancestral Endogenous Virus Glycoproteins Mediates Antibody-Dependent Cellular Cytotoxicity on HIV-1–Infected Cells
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Michaud, Henri-Alexandre, SenGupta, Devi, de Mulder, Miguel, Deeks, Steven G, Martin, Jeffrey N, Kobie, James J, Sacha, Jonah B, and Nixon, Douglas F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Immunization ,Prevention ,HIV/AIDS ,Infectious Diseases ,Biotechnology ,Vaccine Related ,Sexually Transmitted Infections ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Antibodies ,Antibody-Dependent Cell Cytotoxicity ,Endogenous Retroviruses ,HIV Infections ,HIV-1 ,Humans ,Immune Evasion ,RNA ,Viral ,gag Gene Products ,Human Immunodeficiency Virus ,Biochemistry and cell biology - Abstract
The failure of antiviral vaccines is often associated with rapid viral escape from specific immune responses. In the past, conserved epitope or algorithmic epitope selections, such as mosaic vaccines, have been designed to diversify immunity and to circumvent potential viral escape. An alternative approach is to identify conserved stable non-HIV-1 self-epitopes present exclusively in HIV-1-infected cells. We showed previously that human endogenous retroviral (HERV) mRNA transcripts and protein are found in cells of HIV-1-infected patients and that HERV-K (HML-2)-specific T cells can eliminate HIV-1-infected cells in vitro. In this article, we demonstrate that a human anti-HERV-K (HML-2) transmembrane protein Ab binds specifically to HIV-1-infected cells and eliminates them through an Ab-dependent cellular cytotoxicity mechanism in vitro. Thus, Abs directed against epitopes other than HIV-1 proteins may have a role in eliminating HIV-1-infected cells and could be targeted in novel vaccine approaches or immunotherapeutic modalities.
- Published
- 2014
21. Neutralizing Polyclonal IgG Present during Acute Infection Prevents Rapid Disease Onset in Simian-Human Immunodeficiency Virus SHIVSF162P3-Infected Infant Rhesus Macaques
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Jaworski, J. Pablo, Kobie, James, Brower, Zachary, Malherbe, Delphine C., Landucci, Gary, Sutton, William F., Guo, Biwei, Reed, Jason S., Leon, Enrique J., Engelmann, Flora, Zheng, Bo, Legasse, Al, Park, Byung, Dickerson, Mary, Lewis, Anne D., Colgin, Lois A., Axthelm, Michael, Messaoudi, Ilhem, Sacha, Jonah B., Burton, Dennis R., Forthal, Donald N., Hessell, Ann J., and Haigwood, Nancy L.
- Abstract
Simian-human immunodeficiency virus (SHIV) models for human immunodeficiency virus (HIV) infection have been widely used in passive studies with HIV neutralizing antibodies (NAbs) to test for protection against infection. However, because SHIV-infected adult macaques often rapidly control plasma viremia and any resulting pathogenesis is minor, the model has been unsuitable for studying the impact of antibodies on pathogenesis in infected animals. We found that SHIVSF162P3 infection in 1-month-old rhesus macaques not only results in high persistent plasma viremia but also leads to very rapid disease progression within 12 to 16 weeks. In this model, passive transfer of high doses of neutralizing IgG (SHIVIG) prevents infection. Here, we show that at lower doses, SHIVIG reduces both plasma and peripheral blood mononuclear cell (PBMC)-associated viremia and mitigates pathogenesis in infected animals. Moreover, production of endogenous NAbs correlated with lower set-point viremia and 100% survival of infected animals. New SHIV models are needed to investigate whether passively transferred antibodies or antibodies elicited by vaccination that fall short of providing sterilizing immunity impact disease progression or influence immune responses. The 1-month-old rhesus macaque SHIV model of infection provides a new tool to investigate the effects of antibodies on viral replication and clearance, mechanisms of B cell maintenance, and the induction of adaptive immunity in disease progression.
- Published
- 2013
22. T Cells Target APOBEC3 Proteins in Human Immunodeficiency Virus Type 1-Infected Humans and Simian Immunodeficiency Virus-Infected Indian Rhesus Macaques
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Champiat, Stéphane, Garrison, Keith E, Raposo, Rui André Saraiva, Burwitz, Benjamin J, Reed, Jason, Tandon, Ravi, York, Vanessa A, Newman, Laura P, Nimityongskul, Francesca A, Wilson, Nancy A, Almeida, Rafael R, Martin, Jeffrey N, Deeks, Steven G, Rosenberg, Michael G, Wiznia, Andrew A, Spotts, Gerald E, Pilcher, Christopher D, Hecht, Fredrick M, Ostrowski, Mario A, Sacha, Jonah B, and Nixon, Douglas F
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Infectious Diseases ,HIV/AIDS ,Infection ,Good Health and Well Being ,APOBEC-3G Deaminase ,Adult ,Animals ,CD8-Positive T-Lymphocytes ,Cytidine Deaminase ,Cytosine Deaminase ,Female ,Gene Products ,vif ,HIV Infections ,HIV-1 ,Humans ,Macaca mulatta ,Male ,Simian Acquired Immunodeficiency Syndrome ,Simian Immunodeficiency Virus ,Simian immunodeficiency virus ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
APOBEC3 proteins mediate potent antiretroviral activity by hypermutating the retroviral genome during reverse transcription. To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation. However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surfaces of lentivirus-infected cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that these T cell responses may be part of the larger antiretroviral immune response.
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- 2013
23. Data from Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models
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Rhode, Peter R., primary, Egan, Jack O., primary, Xu, Wenxin, primary, Hong, Hao, primary, Webb, Gabriela M., primary, Chen, Xiaoyue, primary, Liu, Bai, primary, Zhu, Xiaoyun, primary, Wen, Jinghai, primary, You, Lijing, primary, Kong, Lin, primary, Edwards, Ana C., primary, Han, Kaiping, primary, Shi, Sixiang, primary, Alter, Sarah, primary, Sacha, Jonah B., primary, Jeng, Emily K., primary, Cai, Weibo, primary, and Wong, Hing C., primary
- Published
- 2023
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24. Supplementary methods, Supplementary tables 1 through 4, and Supplementary figure 1 from Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models
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Rhode, Peter R., primary, Egan, Jack O., primary, Xu, Wenxin, primary, Hong, Hao, primary, Webb, Gabriela M., primary, Chen, Xiaoyue, primary, Liu, Bai, primary, Zhu, Xiaoyun, primary, Wen, Jinghai, primary, You, Lijing, primary, Kong, Lin, primary, Edwards, Ana C., primary, Han, Kaiping, primary, Shi, Sixiang, primary, Alter, Sarah, primary, Sacha, Jonah B., primary, Jeng, Emily K., primary, Cai, Weibo, primary, and Wong, Hing C., primary
- Published
- 2023
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25. Single-dose bNAb cocktail or abbreviated ART post-exposure regimens achieve tight SHIV control without adaptive immunity
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Shapiro, Mariya B., Cheever, Tracy, Malherbe, Delphine C., Pandey, Shilpi, Reed, Jason, Yang, Eun Sung, Wang, Keyun, Pegu, Amarendra, Chen, Xuejun, Siess, Don, Burke, David, Henderson, Heidi, Lewinsohn, Rebecca, Fischer, Miranda, Stanton, Jeffrey J., Axthelm, Michael K., Kahl, Christoph, Park, Byung, Lewis, Anne D., Sacha, Jonah B., Mascola, John R., Hessell, Ann J., and Haigwood, Nancy L.
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- 2020
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26. Therapeutic neutralizing monoclonal antibody administration protects against lethal yellow fever virus infection
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Ricciardi, Michael J., primary, Rust, Lauren N., additional, Pedreño-Lopez, Nuria, additional, Yusova, Sofiya, additional, Biswas, Sreya, additional, Webb, Gabriela M., additional, Gonzalez-Nieto, Lucas, additional, Voigt, Thomas B., additional, Louw, Johan J., additional, Laurino, Fernanda D., additional, DiBello, John R., additional, Raué, Hans-Peter, additional, Barber-Axthelm, Aaron M., additional, Chun, Kimberly, additional, Uttke, Samantha, additional, Raphael, Lidiane M. S., additional, Yrizarry-Medina, Aaron, additional, Rosen, Brandon C., additional, Agnor, Rebecca, additional, Gao, Lina, additional, Labriola, Caralyn, additional, Axthelm, Michael, additional, Smedley, Jeremy, additional, Julander, Justin G., additional, Bonaldo, Myrna C., additional, Walker, Laura M., additional, Messaoudi, Ilhem, additional, Slifka, Mark K., additional, Burton, Dennis R., additional, Kallas, Esper G., additional, Sacha, Jonah B., additional, Watkins, David I., additional, and Burwitz, Benjamin J., additional
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- 2023
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27. Broadly targeted CD8⁺ T cell responses restricted by major histocompatibility complex E
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Hansen, Scott G., Wu, Helen L., Burwitz, Benjamin J., Hughes, Colette M., Hammond, Katherine B., Ventura, Abigail B., Reed, Jason S., Gilbride, Roxanne M., Ainslie, Emily, Morrow, David W., Ford, Julia C., Selseth, Andrea N., Pathak, Reesab, Malouli, Daniel, Legasse, Alfred W., Axthelm, Michael K., Nelson, Jay A., Gillespie, Geraldine M., Walters, Lucy C., Brackenridge, Simon, Sharpe, Hannah R., López, César A., Früh, Klaus, Korber, Bette T., McMichael, Andrew J., Gnanakaran, S., Sacha, Jonah B., and Picker, Louis J.
- Published
- 2016
28. Author Correction: Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding
- Author
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Walters, Lucy C., Harlos, Karl, Brackenridge, Simon, Rozbesky, Daniel, Barrett, Jordan R., Jain, Vitul, Walter, Thomas S., O’Callaghan, Chris A., Borrow, Persephone, Toebes, Mireille, Hansen, Scott G., Sacha, Jonah B., Abdulhaqq, Shaheed, Greene, Justin M., Früh, Klaus, Marshall, Emily, Picker, Louis J., Jones, E. Yvonne, McMichael, Andrew J., and Gillespie, Geraldine M.
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- 2018
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29. OP 2.1 CCR5 in HIV Prevention and Cure
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Wu, Helen L., primary, Webb, Gabriela M., additional, and Sacha, Jonah B., additional
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- 2022
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30. Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species
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Malouli, Daniel, primary, Gilbride, Roxanne M., additional, Wu, Helen L., additional, Hwang, Joseph M., additional, Maier, Nicholas, additional, Hughes, Colette M., additional, Newhouse, Daniel, additional, Morrow, David, additional, Ventura, Abigail B., additional, Law, Lynn, additional, Tisoncik-Go, Jennifer, additional, Whitmore, Leanne, additional, Smith, Elise, additional, Golez, Inah, additional, Chang, Jean, additional, Reed, Jason S., additional, Waytashek, Courtney, additional, Weber, Whitney, additional, Taher, Husam, additional, Uebelhoer, Luke S., additional, Womack, Jennie L., additional, McArdle, Matthew R., additional, Gao, Junwei, additional, Papen, Courtney R., additional, Lifson, Jeffrey D., additional, Burwitz, Benjamin J., additional, Axthelm, Michael K., additional, Smedley, Jeremy, additional, Früh, Klaus, additional, Gale, Michael, additional, Picker, Louis J., additional, Hansen, Scott G., additional, and Sacha, Jonah B., additional
- Published
- 2022
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31. Pandemic 1918 Influenza Virus Does Not Cause Lethal Infection in Rhesus or Cynomolgus Macaques
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Chan, Mable, primary, Tiwary, Meenakshi, additional, Wu, Helen L., additional, Tailor, Nikesh, additional, Vendramelli, Robert, additional, Audet, Jonathan, additional, Warner, Bryce M., additional, Tierney, Kevin, additional, Albietz, Alix, additional, Truong, Thang, additional, Doan, Kaylie, additional, Bello, Alexander, additional, Willman, Marnie, additional, Griffin, Bryan D., additional, Hanley, Patrick W., additional, Lovaglio, Jamie, additional, Safronetz, David, additional, Strong, Jim, additional, Sacha, Jonah B., additional, and Kobasa, Darwyn, additional
- Published
- 2022
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32. Optimization and use of near infrared imaging to guide lymph node collection in rhesus macaques ( Macaca mulatta )
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Smedley, Jeremy V., primary, Bochart, Rachele M., additional, Fischer, Miranda, additional, Funderburgh, Heidi, additional, Kelly, Vanessa, additional, Crank, Hugh, additional, Armantrout, Kim, additional, Shiel, Oriene, additional, Robertson‐LeVay, Mitchell, additional, Sternberger, Nikki, additional, Schmaling, Brian, additional, Roberts, Sheila, additional, Sekiguchi, Vicki, additional, Reusz, Michael, additional, Schwartz, Tiah, additional, Meyer, Kimberly A., additional, Webb, Gabriela, additional, Gilbride, Roxanne M., additional, Dambrauskas, Nicholas, additional, Andrade, Daniela, additional, Wood, Matthew, additional, Labriola, Caralyn, additional, Axthelm, Michael, additional, Derby, Nina, additional, Varco‐Merth, Ben, additional, Fukazawa, Yoshinori, additional, Hansen, Scott, additional, Sacha, Jonah B., additional, Sodora, Donald L., additional, and Sather, D. Noah, additional
- Published
- 2022
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33. Reply to Viel
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Recknor, Christopher, primary, Hansen, Scott G, additional, Gaylis, Norman B., additional, Tiwary, Meenakshi, additional, Sacha, Jonah B., additional, and Yang, Otto O, additional
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- 2022
- Full Text
- View/download PDF
34. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding
- Author
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Walters, Lucy C., Harlos, Karl, Brackenridge, Simon, Rozbesky, Daniel, Barrett, Jordan R., Jain, Vitul, Walter, Thomas S., O’Callaghan, Chris A., Borrow, Persephone, Toebes, Mireille, Hansen, Scott G., Sacha, Jonah B, Abdulhaqq, Shaheed, Greene, Justin M., Früh, Klaus, Marshall, Emily, Picker, Louis J., Jones, E. Yvonne, McMichael, Andrew J., and Gillespie, Geraldine M.
- Published
- 2018
- Full Text
- View/download PDF
35. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques
- Author
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Hessell, Ann J., Jaworski, J. Pablo, Epson, Erin, Matsuda, Kenta, Pandey, Shilpi, Kahl, Christoph, Reed, Jason, Sutton, William F., Hammond, Katherine B., Cheever, Tracy A., Barnette, Philip T., Legasse, Alfred W., Planer, Shannon, Stanton, Jeffrey J., Pegu, Amarendra, Chen, Xuejun, Wang, Keyun, Siess, Don, Burke, David, Park, Byung S., Axthelm, Michael K., Lewis, Anne, Hirsch, Vanessa M., Graham, Barney S., Mascola, John R., Sacha, Jonah B., and Haigwood, Nancy L.
- Subjects
Maternal-fetal exchange -- Health aspects ,Monoclonal antibodies -- Usage ,HIV infection -- Prevention ,Biological sciences ,Health - Abstract
Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1-specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus [SHIV.sub.SF162P3]. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after [CD8.sup.+] T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs., Recent advances in the discovery of human HIV NmAbs that have high potency and breadth of coverage have rekindled an interest in their use as pre-exposure prophylaxis, as well as [...]
- Published
- 2016
- Full Text
- View/download PDF
36. Therapeutic neutralizing monoclonal antibody administration protects against lethal viscerotropic Yellow Fever infection
- Author
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Ricciardi, Michael J., primary, Rust, Lauren N., additional, Pedreño-Lopez, Nuria, additional, Yusova, Sofiya, additional, Biswas, Sreya, additional, Webb, Gabriela M., additional, Fischer, Miranda, additional, Gonsales-Nieto, Lucas, additional, Voigt, Thomas B., additional, Louw, Johan J., additional, Laurino, Fernanda D., additional, DiBello, John R., additional, Raué, Hans-Peter, additional, Raphael, Lidiane M.S., additional, Yrizarry-Medina, Aaron, additional, Rosen, Brandon C., additional, Agnor, Rebecca, additional, Gao, Lina, additional, Labriola, Caralyn, additional, Axthelm, Michael, additional, Smedley, Jeremy, additional, Julander, Justin G., additional, Bonaldo, Myrna C., additional, Walker, Laura M., additional, Slifka, Mark K., additional, Messaoudi, Ilhem, additional, Burton, Dennis R., additional, Kallas, Esper G., additional, Sacha, Jonah B., additional, Watkins, David I., additional, and Burwitz, Benjamin J., additional
- Published
- 2022
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37. Cytomegalovirus Vectors Violate CD8⁺ T Cell Epitope Recognition Paradigms
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Hansen, Scott G., Sacha, Jonah B., Hughes, Colette M., Ford, Julia C., Burwitz, Benjamin J., Scholz, Isabel, Gilbride, Roxanne M., Lewis, Matthew S., Gilliam, Awbrey N., Ventura, Abigail B., Malouli, Daniel, Xu, Guangwu, Richards, Rebecca, Whizin, Nathan, Reed, Jason S., Hammond, Katherine B., Fischer, Miranda, Turner, John M., Legasse, Alfred W., Axthelm, Michael K., Edlefsen, Paul T., Nelson, Jay A., Lifson, Jeffrey D., Früh, Klaus, and Picker, Louis J.
- Published
- 2013
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38. Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species
- Author
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Chang, Xiao L., primary, Reed, Jason S., additional, Webb, Gabriela M., additional, Wu, Helen L., additional, Le, Jimmy, additional, Bateman, Katherine B., additional, Greene, Justin M., additional, Pessoa, Cleiton, additional, Waytashek, Courtney, additional, Weber, Whitney C., additional, Hwang, Joseph, additional, Fischer, Miranda, additional, Moats, Cassandra, additional, Shiel, Oriene, additional, Bochart, Rachele M., additional, Crank, Hugh, additional, Siess, Don, additional, Giobbi, Travis, additional, Torgerson, Jeffrey, additional, Agnor, Rebecca, additional, Gao, Lina, additional, Dhody, Kush, additional, Lalezari, Jacob P., additional, Bandar, Ivo Sah, additional, Carnate, Alnor M., additional, Pang, Alina S., additional, Corley, Michael J., additional, Kelly, Scott, additional, Pourhassan, Nader, additional, Smedley, Jeremy, additional, Bimber, Benjamin N., additional, Hansen, Scott G., additional, Ndhlovu, Lishomwa C., additional, and Sacha, Jonah B., additional
- Published
- 2022
- Full Text
- View/download PDF
39. Gag- and Nef-Specific CD4⁺ T Cells Recognize and Inhibit SIV Replication in Infected Macrophages Early after Infection
- Author
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Sacha, Jonah B., Giraldo-Vela, Juan P., Buechler, Matthew B., Martins, Mauricio A., Maness, Nicholas J., Chung, Chungwon, Wallace, Lyle T., León, Enrique J., Friedrich, Thomas C., Wilson, Nancy A., Hiraoka, Atsunobu, Watkins, David I., and Franchini, Genoveffa
- Published
- 2009
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40. CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab
- Author
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Chang, Xiao L., primary, Wu, Helen L., additional, Webb, Gabriela M., additional, Tiwary, Meenakshi, additional, Hughes, Colette, additional, Reed, Jason S., additional, Hwang, Joseph, additional, Waytashek, Courtney, additional, Boyle, Carla, additional, Pessoa, Cleiton, additional, Sylwester, Andrew W., additional, Morrow, David, additional, Belica, Karina, additional, Fischer, Miranda, additional, Kelly, Scott, additional, Pourhassan, Nader, additional, Bochart, Rachele M., additional, Smedley, Jeremy, additional, Recknor, Christopher P., additional, Hansen, Scott G., additional, and Sacha, Jonah B., additional
- Published
- 2021
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- View/download PDF
41. IMMUNOLOGY: Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E
- Author
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Hansen, Scott G., Wu, Helen L., Burwitz, Benjamin J., Hughes, Colette M., Hammond, Katherine B., Ventura, Abigail B., Reed, Jason S., Gilbride, Roxanne M., Ainslie, Emily, Morrow, David W., Ford, Julia C., Selseth, Andrea N., Pathak, Reesab, Malouli, Daniel, Legasse, Alfred W., Axthelm, Michael K., Nelson, Jay A., Gillespie, Geraldine M., Walters, Lucy C., Brackenridge, Simon, Sharpe, Hannah R., López, César A., Früh, Klaus, Korber, Bette T., McMichael, Andrew J., Gnanakaran, S., Sacha, Jonah B., and Picker, Louis J.
- Published
- 2016
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42. Immune clearance of highly pathogenic SIV infection
- Author
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Hansen, Scott G., Jr, Michael Piatak, Ventura, Abigail B., Hughes, Colette M., Gilbride, Roxanne M., Ford, Julia C., Oswald, Kelli, Shoemaker, Rebecca, Li, Yuan, Lewis, Matthew S., Gilliam, Awbrey N., Xi, Guangwu, Nathan, Whizin, Burwitz, Benjamin J., Planer, Shannon L., Turner, John M., Legasse, Alfred W., Axthelm, Michael K., Nelson, Jay A., Fruh, Klaus, Sacha, Jonah B., Estes, Jacob D., Keele, Brandon F., Eldefsen, Paul T., Lifson, Jeffrey D., and Picker, Louis J.
- Subjects
Immune response -- Research -- Models ,Viral vaccines -- Testing -- Research ,Genetic vectors -- Testing -- Research -- Models ,Simian immunodeficiency virus -- Research -- Development and progression ,Virus research -- Research -- Models ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Cellular immune responses in rhesus macaques (Macaca mulatta) vaccinated with cytomegalovirus vectors expressing SIV proteins are able to stringently control highly pathogenic SIV infection, regardless of the route of challenge, after systemic spread; immunological and virological analyses of protected macaques followed for up to 3 years suggest that persistent immune surveillance by vaccine-elicited immune responses may have cleared the infection. Vaccine combats virulent SIV infection Work on potential vaccines against human immunodeficiency viruses (HIV) and the simian equivalent (SIV) has so far proved largely fruitless. This study makes some progress by exploiting the recent observation that the pathogens appear vulnerable to immune control or pharmacological clearance in the first few hours to days of infection. Rhesus macaques vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors developed durable resistance to the highly pathogenic SIVmac239 after challenge by vaginal and intravenous routes. Some of the vaccinated animals have controlled viral replication for 1 to 3 years with no demonstrable evidence for residual virus, raising the possibility that the vaccine- elicited immune responses may in fact have cleared the initial infection. Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections.sup.1,2,3,4. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69-172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors., Author(s): Scott G. Hansen [sup.1] , Michael Piatak Jr [sup.2] , Abigail B. Ventura [sup.1] , Colette M. Hughes [sup.1] , Roxanne M. Gilbride [sup.1] , Julia C. Ford [sup.1] [...]
- Published
- 2013
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43. CYTOMEGALOVIRUS VACCINE VECTOR 68–1 ELICITS UNIVERSAL, MHC-E-RESTRICTED CD8 T-CELL RESPONSES AGAINST SIV: O2.09
- Author
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Wu, Helen L, Hansen, Scott G, Burwitz, Benjamin J, Hammond, Katherine B, Reed, Jason S, Hughes, Colette M, Ventura, Abigail B, Pathak, Reesab, Malouli, Daniel, Gilbride, Roxanne M, Planner, Shannon L, Legasse, Alfred W, Axthelm, Michael K, Fruh, Klaus, Picker, Louis J, and Sacha, Jonah B
- Published
- 2015
44. RHESUS CYTOMEGALOVIRUS INFECTION OF CYNOMOLGUS MACAQUES REQUIRES THE ANTI-APOPTOTIC VIRAL PROTEIN UL36: O2.01
- Author
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Burwitz, Benjamin J., Malouli, Daniel, Reed, Jason S., Hammond, Katherine B., Ventura, Abigail B., Bimber, Benjamin N., Hancock, Meaghan H., Bhusari, Amruta, Najera, Renee G. Espinosa, Legasse, Alfred W., Axthelm, Michael K., Nelson, Jay A., Streblow, Daniel N., Hansen, Scott G., Picker, Louis J., Fruh, Klaus, and Sacha, Jonah B.
- Published
- 2015
45. Improved delivery of broadly neutralizing antibodies by nanocapsules suppresses SHIV infection in the CNS of infant rhesus macaques
- Author
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Wen, Jing, primary, Cheever, Tracy, additional, Wang, Lan, additional, Wu, Di, additional, Reed, Jason, additional, Mascola, John, additional, Chen, Xuejun, additional, Liu, Cuiping, additional, Pegu, Amarendra, additional, Sacha, Jonah B., additional, Lu, Yunfeng, additional, Haigwood, Nancy L., additional, and Chen, Irvin S. Y., additional
- Published
- 2021
- Full Text
- View/download PDF
46. ENVELOPE-SPECIFIC TFH RESPONSES AND CROSS-NEUTRALIZING ANTIBODIES DEVELOP CONCOMITANTLY IN RHESUS MACAQUES CO-IMMUNIZED WITH HIV ENVELOPE DNA AND PROTEIN: ABSTRACT #40
- Author
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Hessell, Ann J., Malherbe, Delphine C., Burwitz, Benjamin J., Pissani, Franco, Sather, Noah, Robins, Harlan, Pandey, Shilpi, Sutton, William F., Sacha, Jonah B., Stamatatos, Leonidas, and Haigwood, Nancy L.
- Published
- 2014
47. DEFINING THE MHC RESTRICTION OF NOVEL, CMVINDUCED CD8+ T CELLS: ABSTRACT #24
- Author
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Wu, Helen L., Hansen, Scott G, Burwitz, Benjamin J., Hammond, Katherine B., Hughes, Colette M., Ventura, Abigail B., Reed, Jason S., Früh, Klaus, Picker, Louis J., and Sacha, Jonah B.
- Published
- 2014
48. HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
- Author
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Jones, R. Brad, Garrison, Keith E., Mujib, Shariq, Mihajlovic, Vesna, Aidarus, Nasra, Hunter, Diana V., Martin, Eric, John, Vivek M., Zhan, Wei, Faruk, Nabil F., Gyenes, Gabor, Sheppard, Neil C., Priumboom-Brees, Ingrid M., Goodwin, David A., Chen, Lianchun, Rieger, Melanie, Muscat-King, Sophie, Loudon, Peter T., Stanley, Cole, Holditch, Sara J., Wong, Jessica C., Clayton, Kiera, Duan, Erick, Song, Haihan, Xu, Yang, SenGupta, Devi, Tandon, Ravi, Sacha, Jonah B., Brockman, Mark A., Benko, Erika, Kovacs, Colin, Nixon, Douglas F., and Ostrowski, Mario A.
- Subjects
HIV (Viruses) -- Genetic aspects ,T cells -- Genetic aspects ,Gene expression -- Research ,Endogenous retroviruses -- Genetic aspects ,Simian immunodeficiency virus -- Genetic aspects ,Health care industry - Abstract
The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we estab-lish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of [CD4.sup.+] T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific [CD8.sup.+] T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics., Introduction The genetic diversity of HIV-1 is considerable, with amino acids in Env differing by as much as 20% within a subtype and by more than 35% between subtypes and [...]
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- 2012
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49. Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy
- Author
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Verweij, Marieke C., primary, Hansen, Scott G., additional, Iyer, Ravi, additional, John, Nessy, additional, Malouli, Daniel, additional, Morrow, David, additional, Scholz, Isabel, additional, Womack, Jennie, additional, Abdulhaqq, Shaheed, additional, Gilbride, Roxanne M., additional, Hughes, Colette M., additional, Ventura, Abigail B., additional, Ford, Julia C., additional, Selseth, Andrea N., additional, Oswald, Kelli, additional, Shoemaker, Rebecca, additional, Berkemeier, Brian, additional, Bosche, William J., additional, Hull, Michael, additional, Shao, Jason, additional, Sacha, Jonah B., additional, Axthelm, Michael K., additional, Edlefsen, Paul T., additional, Lifson, Jeffrey D., additional, Picker, Louis J., additional, and Früh, Klaus, additional
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- 2021
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50. HLA-E–restricted, Gag-specific CD8+T cells can suppress HIV-1 infection, offering vaccine opportunities
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Yang, Hongbing, primary, Rei, Margarida, additional, Brackenridge, Simon, additional, Brenna, Elena, additional, Sun, Hong, additional, Abdulhaqq, Shaheed, additional, Liu, Michael K. P., additional, Ma, Weiwei, additional, Kurupati, Prathiba, additional, Xu, Xiaoning, additional, Cerundolo, Vincenzo, additional, Jenkins, Edward, additional, Davis, Simon J., additional, Sacha, Jonah B., additional, Früh, Klaus, additional, Picker, Louis J., additional, Borrow, Persephone, additional, Gillespie, Geraldine M., additional, and McMichael, Andrew J., additional
- Published
- 2021
- Full Text
- View/download PDF
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