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Your search keyword '"Jeremy Smedley"' showing total 2 results
Start Over Author "Jeremy Smedley" Journal the journal of clinical investigation
2 results on '"Jeremy Smedley"'

1. Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy

Author

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

Subjects
AIDS/HIV, Medicine
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.

Published
2022
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2. Vaccine-induced myeloid cell population dampens protective immunity to SIV

Author

Dennis M. Klinman, Jeremy Smedley, Blake Frey, Katherine McKinnon, Linda Liu, Yongjun Sui, Mercy Gathuka, Zheng Xia, Brandon F. Keele, Genoveffa Franchini, Huifeng Yu, Yichuan Wang, Jay A. Berzofsky, David Venzon, Sol Langermann, and Alison Hogg

Subjects
Male, Cellular immunity, Modified vaccinia Ankara, medicine.medical_treatment, T cell, Simian Acquired Immunodeficiency Syndrome, Biology, Adaptive Immunity, CD8-Positive T-Lymphocytes, Immune system, Adjuvants, Immunologic, Transforming Growth Factor beta, medicine, Animals, Myeloid Cells, SAIDS Vaccines, General Medicine, Viral Load, Acquired immune system, Virology, Macaca mulatta, Vaccination, medicine.anatomical_structure, Immunology, Female, Simian Immunodeficiency Virus, Adjuvant, CD8, Research Article
Abstract

Vaccines are largely evaluated for their ability to promote adaptive immunity, with little focus on the induction of negative immune regulators. Adjuvants facilitate and enhance vaccine-induced immune responses and have been explored for mediating protection against HIV. Using a regimen of peptide priming followed by a modified vaccinia Ankara (MVA) boost in a nonhuman primate model, we found that an SIV vaccine incorporating molecular adjuvants mediated partial protection against rectal SIVmac251 challenges. Animals treated with vaccine and multiple adjuvants exhibited a reduced viral load (VL) compared with those treated with vaccine only. Surprisingly, animals treated with adjuvant alone had reduced VLs that were comparable to or better than those of the vaccine-treated group. VL reduction was greatest in animals with the MHC class I allele Mamu-A*01 that were treated with adjuvant only and was largely dependent on CD8+ T cells. Early VLs correlated with Ki67+CCR5+CD4+ T cell frequency, while set-point VL was associated with expansion of a myeloid cell population that was phenotypically similar to myeloid-derived suppressor cells (MDSCs) and that suppressed T cell responses in vitro. MDSC expansion occurred in animals receiving vaccine and was not observed in the adjuvant-only group. Collectively, these results indicate that vaccine-induced MDSCs inhibit protective cellular immunity and suggest that preventing MDSC induction may be critical for effective AIDS vaccination.

Published
2014

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