Cutting Edge: T Regulatory Cell Depletion Reactivates Latent Simian Immunodeficiency Virus (SIV) in Controller Macaques While Boosting SIV-Specific T Lymphocytes.
T regulatory cells (Tregs) are critical in shaping the latent HIV/SIV reservoir, as they are preferentially infected, reverse CD4+T cell activation status, and suppress CTL responses. To reactivate latent virus and boost cell-mediated immune responses, we performed in vivo Treg depletion with Ontak (denileukin diftitox) in two SIVsab-infected controller macaques. Ontak induced significant (>75%) Treg depletion and major CD4+T cell activation, and only minimally depleted CD8+T cells. The overall ability of Tregs to control immune responses was significantly impaired despite their incomplete depletion, resulting in both reactivation of latent virus (virus rebound to 103viral RNA copies/ml plasma in the absence of antiretroviral therapy) and a significant boost of SIV-specific CD8+T cell frequency, with rapid clearance of reactivated virus. As none of the latency-reversing agents in development have such dual activity, our strategy holds great promise for cure research.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Tianyu
0000-0002-9427-6694
T
He
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Egidio
E
Brocca-Cofano
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261.
Benjamin B
BB
Policicchio
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Ranjit
0000-0001-7431-8415
R
Sivanandham
Laboratory of Molecular Microbiology, Viral Pathogenesis and Vaccine Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20814; and.
Rajeev
0000-0003-2390-8727
R
Gautam
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Kevin D
KD
Raehtz
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Cuiling
C
Xu
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.|Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261.
Ivona
I
Pandrea
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261; apetreic@pitt.edu.|Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261.|Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Cristian
C
Apetrei
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000008:administration & dosage; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000008:administration & dosage; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D012367:RNA, Viral / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000914:Antibodies, Viral; D000956:Antigens, Viral; D004167:Diphtheria Toxin; D007376:Interleukin-2; D012367:RNA, Viral; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox