title: Kinetics of Myeloid-Derived Suppressor Cell Frequency and Function during Simian Immunodeficiency Virus Infection, Combination Antiretroviral Therapy, and Treatment Interruption.
abstract: During chronic lentiviral infection, poor clinical outcomes correlate both with systemic inflammation and poor proliferative ability of HIV-specific T cells; however, the connection between the two is not clear. Myeloid-derived suppressor cells (MDSC), which expand during states of elevated circulating inflammatory cytokines, may link the systemic inflammation and poor T cell function characteristic of lentiviral infections. Although MDSC are partially characterized in HIV and SIV infection, questions remain regarding their persistence, activity, and clinical significance. We monitored MDSC frequency and function in SIV-infected rhesus macaques. Low MDSC frequency was observed prior to SIV infection. Post-SIV infection, MDSC were elevated in acute infection and persisted during 7 mo of combination antiretroviral drug therapy (cART). After cART interruption, we observed MDSC expansion of surprising magnitude, the majority being granulocytic MDSC. At all stages of infection, granulocytic MDSC suppressed CD4+ and CD8+ T cell proliferation in response to polyclonal or SIV-specific stimulation. In addition, MDSC frequency correlated significantly with circulating inflammatory cytokines. Acute and post-cART levels of viremia were similar, however, the levels of inflammatory cytokines and MDSC were more pronounced post-cART. Expanded MDSC during SIV infection, especially during the post-cART inflammatory cytokine surge, likely limit cellular responses to infection. As many HIV curative strategies require cART interruption to determine efficacy, our work suggests treatment interruption-induced MDSC may especially undermine the effectiveness of such strategies. MDSC depletion may enhance T cell responses to lentiviral infection and the effectiveness of curative approaches.
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA 98195; sandra.dross@cidresearch.org.|Center for Infectious Disease Research, Seattle, WA 98109.
authors.forename: Sandra E
authors.identifier: 0000-0003-1013-6828
authors.initials: SE
authors.lastname: Dross
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98915.|Washington National Primate Research Center, University of Washington, Seattle, WA 98915; and.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Munson
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Washington National Primate Research Center, University of Washington, Seattle, WA 98915; and.
authors.forename: Debra L
authors.identifier: 0000-0002-5822-5558
authors.initials: DL
authors.lastname: Bratt
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98915.|Washington National Primate Research Center, University of Washington, Seattle, WA 98915; and.
authors.forename: Hillary C
authors.initials: HC
authors.lastname: Tunggal
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109.
authors.forename: Ana L
authors.identifier: 0000-0003-0321-5632
authors.initials: AL
authors.lastname: Gervassi
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98915.|Washington National Primate Research Center, University of Washington, Seattle, WA 98915; and.
authors.forename: Deborah H
authors.identifier: 0000-0001-7315-2441
authors.initials: DH
authors.lastname: Fuller
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA 98195.|Immune Modulation Research, Janssen Infectious Diseases and Vaccines BVBA, Beerse 2340, Belgium.
authors.forename: Helen
authors.initials: H
authors.lastname: Horton
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D008253:Macaca mulatta; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus
chemical_list: D044966:Anti-Retroviral Agents