title: Regulatory B cells inhibit cytotoxic T lymphocyte (CTL) activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs.
abstract: During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs) directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG), HIV-infected "elite controllers" (HIVEC), ART-treated (HIVART), and viremic (HIVvir), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4+ T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication.
authors.affiliation: Rush University Medical Center, Department of Immunology and Microbiology, Chicago, Illinois, United States of America.
authors.forename: Basile
authors.initials: B
authors.lastname: Siewe
authors.affiliation: Rush University Medical Center, Department of Immunology and Microbiology, Chicago, Illinois, United States of America.
authors.forename: Jennillee
authors.initials: J
authors.lastname: Wallace
authors.affiliation: Rush University Medical Center, Department of Immunology and Microbiology, Chicago, Illinois, United States of America.
authors.forename: Sonya
authors.initials: S
authors.lastname: Rygielski
authors.affiliation: Iowa City Veterans Affairs Medical Center and the University of Iowa, Departments of Internal Medicine, Microbiology and Immunology, Iowa City, Iowa, United States of America.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
authors.affiliation: HIV/AIDS Division, San Francisco General Hospital, University of California San Francisco (UCSF), San Francisco, California, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Martin
authors.affiliation: HIV/AIDS Division, San Francisco General Hospital, University of California San Francisco (UCSF), San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Rush University Medical Center, Department of Immunology and Microbiology, Chicago, Illinois, United States of America; FC Donders Chair, Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D060151:B-Lymphocytes, Regulatory / Q000502:physiology*; D060890:B7-H1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000821:virology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000502:physiology*; D014766:Viremia / Q000821:virology
chemical_list: D060890:B7-H1 Antigen; D053701:Receptors, Interleukin-10; D016753:Interleukin-10
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