Reduced Chronic Lymphocyte Activation following Interferon Alpha Blockade during the Acute Phase of Simian Immunodeficiency Virus Infection in Rhesus Macaques

• Type of Material: Article
• Authors: Diane Carnathan, Emory University; Benton Lawson, Emory University; Joana Yu, Emory University; Kalpana Patel, Emory University; James M. Billingsley, Emory University; Gregory K. Tharp, Emory University; Olivia M. Delmas, Emory University; Reem Dawoud, Emory University; Peter Wilkinson, Case Western Reserve University; Charles Nicolette, Argos Therapeutics, Inc.; Mark J. Cameron, Case Western Reserve University; Rafick-Pierre Sekaly, Case Western Reserve University; Steven Bosinger, Emory University; Guido Silvestri, Emory University; Thomas Howerton Vanderford, Emory University
• Language: English
• Date: 2018-05-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01760-17
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 92
• Issue: 9
• Grant/Funding Information: This work was funded by P01 AI76174 to Michael Lederman and Guido Silvestri, P51 OD011132 to the YNPRC, and P30 AI050409 to the Emory CFAR.
• Keywords: SIV; interferons; HIV therapy; SIV INFECTION; AIDS; immune activation; Life Sciences & Biomedicine; PERSISTENT LCMV INFECTION; type I interferon; rhesus macaque; SOOTY MANGABEYS; Science & Technology; VIRAL-INFECTION; CLONAL EXPANSION; HIV; IMMUNE ACTIVATION; T-CELLS; CHRONIC HIV-INFECTION; TRANSMISSION; Virology
• Research Categories: Health Sciences, Immunology; Biology, Virology

Abstract

Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection of humans and rhesus macaques (RMs) induces persistently high production of type I interferon (IFN-I), which is thought to contribute to disease progression. To elucidate the specific role of interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIVmac239infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α decreased the levels of activated CD4+and CD8+T cells, as well as B cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-α-blockaded animals supports the hypothesis that IFN-α signaling contributes to lymphocyte activation during SIV infection and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential antiinflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals.