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

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.) SIV infection 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 anti-inflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals. Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system.

Type I IFN signaling blockade by a PASylated antagonist during chronic SIV infection suppresses specific inflammatory pathways but does not alter T cell activation or virus replication

“…In addition, because the 3x weekly ART group had a generally higher VL compared to animals that received twice weekly IFN-1ant ( Fig 4 ), there is likely a threshold where any measurable effect of the antagonist added to the effect of ART is influenced by the viremia at the time antagonist treatment is initiated. Our findings possibly reinforces the importance of timing on the outcome of IFN-I signaling blockade as administration of IFN-I antagonist [ 5 ] and more recently anti-IFN antibody treatment [ 30 ] in SIV infected macaques was shown to reduce T cell activation. The observations in our study also differ from observations made in prior studies on IFN-I blockade in chronically HIV-infected humanized mice which showed reduced expression of ISGs along with enhanced viral suppression and reduced T cell activation [ 15 , 16 ].…”

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

“…In fact, IFNAR blockade during chronic HIV-1 infection in humanized mice restored immune function, leading to better HIV-1 control [31,32]. Neutralization of (most) IFNα subtypes in SIV-infected rhesus macaques prior to infection increased viral loads as expected, but also decreased subsequent immune activation profiles [24]. By contrast, blockade of IFN-I signaling in chronic SIVtreated and untreated rhesus macaques decreased inflammation profiles associated with ISGs but did not reverse T cell exhaustion or activation [33].…”

“…Genetic ablation of IFNAR resulted in higher Friend retrovirus replication in mice co-infected with lactate-dehydrogenase elevating virus, a potent IFN-I inducer [22]. Moreover, IFNAR blockade increased SIV replication in rhesus macaques [23,24]. Administration of IFNα2 decreased retrovirus replication in mice, monkeys and humans [3,18,23].…”

Antibody-Mediated CD4 Depletion Induces Homeostatic CD4 + T Cell Proliferation without Detectable Virus Reactivation in Antiretroviral Therapy-Treated Simian Immunodeficiency Virus-Infected Macaques

“…Sample collection and tissue processing. Longitudinal collection and processing of blood, fine needle aspirates (FNA), or lymph node and rectal biopsy specimens were performed as previously described (33,34,40,41). Briefly, 2 ml of blood samples was used for complete blood count (CBC), the remaining blood was centrifuged to collect plasma, and then peripheral blood mononuclear cells (PBMCs) were collected over density gradient centrifugation using Ficoll (Gibco, Massachusetts).…”