IFN-α blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health.

Louise A Swainson,Richard M Dunham,Peter Wilkinson,Steven G Deeks,Rebecca G Albright,Rafick-Pierre Sekaly,Jacob D Estes,Khader Ghneim,Ashish Arunkumar Sharma,Susan Pereira Ribeiro,Samson Wong,Peter W Hunt,Joseph M Mccune,Michael Piatak

doi:10.1172/jci.insight.153046

Abstract

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti–IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN–inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12–induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti–IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.

Highlights

Type I interferons (TI-IFNs) are pleiotropic cytokines that serve as soluble mediators of response to viral infections and that regulate the expression of genes associated with cell survival/death, proliferation, migration, and metabolism [1,2,3]
It should be noted that no significant association in lymph node (LN) viral DNA (vDNA) levels and incomplete viral suppression was observed, suggesting that the decline in LN vDNA post-treatment was primarily driven by IFN-a blockade (Supplementary Figure 1B)
Humanized mouse studies [31, 32] and this rhesus macaque study demonstrate that, in the setting of chronic antiretroviral therapy (ART)-treated HIV/SIV infection, sustained TI-IFN signaling may contribute to immune dysfunction and foster SIV/HIV persistence, and that blockade of IFN-a can provide clinical benefit

Summary

Introduction

Type I interferons (TI-IFNs) are pleiotropic cytokines that serve as soluble mediators of response to viral infections and that regulate the expression of genes associated with cell survival/death, proliferation, migration, and metabolism [1,2,3]. Persistent TI-IFN signaling during chronic infection, on the other hand, may be detrimental: higher levels of TI-IFN signaling are correlated with immune activation [12, 13], poor immune reconstitution and blunted CD4 T cell homeostasis with ART, and disease progression [14, 15]. These negative effects are likely the result of many mechanisms, including cell death [16], upregulation of immunosuppressive pathways mediated by TGF-b, and CD8 T cell exhaustion [17, 18]. While TI-IFN may be beneficial during acute infection, sustained TI-IFN signaling can contribute to hostmediated immunopathology and disease progression

Methods

Results

Conclusion