Date Published: August 24, 2018
Publisher: Public Library of Science
Author(s): Krystelle Nganou-Makamdop, James M. Billingsley, Zachary Yaffe, Gregory O’Connor, Gregory K. Tharp, Amy Ransier, Farida Laboune, Rodrigo Matus-Nicodemos, Andrea Lerner, Lavina Gharu, Jennifer M. Robertson, Mandy L. Ford, Martin Schlapschy, Nadine Kuhn, Alexandra Lensch, Jeffrey Lifson, Martha Nason, Arne Skerra, Gideon Schreiber, Steven E. Bosinger, Daniel C. Douek, Susan R Ross.
Chronic activation of the immune system in HIV infection is one of the strongest predictors of morbidity and mortality. As such, approaches that reduce immune activation have received considerable interest. Previously, we demonstrated that administration of a type I interferon receptor antagonist (IFN-1ant) during acute SIV infection of rhesus macaques results in increased virus replication and accelerated disease progression. Here, we administered a long half-life PASylated IFN-1ant to ART-treated and ART-naïve macaques during chronic SIV infection and measured expression of interferon stimulated genes (ISG) by RNA sequencing, plasma viremia, plasma cytokines, T cell activation and exhaustion as well as cell-associated virus in CD4 T cell subsets sorted from peripheral blood and lymph nodes. Our study shows that IFN-1ant administration in both ART-suppressed and ART-untreated chronically SIV-infected animals successfully results in reduction of IFN-I-mediated inflammation as defined by reduced expression of ISGs but had no effect on plasma levels of IL-1β, IL-1ra, IL-6 and IL-8. Unlike in acute SIV infection, we observed no significant increase in plasma viremia up to 25 weeks after IFN-1ant administration or up to 15 weeks after ART interruption. Likewise, cell-associated virus measured by SIV gag DNA copies was similar between IFN-1ant and placebo groups. In addition, evaluation of T cell activation and exhaustion by surface expression of CD38, HLA-DR, Ki67, LAG-3, PD-1 and TIGIT, as well as transcriptome analysis showed no effect of IFN-I blockade. Thus, our data show that blocking IFN-I signaling during chronic SIV infection suppresses IFN-I-related inflammatory pathways without increasing virus replication, and thus may constitute a safe therapeutic intervention in chronic HIV infection.
Persistent inflammation during chronic HIV infection is a central contributing factor to immune exhaustion, CD4 T cell depletion and progression to AIDS [1–3]. Previous studies aimed at understanding the nature of this immune dysfunction have revealed a key role for type I interferons (IFN-I). IFN-I has been shown to suppress HIV infection in vitro  and SIV infection in rhesus macaques in vivo . Studies in non-human primates have demonstrated a link between type I IFN responses and pathogenic SIV infection [6–8]. While IFN-I signaling resulting from SIV infection waned during the transition from acute to chronic non-pathogenic infection in SIV natural hosts African green monkeys and sooty mangabeys, a persistent response was associated with pathogenic infection and progression to AIDS in experimental SIV infection of rhesus and pigtail macaques. In humans, plasma levels of IFN-I have been shown to correlate directly with plasma HIV RNA and inversely with CD4 T cell count . Moreover, administration of IFN-I to HIV-infected persons resulted in lower CD4 T cell counts  and increased CD8 T cell activation . These findings attributed, at least in part, the severity of infection and exacerbation of the disease to type I IFN signaling and raised considerable interest in the potential therapeutic benefits of blocking IFN-I during infection. Associations between IFN-I and chronic viral infections have led to numerous studies where IFN-I signaling was manipulated . Blockade of IFN-I signaling with anti-type I IFN receptor (IFNAR) antibody in murine LCMV infection resulted in reduced immune activation and improved viral clearance [13, 14]. Recently, two independent studies showed that administration of anti-IFNAR antibodies to ART-suppressed, HIV-infected humanized mice resulted in reduced immune activation and lowered reservoir size [15, 16]. The efficacy of IFN-blockade in the mouse models has provided a rationale for testing in the SIV-infected non-human primates. In our prior study, we found that blocking IFN-I during acute SIV infection in rhesus macaques resulted in reduced expression of antiviral genes, increased size of the SIV reservoir and accelerated CD4 T cell depletion and progression to AIDS . Quite reasonably, this adverse outcome of IFN-I blockade during acute infection raised major concerns for the safety of IFN-I blockade during chronic HIV infection. As treatment with antiviral drugs reduces but does not completely normalize inflammation and IFN-I signaling [2, 17, 18], it is important to assess the effects of manipulation of IFN-signaling during chronic infection under ART. Thus, our primary objective in the present study was to test the effect of IFN-blockade on both inflammatory status and the control of viral replication during ART-treated and untreated chronic SIV infection in monkeys, and thus to establish the safety profile of this experimental therapy for clinical use in ART-treated HIV infection.
Our findings are primarily relevant to the implementation of IFN-I blockade strategies in clinical HIV studies. Type I IFNs are important mediators of antiviral immunity but their permanent engagement in chronic HIV infection also contributes to a persistent inflammatory state that promotes pathology. As is being advocated for inflammatory diseases such as systemic lupus erythematous or systemic sclerosis , therapeutic blockade of IFN-I signaling could reduce inflammation and improve control of HIV infection. However, adverse outcomes observed in acute SIV infection  raised major safety concerns for the potential use of similar approaches during the chronic stage. Here, we assessed the effect of blocking IFN-I signaling during ART-treated and ART-untreated chronic SIV infection. Our principal findings were: (1) administration of an IFN-I receptor antagonist with prolonged half-life to ART-treated and ART-untreated SIV-infected rhesus macaques showed a therapeutic benefit in terms of lowering inflammation in part as observed by amelioration of ISG expression despite unaltered levels of measured pro-inflammatory cytokines; and (2) in contrast to observations made during acute SIV infection , blockade of IFN-I signaling during chronic SIV infection did not lead to loss of control of viral replication. In this regard, our study shows that in chronic SIV infection, even in situations with residual viral replication, blocking type I IFN signaling did not lead to loss of control of the infection; and supports the rationale that the use of an IFN-I antagonist during chronic HIV infection is safe.