The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection

Abstract

Type-I interferons (IFN-I) are a widely expressed family that could promote antivirus immunity in the process of pathogens invasion. In a human immunodeficiency virus 1 (HIV-1)-infected individual, the production of IFN-I can be detected as early as the acute phase and will persist throughout the course of infection. However, sustained stimulation of immune system by IFN-I also contributes greatly to host-mediated immunopathology and diseases progression. Although the protective effects of IFN-I in the acute phase of HIV-1 infection have been observed, more studies recently focus on their detrimental role in the chronic stage. Inhibition of IFN-I signaling may reverse HIV-1-induced immune hyperactivation and furthermore reduce HIV-1 reservoirs, which suggest this strategy may provide a potential way to enhance the therapeutic effect of antiretroviral therapy. Therefore, we review the role of IFN-I in HIV-1 progression, their effects on different immunocytes, and therapeutic prospects targeting the IFN-I system.

Sustained IFN-I Expression during Established Persistent Viral Infection: A “Bad Seed” for Protective Immunity

“…It is important to consider the complexity of the factors to ensure the safety and the clinical success for blocking IFN-I signaling-based therapy [ 3 , 28 ]. Namely, the timing of such treatment is critical considering that early administration of exogenous IFN-I is usually beneficial for the host and prevents the establishment of persistent infection [ 6 , 27 , 75 ] and, in the case of SIV, early IFNR blockade results in accelerated disease progression leading to AIDS [ 6 ]. As such, it is crucial to increase our knowledge on how sustained IFN-I signaling and timing of IFNR blockade precisely impacts molecular networks and immune cell phenotypes during persistent viral infections.…”

“…Of note, both of these pathways have been found to be overexpressed in chronically HIV-1-infected patients despite induction of antiretroviral therapy (ART) wherein immune function is rescued by blockade even after years of infection [ 9 , 10 , 11 , 12 , 13 , 14 ]. To date, there are well-established lines of evidence placing sustained IFN-I expression as a major contributor of immune activation/inflammation and resultant disease progression during persistent viral infections such as HIV-1 and SIV [ 1 , 3 , 6 , 7 , 8 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. For example, in the non-human primate model of SIV infection, natural hosts that do not progress toward acquired immune deficiency syndrome (AIDS) exhibit lower levels of IFN-I signaling and inflammation when compared to animals harbouring pathogenic infections [ 6 , 30 , 31 , 32 , 33 ].…”

“…More importantly, IFNR blockade reduced cell-associated virus numbers and significantly controlled HIV-1 rebound after ART cessation [ 18 , 38 ]. Thus, it is unsurprising that the use of humanized anti-IFNR blocking antibodies (Abs), which are currently used in a phase I trial in systemic lupus erythematosus and systemic sclerosis [ 39 , 40 ], are now proposed to treat persistent viral infections as a means of reducing chronic inflammation [ 3 , 27 , 41 ].…”

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

“…The type I interferons (IFN-Is) are innate antiviral cytokines that include IFNα (12 different subtypes) and IFNβ [1]. These cytokines significantly inhibited HIV-1 replication in vitro, but human clinical trials with IFNα2 showed only moderate or no inhibitory effects on HIV-1 infection [2,3]. All IFN-Is bind to the same IFN-I receptor that is composed of two subunits, IFNAR1 and IFNAR2, resulting in phosphorylation of JAK1 and TYK2.…”

“…Recent studies highlighted IFNα as a potential adjunct to an HIV-1 curative strategy [6][7][8][9][10]. However, almost all HIV-1 clinical trials with IFNα were performed with only one subtype, IFNα2, with mixed results (reviewed in [2,3]). More recently, IFNα2 treatment of SIV rhesus macaques under antiretroviral therapy did not reduce the latent HIV-1 reservoir [11].…”