IFNα Subtypes in HIV Infection and Immunity

Abstract

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of therapeutic alternatives for viral infections. Within the type I IFN family, 12 IFNα subtypes exist, all binding to the same receptor but displaying significant variations in their biological activities. Currently, clinical treatments for chronic virus infections predominantly rely on a single IFNα subtype (IFNα2a/b). However, the efficacy of this therapeutic treatment is relatively limited, particularly in the context of Human Immunodeficiency Virus (HIV) infection. Recent investigations have delved into alternative IFNα subtypes, identifying certain subtypes as highly potent, and their antiviral and immunomodulatory properties have been extensively characterized. This review consolidates recent findings on the roles of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus (SIV) infections. It encompasses their induction in the context of HIV/SIV infection, their antiretroviral activity, and the diverse regulation of the immune response against HIV by distinct IFNα subtypes. These insights may pave the way for innovative strategies in HIV cure or functional cure studies.

Keywords: HIV; IFNα subtypes; immunotherapy; type I IFNs.

Figure 1

Induction of type I IFNs during retroviral infections. During the HIV life cycle, numerous potential replication intermediates (ssRNA, dsRNA structures, DNA:RNA hybrids, and dsDNA) are present. Some of these are recognized by different PRRs, including TLR7/8, cGAS, DDX3, and RIG-I. Furthermore, the potential sensing of HIV dsRNA structures by TLR3, as well as sensing of HIV DNA by members of the PYHIN family (e.g., absent in melanoma 2 (AIM2) and IFN-γ inducible protein 16 (IFI16)), might also contribute to innate HIV restriction. The detection of HIV DNA or RNA by these different sensors triggers different signaling cascades that lead to the phosphorylation of IRF3 and IRF7. Upon activation, IRF3 and IRF7 translocate to the nucleus, promoting the transcription of type I IFN genes. Created with BioRender.com.

Figure 2

Type I IFN signaling. Binding of type I IFN to the ubiquitously expressed IFNα/β receptor triggers the activation of various signaling cascades. IFNAR consists of the subunits IFNAR1 and IFNAR2, with a higher affinity of IFN for IFNAR2. This leads to initial IFNAR2 binding, followed by IFNAR1 recruitment to form the ternary complex. For canonical signaling, phosphorylation of the receptor unit by Janus kinases (Tyk2 and Jak1) activates transcription factors STAT1 and STAT2, forming together with IRF9 the trimeric ISGF3 complex. ISGF3 translocates to the nucleus, binding to ISRE and inducing the transcription of numerous ISGs. Apart from the canonical JAK-STAT signaling pathway, other non-classical signaling cascades downstream of the IFNAR are also activated upon IFN binding. Created with BioRender.com.

Figure 3

Crystal structure of the IFNAR2-IFNα2-IFNAR1 ternary complex. The ternary IFNAR2-IFNα2b-IFNAR1 complex is depicted with ribbon structures for the receptors and cylinder/plate structure for IFNα2. The five helices of IFNα2 are represented in different colors: aquamarine blue (helix A), pink (helix B), dark purple (helix C), mineral green (helix D), and light purple (helix E). Initially, IFNα binds with a higher affinity to IFNAR2 (shown in dark gray), where helices A and E, along with the AB loop, interact with the D1 and D2 domains of IFNAR2. Subsequently, IFNAR1 (depicted in light gray) is recruited, and its SD1-SD3 domains interact with the helices B, C, and D of IFNα2. This illustration is adapted from [77] and was created using VAST+, PDB ID: 3SE3.