Type I Interferon Responses by HIV-1 Infection: Association with Disease Progression and Control

Abstract

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome and its infection leads to the onset of several disorders such as the depletion of peripheral CD4⁺ T cells and immune activation. HIV-1 is recognized by innate immune sensors that then trigger the production of type I interferons (IFN-Is). IFN-Is are well-known cytokines eliciting broad anti-viral effects by inducing the expression of anti-viral genes called interferon-stimulated genes (ISGs). Extensive in vitro studies using cell culture systems have elucidated that certain ISGs such as APOBEC3G, tetherin, SAM domain and HD domain-containing protein 1, MX dynamin-like GTPase 2, guanylate-binding protein 5, and schlafen 11 exert robust anti-HIV-1 activity, suggesting that IFN-I responses triggered by HIV-1 infection are detrimental for viral replication and spread. However, recent studies using animal models have demonstrated that at both the acute and chronic phase of infection, the role of IFN-Is produced by HIV or SIV infection in viral replication, spread, and pathogenesis, may not be that straightforward. In this review, we describe the pluses and minuses of HIV-1 infection stimulated IFN-I responses on viral replication and pathogenesis, and further discuss the possibility for therapeutic approaches.

Keywords: human immunodeficiency virus type 1; humanized mouse; innate immunity; interferon-stimulated gene; intrinsic immunity; restriction factor; type I interferon.

Figure 1

Pattern recognition receptors (PRRs) for human immunodeficiency virus type 1 (HIV-1) recognition and the following pathway for triggering type I interferon (IFN-I) expression. Cellular actions are indicated in green (in italic) with arrows, and viral replication steps are indicated in red (in italic) with arrows. Cellular actions triggered by PRRs [IFN-γ inducible protein 16 (IFI16), cyclic GMP-AMP synthase (cGAS) and toll-like receptor 7 (TLR7)] are indicated in blue (in italic) with arrows. Cellular organelle, viral components, and sensor-related molecules are indicated in green, red, and blue, respectively. “P” with yellow circle indicates phosphorylation. The detail of each step is described in the main text.

Figure 2

Type I interferons (IFN-I)-initiated signaling pathway leading to interferon-stimulated gene (ISG) expression. Cellular actions triggered by IFN-I [Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway] are indicated in purple (in italic) with arrows. Cellular organelle and the cellular molecules related to JAK/STAT pathway are indicated in green and purple, respectively. The detail of each step is described in the main text. “P” with yellow circle indicates phosphorylation.

Figure 3

Restriction factors (RFs) controlling human immunodeficiency virus type 1 (HIV-1) replication and viral antagonists. Viral replication steps are indicated in red (in italic) with arrows. The RFs inhibiting viral replication at respective step are indicated in cyan, while the viral accessory proteins counteracting the action of certain RFs are indicated in red. Cellular organelle and viral components are indicated in green and red, respectively. The detail of each step is described in the main text.