Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning

Abstract

Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. It is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for HIV-1. It has been long accepted that the restriction factor tripartite motif protein 5 isoform alpha (TRIM5α) restricts HIV-1 infection in a species-specific manner, with rhesus macaque TRIM5α strongly restricting HIV-1, and human TRIM5α having a minimal restriction capacity. However, several recent studies underscore human TRIM5α as a cell-dependent HIV-1 restriction factor. Here, we present an overview of the latest research on human TRIM5α and propose a novel conceptualization of TRIM5α as a restriction factor with a varied portfolio of antiviral functions, including mediating HIV-1 degradation through autophagy- and proteasome-mediated mechanisms, and acting as a viral sensor and effector of antiviral signaling. We have also expanded on the protective antiviral roles of autophagy and outline the therapeutic potential of autophagy modulation to intervene in chronic HIV-1 infection.

Keywords: CD4+ T cells; HIV-1 restriction; Langerhans cells; Langerin; TRIM5α; antiviral immunity; autophagy; dendritic cells; macrophages; viral evasion.

Figure 1

Structure and functions of TRIM5α. (A) Rhesus (rh)TRIM5α, human (hu)TRIM5α, and TRIMCyp protein domain organization and associated functions. Key amino acid residues impacting antiviral functions per protein domain are depicted. (B) Schematic overview of the main steps of HIV-1 virus replication cycle (center panel, in grey), and the proteasome-directed (left panel, in orange) and autophagy-directed (right panel, in purple) TRIM5α-mediated mechanisms of HIV-1 restriction. RING: really interesting new gene, CC: coiled-coil, LC3: microtubule-associated protein 1A/1B-light chain 3, ULK1: Unc-51 like autophagy activating kinase 1, ATG: autophagy related, Ub: ubiquitin, L1: linker 1, L2: linker 2.

Figure 2

Cell-specific TRIM5α-mediated HIV-1 restriction. Langerhans cells, which reside within the mucosal epithelium (A), are able to restrict HIV-1 infection via a TRIM5α-mediated mechanism (B). At steady-state, the Langerhans cell-specific receptor Langerin is in association with a TRIM5α-ATG16L1 complex. Binding of Langerin to HIV-1 results in the internalization of the virus. Upon viral fusion, human TRIM5α mediates recruitment of ATG5 to form the TRIM5α–ATG16L1–ATG5–HIV-1p24 capsid complex, which promotes autophagosome formation and subsequent degradation of the viral capsid, thereby preventing HIV-1 infection and transmission by human Langerhans cells. Contrastingly, human and non-human primate dendritic cells, which reside within the submucosa (A), lack efficient TRIM5α-mediated retroviral restriction (C). Submucosal dendritic cells capture HIV-1 via the receptor DC-SIGN, which promotes productive HIV-1 infection of dendritic cells. Upon binding of HIV-1 to dendritic cells, TRIM5α dissociates from the DC-SIGN signalosome, and TRIM5α is trapped in nuclear Cajal bodies via a SUMOylation-dependent manner, thereby preventing cytosolic TRIM5α from forming a complex with the incoming viral capsid. In addition, autophagy is inhibited by the HIV-1 protein Env. Altogether, this results in HIV-1 escape from human TRIM5α/autophagy-mediated HIV-1 restriction mechanisms. (D) Upon fusion of the viral capsid with the macrophage membrane, the host protein CypA readily binds the incoming HIV-1 capsid. CypA coating of the capsid blocks the interaction of human TRIM5α with the viral capsid, and thereby prevents human TRIM5α-mediated restriction in macrophages. In macrophages, HIV-1 hijacks the early stages of the autophagy pathway for HIV-1 Gag processing. In addition, HIV-1 Nef inhibits the late degradative stages of autophagy thereby preventing lysosomal viral degradation. (E) The autophagy machinery is also downregulated in CD4⁺ T cells by the HIV-1 proteins Vif and Nef. HIV-1 can thereby integrate into the host genome in CD4⁺ T cells unhindered, to replicate and be released. Similar to macrophages, upon fusion of the viral capsid with the CD4⁺ T cell membrane, CypA binds the incoming HIV-1 capsid, preventing human TRIM5α-mediated restriction in CD4⁺T cells. S: small ubiquitin-like modifier (SUMO), CypA: Cyclophilin A.

Figure 3

TRIM5α-mediated regulation of innate immune signaling and molecular inflammation. The TAK1 signaling pathway is activated upon TLR4 stimulation, or upon sensing of viral capsid by TRIM5α. Subsequently, the E3 ligase activity of TRAF6 is activated and, together with the E2 ubiquitin conjugating enzyme complex UEV1A-UBC13, promotes K63-chain linked ubiquitination and autophosphorylation of the TAK1-TAB complex. In the context of HIV-1 infection, sensing of the viral capsid by TRIM5α initiates its E3 ligase activity resulting in K63-chain linked ubiquitination and autophosphorylation of the TAK1-TAB complex. Subsequently, the TAK1-TAB complex activates the transcription factors NF-kB and AP-1, leading to the transcription and ultimately secretion of pro-inflammatory cytokines such as IL-6 and IL-8. The autophagy-related proteins ULK1, Beclin1 and ATG7 are essential for TRIM5α to function as an innate immune sensor. However, precisely how they contribute to the TRIM5α-mediated inflammation is as yet uncertain. TLR4: toll-like receptor 4, TAK1: transforming growth factor-β-activated kinase 1, TAB: TAK1-binding protein, UEV1A: ubiquitin-conjugating enzyme E2 variant 1A, UBC13: ubiquitin-conjugating enzyme E2 13, AP-1: activating protein 1, NF-κB: nuclear factor κB, Ub: ubiquitin, P: phosphate, IL: interleukin.