Interactions between HIV-1 and the cell-autonomous innate immune system

Abstract

HIV-1 was recognized as the cause of AIDS in humans in 1984. Despite 30 years of intensive research, we are still unraveling the molecular details of the host-pathogen interactions that enable this virus to escape immune clearance and cause immunodeficiency. Here we explore a series of recent studies that consider how HIV-1 interacts with the cell-autonomous innate immune system as it navigates its way in and out of host cells. We discuss how these studies improve our knowledge of HIV-1 and host biology as well as increase our understanding of transmission, persistence, and immunodeficiency and the potential for therapeutic or prophylactic interventions.

Figure 1

Innate Immune IFN Responses and Caspase-1-Mediated Activation of Cytokines or Cell Death Are Functionally Coupled by Upstream PRRs for Viral DNA Sensors: cGAS, cGAMP synthase; IFI16, IFN-inducible protein 16; DAI, DNA-dependent activator of IRFs; DDX41, DEAD Asp-Glu-Ala-Asp box polypeptide 41. Adapters and transcription factors: ASC, activating signal cointegrator 1; STING, stimulator of IFN gene; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IRF3, IFN regulatory factor 3.

Figure 2

The Relationship between HIV-1, DNA Sensors, and IFN Production Determines Successful Replication versus Abortive Infection and Cell Death (A–F) In macrophages, recruitment of host factors (CPSF6 and CypA) to the HIV-1 capsid, shown as a blue border (A), and degradation of cytoplasmic viral DNA by the exonuclease TREX1 (B) prevents IFN responses and allows HIV-1 to establish productive infection. Mutations in capsid or small molecule inhibitors that prevent binding of CypA lead to IFN responses due to cGAS-mediated detection of the DNA products of HIV-1 reverse transcription (RT) even in the presence of TREX1 (C). In T cells, the sensing of incomplete RT products by IFI16 led to activation of the inflammasome and caspase-1-dependent cell death as well as stimulation of the IFN responses (D). Cell death in T cells has also been attributed to a DNA protein kinase (DNA PK)-dependent DNA damage response that involves p53 and histone H2AX and results from incomplete HIV-1 DNA integration events (E). Mx2 is an exemplar for the antiviral effectors that are induced after sensing and that restrict viral infection. Mx2 restricts HIV-1 nuclear entry, and no viral countermeasures are known (F). Mx2 does not fully account for IFN-mediated restriction of wild-type HIV-1, suggesting the presence of further, yet-unidentified restriction factors.

Figure 3

Type 1 IFN May Have Positive and Negative Effects Requiring Different Therapeutic Strategies at Each Stage of the Course of HIV-1 Disease (A–C) Changes to CD4-positive T cells (CD4), type 1 IFN, and HIV-1 viral load (HIV VL) are represented schematically over the course of HIV-1 infection. We propose that HIV-1 goes under the radar of innate immune detection and hence evades IFN restriction in the eclipse phase that follows virus inoculation (A), allowing it to establish a foothold in host cells. The viremia that then arises from massive virus propagation in T cells is associated with significant T cell death and a systemic type 1 IFN response (B). Innate immune responses that link induction of IFN and activation of the inflammasome may contribute to the control of viremia, but also mediate T cell death by pyroptosis. Chronic IFN responses associated with persistent viremia may contribute to progressive HIV-1 disease associated with chronic immune activation (C). The different roles for innate immune responses to HIV-1 at each stage may offer specific therapeutic opportunities, such as enhancing innate immune detection by uncloaking the virus to reduce transmission efficiency, targeting caspase-1 activation to reduce T cell death without compromising IFN-mediated restriction during primary HIV-1 disease, and inhibiting HIV-1 induction of IFN in chronic infection to attenuate progressive disease.