Interplay between Intrinsic and Innate Immunity during HIV Infection

Abstract

Restriction factors are antiviral components of intrinsic immunity which constitute a first line of defense by blocking different steps of the human immunodeficiency virus (HIV) replication cycle. In immune cells, HIV infection is also sensed by several pattern recognition receptors (PRRs), leading to type I interferon (IFN-I) and inflammatory cytokines production that upregulate antiviral interferon-stimulated genes (ISGs). Several studies suggest a link between these two types of immunity. Indeed, restriction factors, that are generally interferon-inducible, are able to modulate immune responses. This review highlights recent knowledge of the interplay between restriction factors and immunity inducing antiviral defenses. Counteraction of this intrinsic and innate immunity by HIV viral proteins will also be discussed.

Keywords: HIV-1; host restriction factors; immune responses; innate immune sensing; interferon; viral counteraction.

Figure 1

Simplified overview of several pattern recognition receptors (PRRs) signaling after pathogen-associated-molecular patterns (PAMPs) recognition. Signal transduction cascades leading to the production of type I interferon (IFN-I) and pro-inflammatory cytokines after Toll-like-receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) activation are described. See the text for more details. MyD88: myeloid differentiation factor 88, MAL: MyD88-adaptor-like, TRIF: TIR domain-containing adaptor-inducing IFN-β, TRAM: TRIF-related adaptor molecule, IRAK: interleukin-1 receptor-associated kinase, TRAF6: TNF receptor associated factor 6, TAK1: transforming growth factor beta-activated kinase 1, MAPK: mitogen-activated protein kinase, IKK: IκB kinase, NF-κB: nuclear factor-kappa B, IRF: IFN-regulatory factor, TBK1: tank-binding kinase 1, MAVS: mitochondrial antiviral-signaling, FADD: Fas-associated protein with death domain.

Figure 2

Schematic representation of HIV sensing by PRRs leading to the expression of antiviral restriction factors and shaping of immunity by restriction factors. Detection of HIV PAMPs by PRRs leads to activation of the transcription factors IRF and NF-κB driving the expression of IFN-I and inflammatory cytokines, respectively. IFN-I binds to IFNAR (IFN-α/β receptor chain) and activates transcription of interferon-stimulated genes (ISGs) including the restriction factors interferon-inducible transmembrane (IFITM) proteins, tripartite motif (TRIM)5α, apolipoprotein B mRNA-editing enzyme catalytic subunit-like 3G (APOBEC3G/A3G) and bone marrow stromal antigen 2 (BST-2). Antiviral functions of restriction factors are indicated by red arrows. Feedback of restriction factors on immunity are depicted by green arrows (induction: solid lines, inhibition: dotted lines). Counteractions by viral proteins are depicted in pink. Only restriction factors that are both induced by immunity and have an effect on immunity are illustrated. pDC: plasmacytoid dendritic cells, NK: natural killer cells, RT: reverse transcription, TLR: Toll-like receptors, RIG-I: retinoic acid-inducible gene I, cGAS: cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase, cGAMP: cyclic GMP-AMP, STING: stimulator of interferon genes, IFI16: interferon gamma inducible protein 16, IRF: IFN-regulatory factor, ssRNA: single-stranded RNA, dsDNA: double-stranded DNA, TCR: T cell receptor, MHC-I pep: major histocompatibility complex I associated with a peptide.