Innate antiviral immune signaling, viral evasion and modulation by HIV-1

Abstract

The intracellular innate antiviral response in human cells is an essential component of immunity against virus infection. As obligate intracellular parasites, all viruses must evade the actions of the host cell's innate immune response in order to replicate and persist. Innate immunity is induced when pathogen recognition receptors of the host cell sense viral products including nucleic acid as "non-self". This process induces downstream signaling through adaptor proteins to activate latent transcription factors that drive the expression of genes encoding antiviral and immune modulatory effector proteins that restrict virus replication and regulate adaptive immunity. The interferon regulatory factors (IRFs) are transcription factors that play major roles in innate immunity. In particular, IRF3 is activated in response to infection by a range of viruses including RNA viruses, DNA viruses and retroviruses. Among these viruses, human immunodeficiency virus type 1 (HIV-1) remains a major global health problem mediating chronic infection in millions of people wherein recent studies show that viral persistence is linked with the ability of the virus to dysregulate and evade the innate immune response. In this review, we discuss viral pathogen sensing, innate immune signaling pathways and effectors that respond to viral infection, the role of IRF3 in these processes and how it is regulated by pathogenic viruses. We present a contemporary overview of the interplay between HIV-1 and innate immunity, with a focus on understanding how innate immune control impacts infection outcome and disease.

Keywords: HIV; ISG; innate immunity; interferon; virus.

Fig. 1.

The HIV-1 life cycle and points of PRR sensing. Upon binding to CD4/coreceptor and viral entry into target cells (left), the HIV-1 capsid is exposed, which is sensed albeit inefficiently by TRIM5. The related SIV is sensed robustly by TRIM5 while HIV-1 is sensed effectively by TRIM5 in nonhuman primate cells. Once the capsid uncoats, genomic RNA (gRNA) accesses the cytoplasm for reverse transcription, which generates single-stranded and double-stranded viral DNA (vDNA). This DNA then integrates into the host genome (hDNA). Transcription of the integrated vDNA into viral messenger RNA (vmRNA) is necessary for HIV-1 protein translation, while new gRNA is transcribed for nascent virions. RIG-I may sense gRNA, while sensing of vDNA and vmRNA occurs through DNA and RNA sensing pathways, including cGAS/STING and other pathways that signal IRF3 activation. Tetherin senses accumulating virions at the cell surface. In pDCs (right), HIV-1 RNA is sensed by TLR7 in the endosome and may arrive there by endocytosis or autophagy.

Fig. 2.

Convergence of antiviral sensing pathways on IRF3. Viruses containing RNA genomes, when endocytosed, present RNA ligands for TLR3 in endosomes, which then signals through TRIF to activate IRF3. RNA PAMPs generated during viral replication can be detected in the cytosol by the RLRs or other DexD/H helicases that signal through MAVS or TRIF, respectively. Viral DNA in the cytoplasm either is sensed directly by molecules such as cGAS, which signals through STING, or is transcribed by RNA pol III to generate RIG-I ligands. For simplicity, MAVS is shown on the mitochondrion, and STING on the endoplasmic reticulum (ER), though both molecules are localized to multiple intracellular membranes. Activation of these various pathways leads to IRF3 phosphorylation, dimerization, nuclear translocation and the transcription of IFN-β.

Fig. 3.

Schematic of IRF3 functional domains. NLS, nuclear localization sequence; NES, nuclear export sequence; PRO, proline-rich region; SRR, serine-rich region.