Resolution of immune activation defines nonpathogenic SIV infection

Abstract

Natural nonhuman primate hosts of SIV do not succumb to AIDS despite significant viral replication, a phenomenon attributed to reduced levels of chronic and deleterious "immune activation." Two studies in this issue of the JCI, by Bosinger et al. and Jacquelin et al., now show that SIV induces vigorous immune activation and upregulation of IFN-stimulated genes in both natural and susceptible hosts, but strikingly, the responses resolve only in the former (see the related articles, beginning on pages 3556 and 3544, respectively). Thus, natural hosts for SIV actively engage mechanisms to abort sustained immune activation and its associated harmful effects.

Figure 1. Transcriptional profile of pathogenic and nonpathogenic SIV infections.

(A) Nonpathogenic SIV infections in SMs and AGMs are characterized by sustained CD4⁺ T cell counts and controlled viremia (viral load [VL]). There is early upregulation of transcripts for viral restriction factors (blue), of genes associated with dampening of T cell activation (pink), of antimicrobial defensins (red), and of ISGs (green). However, the expression of ISGs resolves rapidly, possibly due to upregulation of suppressors of the IFN response (yellow). Transcripts for the immune-dampening genes TGFB and IL10 are upregulated in chronic infection (pink). Myxovirus influenza virus resistance protein 1 (MX1) and IP10 are antiviral factors. Melanoma differentiation–associated protein 5 (MDA5) and retinoic acid–inducible gene I (RIG-I) are intracellular sensors of RNA viruses. IRF7, IFN regulatory factor 7. (B) In contrast, SIV infection of RMs is characterized by eventual loss of CD4⁺ T cells and corresponding loss of control of viremia. RMs have chronic expression of ISGs, accompanied by enhanced expression of proapoptotic factors (purple), as well as markers of T cell activation and exhaustion and of inflammation (pink). Antiviral host restriction factors: apolipoprotein B mRNA–editing enzyme, catalytic polypeptide–like 3 (APOBEC3), T cell receptor–interacting molecule (TRIM) family members. T cell–associated inhibitory factors: LAG3, IL10, programmed cell death ligand 1 (PDL1), soluble galactoside-binding lectin 3 (LGALS3; also known as galectin-3, a proapoptotic ISG), and IDO. Suppressors of IFN: adenosine deaminase, RNA-specific (ADAR), laboratory of genetics and physiology 2 (LGP2), and IFN-stimulated gene 15 (ISG15). Proapoptotic molecules: TRAIL and B cell CLL/lymphoma 2-like 14 (BCL2L14). Markers of T cell activation and exhaustion: MKI67 (marker of proliferation), CD38, CCR5, CXCL9, and CXCL11, TIM3, IL7-receptor (IL7R), and LAG3.

Figure 2. Possible strategies for manipulation of innate immunity in pathogenic infections.

Chronic immune activation is a multifactorial process driven by many cell types, including conventional DCs (cDCs), pDCs, T cells, or NK cells. DCs recognizing HIV or microbial components through TLRs or other pattern recognition receptors secrete IFN-α and inflammatory cytokines, inducing activation of other cell types (e.g., NK cells). Activated NK cells can lyse virally infected cells directly or through ADCC. Inhibitors of the TLR pathway or of cytokine signaling can be used to tune down the inflammatory response. For example, chloroquine (14) and short oligonucleotides (ODNs) block activation of endosomal TLR. Rapamycin inhibits mammalian target of rapamycin (mTOR) signaling, necessary for recruitment of MyD88 to TLRs (16). STAT decoys can inhibit the transcriptional program induced in target cells by inflammatory cytokines. Synthetic mimetics of defensins, peptides with antimicrobial activity, could be used to protect gut epithelium from bacterial invasion and enhance anti-HIV immune responses. TRAF6, TNF receptor–associated factor 6; IRAK1, IL-1 receptor–associated kinase 1.