Immunology And Pathology Of Acute and Chronic Murine Leukemia Virus Infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

In FY2021 the Retroviral Immunology Section completed a project identifying the first checkpoint response triggered during innate immunity to a pathogen. Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, could lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile. (Tal et al. mBio 11: e01293-20. 2020). We tested the hypothesis that CD47 blockade could enhance immune responses and recovery from infection using the lymphocytic choriomeningitis virus mouse model. Immunotherapeutic Blockade of CD47 inhibitory signaling enhanced both innate and adaptive immune responses by stimulating antigen presentation by dendritic cells and producing faster and more vigorous CD8+ T cell responses.(Cham et al. Cell Reports 31:107494. 2020). We also finished a collaboration with the Santiago lab to determine whether different Type I Interferons (IFN-Is) can deliver different cellular signals even though they are all recognized by a single receptor. IFN-Is are innate antiviral cytokines that include 12 different IFNalpha subtypes and IFNbeta that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNalpha subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNbeta in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNalpha subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNalpha subtypes. Notably, IFNbeta induced a broader interferome than the individual IFNalpha subtypes. Since IFNbeta, and not IFNalpha, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNbeta-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naive persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNbeta levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNbeta-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNbeta and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNbeta may drive HIV-1 pathogenesis in the gut.