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Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1P; splenic ROR[gamma]t+[CD4.sup.+] T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colonic lymphocytes to indole increased the expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA., Introduction Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are 2 forms of inflammatory arthritis characterized by progressive joint inflammation leading to articular destruction. While there are genetic associations of MHC and [...]

People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH.

Objective(s)Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear.DesignSamples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection (n = 24) and age/sex-balanced uninfected controls (n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals (n = 15) and uninfected controls (n = 15).MethodsThe expression of 12 IFNα subtypes, IFNβ and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined.ResultsIFNα1, IFNα2, IFNα4, IFNα5 and IFNα8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNβ was undetectable. By contrast, IFNβ was upregulated and all IFNα subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls.ConclusionThe IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNβ being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response.

BackgroundWe examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study.MethodsCases were 143 human immunodeficiency virus (HIV)-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events.ResultsInflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event.ConclusionsInflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease.Clinical trials registrationNCT00001137.

BackgroundHIV-1 infection is associated with intestinal inflammation, changes in the enteric microbiota (dysbiosis), and intestinal epithelial cell damage. NKp44 innate lymphoid cells (ILCs) play an important role in epithelial barrier maintenance through the production of interleukin (IL)-22 but also display functional plasticity and can produce inflammatory cytokines [eg, interferon gamma (IFNγ)] in response to cytokine milieu and stimulatory signals. The objective of this pilot study was to enumerate frequencies of IL-22 and IFNγ-expressing colonic NKp44 ILCs during untreated, chronic HIV-1 infection.SettingA cross-sectional study was performed to compare numbers of cytokine-expressing ILCs in colonic biopsies of untreated, chronic HIV-1 infected (n = 22), and uninfected (n = 10) study participants. Associations between cytokine ILC and previously established measures of virological, immunological, and microbiome indices were analyzed.MethodsMulticolor flow cytometry was used to measure the absolute number of colonic CD3NKp44CD56 ILCs expressing IL-22 or IFNγ after in vitro mitogenic stimulation.ResultsNumbers of colonic NKp44 ILCs that expressed IFNγ were significantly higher in HIV-1 infected versus uninfected persons and positively correlated with relative abundances of dysbiotic bacterial species in the Xanthomonadaceae and Prevotellaceae bacterial families and with colonic myeloid dendritic cell and T-cell activation.ConclusionHigher numbers of inflammatory colonic ILCs during untreated chronic HIV-1 infection that associated with dysbiosis and colonic myeloid dendritic cell and T-cell activation suggest that inflammatory ILCs may contribute to gut mucosal inflammation and epithelial barrier breakdown, important features of HIV-1 mucosal pathogenesis.

Commensal organisms appear to play significant roles in normal homeostasis as well as in the pathogenesis of HIV infection in a number of different organ systems. On November 17th and 18th, 2016, leading researchers from around the world met to discuss their insights on advances in our understanding of HIV and the microbiome at the National Institutes of Health (NIH) in Bethesda. Dr. Elhanan Borenstein of the University of Washington gave a keynote address where he discussed new developments in systems biology which hold the promise of illuminating the pathways by which these organisms interact with human physiology. He suggested that we need to get past correlations in microbiome research by using models and informatics which incorporate metagenomics to predict functional changes in the microbiome.

BackgroundHIV-1 infection is associated with intestinal inflammation, changes in the enteric microbiota (dysbiosis), and intestinal epithelial cell damage. NKp44 innate lymphoid cells (ILCs) play an important role in epithelial barrier maintenance through the production of interleukin (IL)-22 but also display functional plasticity and can produce inflammatory cytokines [eg, interferon gamma (IFNγ)] in response to cytokine milieu and stimulatory signals. The objective of this pilot study was to enumerate frequencies of IL-22 and IFNγ-expressing colonic NKp44 ILCs during untreated, chronic HIV-1 infection.SettingA cross-sectional study was performed to compare numbers of cytokine-expressing ILCs in colonic biopsies of untreated, chronic HIV-1 infected (n = 22), and uninfected (n = 10) study participants. Associations between cytokine ILC and previously established measures of virological, immunological, and microbiome indices were analyzed.MethodsMulticolor flow cytometry was used to measure the absolute number of colonic CD3NKp44CD56 ILCs expressing IL-22 or IFNγ after in vitro mitogenic stimulation.ResultsNumbers of colonic NKp44 ILCs that expressed IFNγ were significantly higher in HIV-1 infected versus uninfected persons and positively correlated with relative abundances of dysbiotic bacterial species in the Xanthomonadaceae and Prevotellaceae bacterial families and with colonic myeloid dendritic cell and T-cell activation.ConclusionHigher numbers of inflammatory colonic ILCs during untreated chronic HIV-1 infection that associated with dysbiosis and colonic myeloid dendritic cell and T-cell activation suggest that inflammatory ILCs may contribute to gut mucosal inflammation and epithelial barrier breakdown, important features of HIV-1 mucosal pathogenesis.

ObjectiveGut microbial translocation is a major driving force behind chronic immune activation during HIV-1 infection. HIV-1-related intestinal dysbiosis, including increases in mucosa-associated pathobionts, may influence microbial translocation and contribute to mucosal and systemic inflammation. Thus, it is critical to understand the mechanisms by which gut microbes and their metabolic products, such as butyrate, influence immune cell function during HIV-1 infection.DesignA cross-sectional study was performed to compare the relative abundance of butyrate-producing bacterial (BPB) species in colonic biopsies and stool of untreated, chronic HIV-1-infected (n = 18) and HIV-1-uninfected (n = 14) study participants. The effect of exogenously added butyrate on gut T-cell activation and HIV-1 infection was evaluated using an ex-vivo human intestinal cell culture model.MethodsSpecies were identified in 16S ribosomal RNA sequence datasets. Ex-vivo isolated lamina propria mononuclear cells were infected with C-C chemokine receptor type 5-tropic HIV-1Bal, cultured with enteric gram-negative bacteria and a range of butyrate doses, and lamina propria T-cell activation and HIV-1 infection levels measured.ResultsRelative abundance of total BPB and specifically of Roseburia intestinalis, were lower in colonic mucosa of HIV-1-infected versus HIV-1-uninfected individuals. In HIV-1-infected study participants, R. intestinalis relative abundance inversely correlated with systemic indicators of microbial translocation, immune activation, and vascular inflammation. Exogenous butyrate suppressed enteric gram-negative bacteria-driven lamina propria T-cell activation and HIV-1 infection levels in vitro.ConclusionReductions in mucosal butyrate from diminished colonic BPB may exacerbate pathobiont-driven gut T-cell activation and HIV replication, thereby contributing to HIV-associated mucosal pathogenesis.

Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases., Introduction Persistent immune activation and inflammation are hallmarks of chronic HIV/SIV infection and strong predictors of disease progression, independent of plasma viral loads (pVLs), or peripheral [CD4.sup.+] T cell counts [...]

UnlabelledAbnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.Clinical trials registrationNCT 01543958.

BackgroundDefining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.MethodsWe conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.ResultsHigher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.ConclusionsInterventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137.

A study is conducted to determine whether increased sequence variation occurs in regions of endogenous HIV-1 targeted by HIV-1-specific CD4(super +) T cells. The presence of increased variation would be suggestive immune evasion by HIV-1.