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Macrophages are critical orchestrators of tissue immunity, from the initiation and resolution of antimicrobial immune responses to the subsequent repair of damaged tissue. Murine studies have demonstrated that tissue-resident macrophages are comprised of a mixture of yolk sac-derived cells that populate the tissue before birth and hematopoietic-derived replacements that are recruited in adult tissues both at steady-state and in increased numbers in response to tissue damage or infection. While resident macrophages in some murine tissues are readily turned over and replaced, other tissues primarily retain their original, yolk sac-derived complement of macrophages. How this translates to species that are constantly under immunologic challenge, such as humans, is unknown. To understand the ontogeny and longevity of tissue-resident macrophages in nonhuman primates (NHPs), we employ a model of autologous HSPC transplantation with HSPCs genetically modified to express individual bar-coded markers allowing for subsequent analysis of clonal differentiation of leukocyte subsets. We study the contribution of HSPC to tissue-macrophages and their clonotypic profiles relative to leukocyte subsets across tissues and peripheral blood. We also use in vivo bromodeoxyuracil infusions to monitor tissue macrophage turnover in NHPs at steady state. We find that, in all anatomic sites we studied, HSPC contribute to tissue-resident macrophage populations. Their clonotypic profile is dynamic and overlaps significantly with the clonal hierarchy of contemporaneous monocytes in peripheral blood. Moreover, we find evidence of tissue-macrophage turnover at steady state in otherwise unmanipulated NHPs. These data demonstrate the life span of tissue-resident macrophages can be limited and they can be replenished from HSPCs. Thus, in primates not all yolk-sac derived tissue-macrophages survive for the duration of the host’s life.

The success of poxviruses as pathogens depends upon their antagonism of host responses by multiple immunomodulatory proteins. The largest of these expressed by ectromelia virus (the agent of mousepox) is C15, one member of a well-conserved poxviral family previously shown to inhibit T cell activation. Here, we demonstrate by quantitative immunofluorescence imaging that C15 also limits contact between natural killer (NK) cells and infected cells in vivo. This corresponds to an inhibition in the number of total and degranulating NK cells, ex vivo and in vitro, with no detectable impact on NK cell cytokine production nor the transcription of factors related to NK cell recruitment or activation. Thus, in addition to its previously identified capacity to antagonize CD4 T cell activation, C15 inhibits NK cell cytolytic function, which results in increased viral replication and dissemination in vivo. This work builds on a body of literature demonstrating the importance of early restriction of virus within the draining lymph node.summaryPoxvirus B22 family proteins are important virulence factors known to inhibit T cell functions. Peauroi et al. identify a novel function of the ectromelia virus homolog, C15, which inhibits NK cell-target contact and cytolytic function to facilitate early viral spread.(Provide a short, ∼40-word summary statement for the online JEM table of contents and alerts. This summary should describe the context and significance of the findings for a general readership; it should be written in the present tense and refer to the work in the third person.)

Microbial translocation contributes to persistent inflammation in both treated and untreated HIV infection. Although translocation is due in part to a disintegration of the intestinal epithelial barrier, there is a bias towards the translocation of Proteobacteria. We hypothesized that intestinal epithelial microvesicle cargo differs after HIV infection and contributes to biased translocation. We isolated gastrointestinal luminal microvesicles before and after progressive simian immunodeficiency virus (SIV) infection in rhesus macaques and measured miRNA and antimicrobial peptide content. We demonstrate that these microvesicles display decreased miR-28-5p, -484, -584-3p, and -584-5p, and let-7b-3p, as well as increased beta-defensin 1 after SIV infection. We further observed dose-dependent growth sensitivity of commensal Lactobacillus salivarius upon co-culture with isolated microvesicles. Infection-associated microvesicle differences were not mirrored in non-progressively SIV-infected sooty mangabeys. Our findings describe novel alterations of antimicrobial control after progressive SIV infection that influence the growth of translocating bacterial taxa. These studies may lead to the development of novel therapeutics for treating chronic HIV infection, microbial translocation, and inflammation.

Mycobacterium genavense is a challenging opportunistic pathogen to diagnose and manage in patients with human immunodeficiency virus (HIV). Persistent immunosuppression or protracted immune reconstitution inflammatory syndrome can lead to complicated clinical courses. We describe 3 cases of M. genavense in patients with HIV representing the spectrum between disease burden and strength of immune response.

Tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) is a serious complication of starting combination antiretroviral therapy (cART). TB-IRIS emerges early after cART initiation and is characterized by rapid expansions of TB-specific CD4+ T cells and high levels of inflammatory mediators driven by CD4+ T cells. The effects of TB-IRIS on HIV populations are unknown, but could result in profound expansion and elimination of HIV infected cells via cellular activation and acute inflammation. We investigated immediate and long-term effects of TB-IRIS on HIV infected cells with and without TB-IRIS. We measured plasma HIV RNA, cell-associated HIV RNA and HIV DNA levels and compared genetic characteristics of HIV populations after prolonged cART. We found that TB-IRIS was associated with more diverse HIV DNA populations and HIV reservoirs after IRIS were distinct from pre-therapy populations, suggesting that TB-IRIS can shape the HIV reservoir with detrimental implications for HIV remission strategies.

CD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells. The first inherited loss of any functional component of CD4, including soluble CD4, is clinically distinct from any other congenital or acquired CD4 T-cell defect and characterized by compensatory changes in T-cell subsets and functional impairment of B cells, monocytes, and natural killer cells.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is an aberrant inflammatory response in individuals with advanced human immunodeficiency virus (HIV) infection, after antiretroviral therapy (ART) initiation. The pathogenesis of Mycobacterium avium complex (MAC)–associated IRIS has not been fully elucidated. METHODS: We investigated monocyte and CD4(+) T-cell responses in vitro, tumor necrosis factor (TNF) expression in tissues, and plasma cytokines and inflammatory markers, in 13 HIV-infected patients with MAC-IRIS and 14 HIV-uninfected patients with pulmonary MAC infection. RESULTS: Prior to ART, HIV-infected compared with HIV-uninfected patients, had reduced TNF(+) monocytes (P = .013), although similar cytokine (interferon gamma [IFN-γ], TNF, interleukin 2 [IL-2], and interleukin 17 [IL-17])–expressing CD4(+) T cells. During IRIS, monocyte cytokine production was restored. IFN-γ(+) (P = .027), TNF(+) (P = .004), and polyfunctional CD4(+) T cells (P = 0.03) also increased. These effectors were T-bet(low), and some expressed markers of degranulation and cytotoxic potential. Blockade of cytotoxic T-lymphocyte associated protein 4 and lymphocyte activation gene-3 further increased CD4(+) T-cell cytokine production. Tissue immunofluorescence showed higher proportions of CD4(+) and CD68(+) (monocyte/macrophage) cells expressed TNF during IRIS compared with HIV-uninfected patients. Plasma IFN-γ (P = .048), C-reactive protein (P = .008), and myeloperoxidase (P < .001) levels also increased, whereas interleukin 10 decreased (P = .008) during IRIS. CONCLUSIONS: Advanced HIV infection was associated with impaired MAC responses. Restoration of monocyte responses and expansion of polyfunctional MAC-specific T-bet(low) CD4(+) T cells with cytotoxic potential after ART initiation may overwhelm existing regulatory and inhibitory mechanisms, leading to MAC-IRIS.

In this review, we will describe the immunopathogies of immune reconstitution inflammatory syndrome, IRIS. IRIS occurs in a small subset of HIV patient, initiating combination antiretroviral therapy (ART), where immune reconstitution becomes dysregulated, resulting in an overly robust antigen-specific inflammatory reaction. We will discuss IRIS in terms of the associated coinfections: mycobacteria, cryptococci, and viruses.

Paradoxical inflammatory reactions associated with treatment of neurotuberculosis can lead to severe morbidity and mortality and may not be controlled by steroids alone. We report the use of the Janus kinase inhibitor ruxolitinib to treat a steroid-refractory neurotuberculosis paradoxical reaction.

Background Mycobacterium genavense is an opportunistic pathogen in HIV patients that is difficult to culture and difficult to manage clinically. Here we describe three cases of HIV patients with Mycobacterium genavense with courses representing the spectrum of M.genavense presentations in the current ART era complicated by differing divergent immune responses. Methods Two patients were in a longitudinal study at NIAID enrolling patients with HIV and suspected IRIS (PANDORA) (NCT02147405) and one was seen at St. James’s hospital in Dublin. Frozen peripheral blood mononuclear cells were collected at the time of presentation and were used for in vitro stimulation with irradiated M. genavenese in cases 1 and 2 to detect production of cytokines by CD4 T cells. Results Pt 1: 27-year old male with M. genavense presenting as diarrhea, abdominal pain, skin nodules, hepatosplenomegaly, and lymphadenopathy (LAN) that persisted on one year of anti-mycobacterial therapy and ART. No CD4 T-cell cytokine response to M. genevense genavense was detected (Fig 1). He received interferon-g and optimization of his antimycobacterial regimen with improvement of symptoms and decreased pathogen burden on repeated biopsies. Pt 2: 55-year old female with M. genavense IRIS manifesting as fevers and abdominal pain that persisted for 10 months on ART (CD4 109 cells/µmL) requiring intermittent corticosteroid use complicated by adrenal insufficiency. She had evidence of CD4 T-cell response to M. genavense in vitro and improved with optimization of her anti-mycobacterial and corticosteroid regimen. Pt 3: 39-year-old male with M. genavense IRIS presenting as fevers, LAN, pleuritic chest pain, and abdominal pain on ART (CD4 19 c/mµL) persisting despite immunologic response to ARV therapy (CD4 recovery to 419 c/mL), appropriate anti-mycobacterial therapy and corticosteroids. He required 4 doses of infliximab (5 mg/kg IV) that facilitated tapering of prednisone. Conclusion The clinical presentation of Mycobacterium genavense in HIV patients in the ARV era range from disseminated disease with poor immune reconstitution to persistent or severe IRIS requiring immune suppression. Effective clinical outcomes relied on appropriate anti-mycobacterial and either immune-boosting or immune-suppressive therapies. Disclosures All authors: No reported disclosures.

The management of corticosteroid refractory immune reconstitution inflammatory syndrome (IRIS) is currently unclear. Infliximab administration was associated with clinical improvement without significant adverse events in 3 patients with mycobacterial IRIS. Immunologic and virologic responses to antiretroviral therapy were unaffected. Tumor necrosis factor blockade may be beneficial for IRIS and warrants further study in clinical trials.