Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT's immune involvement is primarily due to strong pro-inflammatory ...responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been found that memory T cells accumulate in AT, where they provide efficient secondary responses against viral pathogens. These observations have prompted researchers to re-evaluate the links between obesity and susceptibility to infections. In contrast, AT serves as a reservoir for several persistence pathogens, such as human adenovirus Ad-36,
,
, influenza A virus, and cytomegalovirus (CMV). The presence and persistence of bacterial DNA in AT has led to the concept of a tissue-specific microbiota. The unexpected coexistence of immune cells and pathogens within the specific AT environment is intriguing, and its impact on anti-infectious immune responses requires further evaluation. AT has been recently identified as a site of HIV persistence. In the context of HIV infection, AT is targeted by both the virus and the antiretroviral drugs. AT's intrinsic metabolic features, large overall mass, and wide distribution make it a major tissue reservoir, and one that may contribute to the pathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral, and pharmacological aspects that contribute to HIV persistence in AT. We also evaluate the respective impacts of both intrinsic and HIV-induced factors on AT's involvement as a viral reservoir. Lastly, we examine the potential consequences of HIV persistence on the metabolic and immune activities of AT.
PURPOSE OF REVIEWRecent studies have been published characterizing the epidemiology of elite controllers. The demographic features, clinical characteristics, and HIV disease outcomes of elite ...controllers are summarized.
RECENT FINDINGSElite controllers are defined by the ability to spontaneously suppress plasma viremia. Despite differing definitions in the literature, studies have shown that elite control of HIV infection is established soon after seroconversion and occurs in less than 1% of HIV-infected individuals. Elite controllers are demographically heterogeneous with diverse racial backgrounds and modes of HIV transmission, though genetic studies demonstrate an overrepresentation of protective HLA alleles. Elite controllers typically have elevated CD4 cell counts, stable CD4 trajectories, and more favorable clinical outcomes compared with viremic patients. A proportion of elite controllers, however, may experience HIV disease progression with loss of virologic control, CD4 cell declines, and rarely AIDS-defining events.
SUMMARYElite controllers are a subgroup of HIV-infected individuals characterized by the ability to spontaneously maintain virologic control. The mechanisms underlying elite control are aggressively being sought to guide vaccine development and novel therapeutic strategies. As elite control may be a temporary state, the ability to distinguish and further characterize elite controllers with long-term clinical success from those with HIV disease progression is of major importance.
Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated ...with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunoregulatory receptors are essential for orchestrating an immune response as well as appropriate inflammation in infectious and non-communicable diseases. Among them, leukocyte ...immunoglobulin-like receptors (LILRs) consist of activating and inhibitory receptors that play an important role in regulating immune responses modulating the course of disease progression. On the one hand, inhibitory LILRs constitute a safe-guard system that mitigates the inflammatory response, allowing a prompt return to immune homeostasis. On the other hand, because of their unique capacity to attenuate immune responses, pathogens use inhibitory LILRs to evade immune recognition, thus facilitating their persistence within the host. Conversely, the engagement of activating LILRs triggers immune responses and the production of inflammatory mediators to fight microbes. However, their heightened activation could lead to an exacerbated immune response and persistent inflammation with major consequences on disease outcome and autoimmune disorders. Here, we review the genetic organisation, structure and ligands of LILRs as well as their role in regulating the immune response and inflammation. We also discuss the LILR-based strategies that pathogens use to evade immune responses. A better understanding of the contribution of LILRs to host-pathogen interactions is essential to define appropriate treatments to counteract the severity and/or persistence of pathogens in acute and chronic infectious diseases lacking efficient treatments.
Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on ...efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.
Patients with advanced solid tumors treated at Gustave Roussy with an anti–PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged < 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.
Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 < 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70–93) and 59 years old (17–69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III–IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.
Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.
•Incidence of grade ≥ II immune related adverse events (irAEs) is higher in older.•Older patients are more prone to having multiple irAEs.•Prescribers should monitor closely older patients during anti-PD(L)1 treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
The aim of this study was to quantify the contribution of FDG PET to the diagnostic assessment of fever of unknown origin (FUO), taking into account the diagnostic limitations resulting from ...the composite nature of this entity.
Methods
The PubMed/MEDLINE database was searched from 2000 to September 2015. Original articles fulfilling the following criteria were included: (1) FUO as the initial diagnosis, (2) no immunosuppressed or nosocomial condition, (3) final diagnosis not based on PET, (4) a follow-up period specified, (5) adult population, and (6) availability of adapted data for calculation of odds ratios (ORs). ORs were computed for each study and then pooled using a random effects model. Stratification-based sensitivity analyses were finally performed using the following prespecified criteria: (a) study design, (b) PET device, (c) geographic area, and (d) follow-up period.
Results
A meta-analysis of the 14 included studies showed that normal PET findings led to an increase in the absolute final diagnostic rate of 36 % abnormal PET findings to an increase of 83 %, corresponding to a pooled OR of 8.94 (95 % CI 4.18 – 19.12,
Z
= 5.65;
p
< 0.00001). The design of the studies influenced the results (OR 2.92, 95 % CI 1.00 – 8.53 for prospective studies; OR 18,57, 95 % CI 7.57 – 45.59 for retrospective studies;
p
= 0.01), whereas devices (dedicated or hybrid), geographic area and follow-up period did not.
Conclusion
Abnormal PET findings are associated with a substantially increased final diagnostic rate in FUO. Consequently, FDG PET could be considered for inclusion in the first-line diagnostic work-up of FUO. Further randomized prospective studies with standardized FDG PET procedures are warranted to confirm this first-line position.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers ...them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been ...associated with a strong, multifunctional specific CD8⁺ T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8⁺ T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8⁺ T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8⁺ T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4⁺ T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8⁺ T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8⁺ T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4⁺ T cells and was observed only with autologous CD4⁺ T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8⁺ T cells could account for the control of viral replication in HIC.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of ...sustained response. In total, 173 patients received 4 infusions of 375 mg/m2 and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician’s preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count ≥30 × 109/L and ≥2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295.
•Tolerance of rituximab is acceptable in ITP, and with its benefit/risk ratio may remain a valid option for treating ITP in adults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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