Summary
The description of highly exposed individuals who remain seronegative (HESN) despite repeated exposure to human immunodeficiency virus (HIV)‐1 has heightened interest in identifying potential ...mechanisms of HIV‐1 resistance. HIV‐specific humoral and T cell‐mediated responses have been identified routinely in HESN subjects, although it remains unknown if these responses are a definitive cause of protection or merely a marker for exposure. Approximately half of HESN lack any detectible HIV‐specific adaptive immune responses, suggesting that other mechanisms of protection from HIV‐1 infection also probably exist. In support of the innate immune response as a mechanism of resistance, increased natural killer (NK) cell activity has been correlated with protection from infection in several high‐risk cohorts of HESN subjects, including intravenous drug users, HIV‐1 discordant couples and perinatally exposed infants. Inheritance of protective NK KIR3DL1high and KIR3DS1 receptor alleles have also been observed to be over‐represented in a high‐risk cohort of HESN intravenous drug users and HESN partners of HIV‐1‐infected subjects. Other intrinsic mechanisms of innate immune protection correlated with resistance in HESN subjects include heightened dendritic cell responses and increased secretion of anti‐viral factors such as β‐chemokines, small anti‐viral factors and defensins. This review will highlight the most current evidence in HESN subjects supporting the role of epithelial microenvironment and the innate immune system in sustaining resistance against HIV‐1 infection. We will argue that as a front‐line defence the innate immune response determines the threshold of infectivity that HIV‐1 must overcome to establish a productive infection.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre‐exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current ...adherence measurements are inadequate for real‐time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP.
Methods
We developed a urine assay using high‐performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV‐positive subjects with undetectable viral loads on a TDF/FTC‐based regimen, (2) healthy HIV‐negative subjects who received a single dose of TDF/FTC, and (3) HIV‐negative subjects receiving daily TDF/FTC as PrEP for 24 weeks.
Results
The urine assay detected TFV with greater sensitivity than plasma‐based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log‐linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10–1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement.
Conclusions
We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point‐of‐care test and be a useful tool to monitor adherence to PrEP.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundNatural killer (NK) cells and plasmacytoid and myeloid dendritic cells (DCs) are depleted, and their function impaired, in advanced adult human immunodeficiency virus (HIV)–1 infection. ...Studies in perinatally infected children are lacking MethodsPercentages of NK cells and plasmacytoid and myeloid DCs were evaluated by flow cytometry. Forty children with perinatal HIV-1 infection were compared with 11 age-matched, uninfected children. Plasmacytoid and myeloid DC function was evaluated by activation-induced cytokine secretion ResultsVirally suppressed children had normal levels of circulating plasmacytoid and myeloid DCs and total NK cells but had sustained depletion of a mature (CD3−/161+/56+/16+) NK cell subset and decreased interferon-α secretion by plasmacytoid DCs. Despite similar viral loads, percentages of myeloid and plasmacytoid DCs and mature NK cells were significantly lower in viremic children with a history of decreasing CD4+ cell percentages, compared with children with stable CD4+ cell counts ConclusionsChildren achieve partial reconstitution of myeloid and plasmacytoid DCs and NK cells during viral suppression; irrespective of viral load, a clinical history of decreasing CD4+ cell percentage is associated with greater depletion of these subsets. We hypothesize that the evaluation of selected innate-immunity effector cells may serve as a marker of CD4+ cell loss in pediatric HIV-1 infection
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Summary
The impact of hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono‐infected when compared to HIV/HCV co‐infected on antiretroviral therapy (ART) remains poorly ...understood. A total of 78 African American subjects HCV viraemic/naïve to HCV treatment (33 HCV genotype 1 mono‐infected, 45 ART‐treated HIV/HCV genotype 1 co‐infected) were studied. Clinical and liver enzyme measurements were performed. Whole blood was analysed for immune subset changes by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used for same‐day constitutive and in vitro Interferon (IFN)‐α‐induced signal transducer and activator of transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition‐mediated IFN‐γ production. Statistical analysis was performed using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T‐cell activation/exhaustion, and constitutive STAT‐1 phosphorylation compared to HCV. In contrast, CD4+FoxP3+CD25+ frequency, IFN‐αR expression on NK cells, as well as constitutive and IFN‐α‐induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load and CD4+ T‐cell count had an opposite effect between the two groups on NK cell activity and T‐cell activation, respectively. HCV viral load in ART‐treated HIV/HCV co‐infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono‐infection. The more pronounced immune modulation noted in ART‐treated HIV‐co‐infected/untreated HCV viraemic subjects may impact HCV disease progression and/or response to immunotherapy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
DC‐SIGN is a C‐type lectin, highly expressed on the surface ofimmature dendritic cells (DCs), that mediates efficient infection of Tcells in trans by its ability to bind HIV‐1, HIV‐2, and SIV. ...Inaddition, the ability of DC‐SIGN to bind adhesion molecules on surfacesof naïve T cells and endothelium also suggests its involvementin T‐cell activation and DC trafficking. To gain further insights intothe range of expression and potential functions of DC‐SIGN, weperformed a detailed analysis of DC‐SIGN expression in adult and fetaltissues and also analyzed its regulated expression on cultured DCs andmacrophages. First, we show that DC‐SIGN expression is restricted tosubsets of immature DCs in tissues and on specialized macrophages inthe placenta and lung. There were no overt differences between DC‐SIGNexpression in adult and fetal tissues except that DC‐SIGN expression inalveolar macrophages was only present after birth. Similarly, intissues, DC‐SIGN was observed primarily on immature (CD83‐negative)DCs. Secondly, in the peripheral blood, we found expression of DC‐SIGNon a small subset of BDCA‐2+ plasmacytoid DC precursors (pDC2),concordant with our finding of large numbers of DC‐SIGN‐positive cellsin allergic nasal polyps (previously shown to be infiltrated by DC2).Triple‐label confocal microscopy indicated that DC‐SIGN was colocalizedwith BDCA‐2 and CD123 on DCs in nasal polyp tissue. Consistent withthis finding is our observation that DC‐SIGN can be up‐regulated onmonocyte‐derived macrophages upon exposure to the Th2 cytokine, IL‐13. In summary, our data demonstrate the relevant populations of DC andmacrophages that express DC‐SIGN in vivo where it may impact theefficiency of virus infection and indicate that DC‐SIGN expression maybe involved in the Th2 axis of immunity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Dendritic cells (DC) have an instrumental role in the activation and function of both innate and adaptive immune responses. In humans, at least two distinct DC subsets have been characterized based ...on phenotypic markers: the myeloid DC (MDC) and the plasmacytoid DC (PDC). Both subsets are critical producers of cytokines (IL-12 for MDC and type I/II IFNs for PDC) and are functionally different. We show in this study that HIV(+) individuals have a significant decrease in the number of the Lin(-)HLA-DR(+)CD123(+) and BDCA-2(+) PDC compared with uninfected donors (p = 0.0001). HIV(+) individuals also have a sustained impairment in viral-induced IFN-alpha production (p < 0.0001). The decrease of the PDC subsets did not correlate with CD4 count or viral load and was not reversed in subjects under virally suppressive treatment, suggesting an irreversible change after infection. By contrast, the absolute number and median frequency of MDC in HIV-infected individuals were similar to those observed in uninfected controls, while a significant decrease was present in subjects with >5000 HIV-1 copies/ml. The inverse association with viral load of the MDC number, but not of IFN-alpha secretion or the number of PDC, suggests a role for MDC in viral control. Our data suggest that DC subsets are differentially reconstituted during the immune recovery associated with antiviral therapy. The persistent impairment of certain DC subsets may result in a sustained defect in DC-mediated innate immune functions despite an effective treatment regimen.
Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing ...protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.
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