ABSTRACT
The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages. It is now clear, however, that the transition from human fetal-to-adult T cell identity and function does not occur due to a binary switch between distinct fetal and adult lineages. Rather, recent evidence from single cell analysis suggests that during the latter half of fetal development a gradual, progressive transition occurs at the level of hematopoietic stem-progenitor cells (HSPCs) which is reflected in their T cell progeny. At a transcriptional level, clusters of genes are up- and down-regulated with sequenced timing, suggesting that the transition is under the control of master regulatory factors, including epigenetic modifiers. The net effect is still one of "molecular layering," that is, the continuous layering of iterative generations of HSPCs and T cells that arise through progressive changes in gene expression. This review will focus on recent discoveries that elucidate mechanisms of fetal T cell function and the transition from fetal to adult identity. The epigenetic landscape of fetal T cells facilitates their ability to fulfill the dominant fetal mandate of generating tolerance against self, maternal, and environmental antigens by supporting their predisposition to differentiate into CD25+ FoxP3+ regulatory T cells (TRegs ). We will explore how the coordinated development of two complementary populations of fetal T cells-conventional T cells dominated by TRegs and tissue-associated memory effector cells with innate-like inflammatory potential-is crucial not only for maintaining intrauterine immune quiescence but also for facilitating an immune response that is appropriately tuned for the bombardment of antigen stimulation that happens at birth.
Subject(s)
Hematopoietic Stem Cells , Transcription Factors , Infant, Newborn , Humans , Cell Lineage , Hematopoiesis/physiologyABSTRACT
Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.
Subject(s)
Combined Modality Therapy , HIV Infections/therapy , Health Resources , Health Services Needs and Demand , Needs Assessment , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Global Health , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV Infections/immunology , HIV-1/drug effects , HIV-1/genetics , HIV-1/immunology , Humans , Receptors, CCR5/deficiency , Receptors, CCR5/genetics , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.
Subject(s)
Anti-Retroviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/pathology , Cell Differentiation , HIV Infections/virology , HIV-1/immunology , Viral Load , Virus Replication , Adult , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/virology , Case-Control Studies , DNA, Viral/analysis , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/pathology , HIV-1/drug effects , HIV-1/genetics , Humans , Male , Middle AgedSubject(s)
Gene Editing , Genetic Therapy , Health Services Accessibility , Hematopoietic Stem Cell Transplantation , Hemoglobinopathies , Humans , Genetic Therapy/methods , United States , Hematopoietic Stem Cells/physiology , Gene Editing/methods , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/therapy , beta-Thalassemia/genetics , beta-Thalassemia/therapy , Hematopoietic Stem Cell Transplantation/methods , Hemoglobinopathies/genetics , Hemoglobinopathies/therapySubject(s)
Fetus/immunology , Gene Regulatory Networks/immunology , Histocompatibility, Maternal-Fetal , Placenta/immunology , Pregnancy Complications/prevention & control , Animals , Cell Communication/immunology , Cytokines/biosynthesis , Cytokines/immunology , Female , Gene Expression Regulation , Humans , Immune Tolerance , Immunity, Innate , Infant, Newborn , Infant, Premature/immunology , Pregnancy , Pregnancy Complications/immunology , Pregnancy Complications/pathology , Species Specificity , Uterus/immunologyABSTRACT
The kynurenine pathway (KP) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. In HIV infection, KP activity is consistently associated with reduced CD4 T cell counts and elevated levels of T cell activation and viral load; it also independently predicts mortality and morbidity from non-AIDS events. Kynurenine 3-monooxygenase (KMO) is a therapeutically important target in the KP. Using the nonhuman primate model of SIV infection in rhesus macaques, we investigated whether KMO inhibition could slow the course of disease progression. We used a KMO inhibitor, CHDI-340246, to perturb the KP during early acute infection and followed the animals for 1 y to assess clinical outcomes and immune phenotype and function during pre-combination antiretroviral therapy acute infection and combination antiretroviral therapy-treated chronic infection. Inhibition of KMO in acute SIV infection disrupted the KP and prevented SIV-induced increases in downstream metabolites, improving clinical outcome as measured by both increased CD4+ T cell counts and body weight. KMO inhibition increased naive T cell frequency and lowered PD-1 expression in naive and memory T cell subsets. Importantly, early PD-1 expression during acute SIV infection predicted clinical outcomes of body weight and CD4+ T cell counts. Our data indicate that KMO inhibition in early acute SIV infection provides clinical benefit and suggest a rationale for testing KMO inhibition as an adjunctive treatment in SIV/HIV infection to slow the progression of the disease and improve immune reconstitution.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Kynurenine 3-Monooxygenase/antagonists & inhibitors , Programmed Cell Death 1 Receptor/biosynthesis , Pyrimidines/pharmacology , Simian Acquired Immunodeficiency Syndrome/immunology , Animals , Anti-Retroviral Agents/pharmacology , Body Weight/drug effects , CD4-Positive T-Lymphocytes/drug effects , Enzyme Inhibitors/pharmacology , Macaca mulatta , Programmed Cell Death 1 Receptor/drug effects , Simian Acquired Immunodeficiency Syndrome/metabolismABSTRACT
TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trial NCT00594880.
Subject(s)
Antiretroviral Therapy, Highly Active , Epithelial Cells/metabolism , HIV Infections/metabolism , HIV-1/physiology , Intestinal Mucosa/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3/metabolism , Adult , Animals , Epithelial Cells/drug effects , Epithelial Cells/virology , Female , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/drug effects , Humans , Intestines/drug effects , Intestines/virology , Male , Mice , Middle Aged , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Viral LoadABSTRACT
The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.
Subject(s)
Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , Cell Proliferation , Hepacivirus/immunology , Hepatitis C, Chronic/drug therapy , Immunologic Memory/immunology , Adaptive Immunity/immunology , Antibodies, Viral/blood , Drug Therapy, Combination , Female , Hepatitis C, Chronic/immunology , Humans , Immunity, Innate/immunology , Interferon-alpha/therapeutic use , Longitudinal Studies , Lymphocyte Activation/immunology , Male , Middle Aged , Oligopeptides/therapeutic use , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , Proline/therapeutic use , Prospective Studies , Recombinant Proteins/therapeutic use , Ribavirin/therapeutic use , T-Box Domain Proteins/biosynthesis , Treatment OutcomeABSTRACT
Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to noninherited Ags on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4+FOXP3+CD25+ regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared with adult T cells, fetal naive CD4+ T cells exhibit a strong predisposition to differentiate into Tregs when stimulated. This effect is mediated by the TCR and TGF-ß pathways, and fetal T cells show significantly increased Treg differentiation in response to anti-CD3 and TGF-ß stimulation. Naive fetal T cells also exhibit increased signaling through the TGF-ß pathway, with these cells demonstrating increased expression of the signaling mediators TGF-ßRI, TGF-ßRIII, and SMAD2, and higher levels of SMAD2/SMAD3 phosphorylation. Increased fetal Treg differentiation is mediated by the RNA-binding protein Lin28b, which is overexpressed in fetal T cells as compared with adult cells. When Lin28b expression is decreased in naive fetal T cells, they exhibit decreased Treg differentiation that is associated with decreased TGF-ß signaling and lowered expression of TGF-ßRI, TGF-ßRIII, and SMAD2. Lin28b regulates the maturation of let-7 microRNAs, and these TGF-ß signaling mediators are let-7 targets. We hypothesize that loss of Lin28b expression in fetal T cells leads to increased mature let-7, which causes decreased expression of TGF-ßRI, TGF-ßRIII, and SMAD2 proteins. A reduction in TGF-ß signaling leads to reduced Treg numbers.
Subject(s)
Cell Differentiation/immunology , Fetus/immunology , RNA-Binding Proteins/immunology , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , Transforming Growth Factor beta/immunology , CD3 Complex/immunology , Female , Fetus/cytology , Gene Expression Regulation, Developmental/immunology , Humans , Male , MicroRNAs/immunology , Protein Serine-Threonine Kinases/immunology , Receptor, Transforming Growth Factor-beta Type I , Receptor, Transforming Growth Factor-beta Type II , Receptors, Antigen, T-Cell/immunology , Receptors, Transforming Growth Factor beta/immunology , Smad2 Protein/immunology , T-Lymphocytes, Regulatory/cytologyABSTRACT
BACKGROUND: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. METHODS AND FINDINGS: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. CONCLUSIONS: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
Subject(s)
Anti-Retroviral Agents/therapeutic use , Biomarkers/analysis , HIV Infections/drug therapy , HIV-1 , Adult , Flow Cytometry , HIV Infections/immunology , HIV Infections/virology , Humans , Male , Middle Aged , Phenotype , Prospective Studies , Recurrence , Secondary Prevention , Treatment OutcomeABSTRACT
UNLABELLED: Strategies aimed at eliminating persistent viral reservoirs from HIV-1-infected individuals have focused on CD4(+) T-cell reservoirs. However, very little attention has been given to approaches that could promote elimination of tissue macrophage reservoirs. HIV-1 infection of macrophages induces phosphorylation of colony-stimulating factor 1 receptor (CSF-1R), which confers resistance to apoptotic pathways driven by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thereby promoting viral persistence. In this study, we assessed whether CSF-1R antagonists (PLX647, PLX3397, and PLX5622) restored apoptotic sensitivity of HIV-1-infected macrophages in vitro PLX647, PLX3397, and PLX5622 at clinically relevant concentrations blocked the activation of CSF-1R and reduced the viability of infected macrophages, as well as the extent of viral replication. Our data show that strategies targeting monocyte colony-stimulating factor (MCSF) signaling could be used to promote elimination of HIV-1-infected myeloid cells and to contribute to the elimination of persistent viral reservoirs. IMPORTANCE: As the HIV/AIDS research field explores approaches to eliminate HIV-1 in individuals on suppressive antiviral therapy, those approaches will need to eliminate both CD4(+) T-cell and myeloid cell reservoirs. Most of the attention has focused on CD4(+) T-cell reservoirs, and scant attention has been paid to myeloid cell reservoirs. The distinct nature of the infection in myeloid cells versus CD4(+) T cells will likely dictate different approaches in order to achieve their elimination. For CD4(+) T cells, most strategies focus on promoting virus reactivation to promote immune-mediated clearance and/or elimination by viral cytopathicity. Macrophages resist viral cytopathic effects and CD8(+) T-cell killing. Therefore, we have explored clearance strategies that render macrophages sensitive to viral cytopathicity. This research helps inform the design of strategies to promote clearance of the macrophage reservoir in infected individuals on suppressive antiviral therapy.
Subject(s)
Aminopyridines/pharmacology , HIV Infections/immunology , HIV-1/immunology , Macrophages/immunology , Pyrroles/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , TNF-Related Apoptosis-Inducing Ligand/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , Cells, Cultured , HIV Infections/drug therapy , HIV Infections/virology , Humans , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/drug effects , Macrophages/pathology , Macrophages/virology , Virus Latency , Virus Replication/drug effects , Virus Replication/immunologyABSTRACT
Untreated HIV disease is associated with chronic immune activation and CD4(+) T cell depletion. A variety of mechanisms have been invoked to account for CD4(+) T cell depletion in this setting, but the quantitative contributions of these proposed mechanisms over time remain unclear. We turned to the DO11.10 TCR transgenic mouse model, where OVA is recognized in the context of H-2(d), to explore the impact of chronic antigenic stimulation on CD4(+) T cell dynamics. To model dichotomous states of persistent Ag exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, IL-1ß. In both cases, circulating Ag-specific CD4(+) T cells were depleted. However, in the absence of IL-1ß, there was limited proliferation and effector/memory conversion of Ag-specific T cells, depletion of peripheral CD4(+) T cells in hematolymphoid organs, and systemic induction of regulatory Foxp3(+)CD4(+) T cells, as often observed in late-stage HIV disease. By contrast, when OVA peptide was administered in the presence of IL-1ß, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between Ag-stimulated DO11.10 TCR transgenic mice and HIV-infected humans, our data suggest that CD4(+) T cell depletion in the setting of HIV disease may reflect, at least in part, chronic Ag exposure in the absence of proinflammatory signals and/or appropriate APC functions.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Interleukin-1beta/pharmacology , Amino Acid Sequence , Animals , Female , Lymph Nodes/immunology , Lymphocyte Activation , Male , Mice , Mice, Transgenic , Molecular Sequence Data , Ovalbumin/immunology , Spleen/immunology , T-Lymphocytes, Regulatory/immunologySubject(s)
Genetic Therapy , Health Resources , Developing Countries , Genetic Therapy/methods , Genetic Therapy/trends , HumansABSTRACT
A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.
Subject(s)
Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , CD4-CD8 Ratio , CD8-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV Infections/epidemiology , Lymphocyte Activation , T-Lymphocyte Subsets/pathology , Adult , Case-Control Studies , Cohort Studies , Female , HIV Infections/immunology , HIV-1 , Humans , Lymphocyte Count , Male , Morbidity , Mortality , Risk Factors , T-Lymphocyte Subsets/immunology , Treatment OutcomeABSTRACT
Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines. Fetal monocytes phosphorylate canonical and noncanonical STATs and respond more strongly to IFN-γ, IL-6, and IL-4 than adult monocytes. We demonstrate a higher ratio of SOCS3 to IL-6 receptor in adult monocytes than in fetal monocytes, potentially explaining differences in STAT phosphorylation. Additionally, IFN-γ signaling results in upregulation of antigen presentation and costimulatory machinery in adult, but not fetal, monocytes. These findings represent the first evidence that primary human fetal and adult monocytes are functionally distinct, potentially explaining how these cells respond differentially to cytokines implicated in development, in utero infections, and the pathogenesis of preterm labor.
Subject(s)
Fetus/immunology , Fetus/metabolism , Monocytes/immunology , Monocytes/metabolism , Adult , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Cytokines/metabolism , Fetus/cytology , Humans , Monocytes/cytology , Myelopoiesis , Oligonucleotide Array Sequence Analysis , Phosphorylation , Promoter Regions, Genetic , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , Signal Transduction , TranscriptomeABSTRACT
Monocyte activation during HIV-1 infection is associated with increased plasma levels of inflammatory markers and increased risk for premature development of age-related diseases. Because activated monocytes primarily use glucose to support cellular metabolism, we hypothesized that chronic monocyte activation during HIV-1 infection induces a hypermetabolic response with increased glucose uptake. To test this hypothesis, we evaluated glucose transporter 1 (Glut1) expression and glucose uptake by monocyte subpopulations in HIV-seropositive (HIV(+)) treatment-naive individuals (n = 17), HIV(+) individuals on combination antiretroviral therapy with viral loads below detection (n = 11), and HIV-seronegative (HIV(-)) individuals (n = 16). Surface expression of Glut1 and cellular uptake of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2 deoxyglucose were analyzed by flow cytometry on monocyte subpopulations. Irrespective of treatment status, monocytes from HIV(+) persons had significantly increased surface expression of Glut1 compared with those from HIV(-) controls. Nonclassical (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocyte subpopulations showed higher Glut1 expression than did classical (CD14(++)CD16(-)) monocytes. Intermediate monocytes from treatment-naive HIV(+) individuals also showed increased uptake of 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2 deoxyglucose compared with those from HIV(-) controls. Our results show that HIV infection is associated with increased glucose metabolism in monocytes and that Glut1 expression by proinflammatory monocytes is a potential marker of inflammation in HIV-infected subjects. However, the possibility exists whereby other Gluts such as Glut3 and Glut4 may also support the influx of glucose into activated and inflammatory monocyte populations.
Subject(s)
Glucose Transporter Type 1/metabolism , Glucose/metabolism , HIV Infections/immunology , HIV/immunology , Monocytes/immunology , Adult , Aged , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/adverse effects , Australia , Biomarkers/metabolism , Drug Combinations , Female , Glucose/analogs & derivatives , Glucose Transporter Type 1/genetics , HIV Infections/therapy , HIV Seropositivity , Humans , Inflammation Mediators/metabolism , Male , Middle Aged , Monocytes/drug effects , Monocytes/virology , Up-RegulationABSTRACT
The study of HIV-infected "controllers" who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of "elite" controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).
Subject(s)
Anti-Retroviral Agents/administration & dosage , Atherosclerosis , HIV Infections , HIV-1/physiology , RNA, Viral/blood , Virus Replication/drug effects , Adult , Atherosclerosis/blood , Atherosclerosis/drug therapy , Atherosclerosis/etiology , Biomarkers/blood , Female , HIV Infections/blood , HIV Infections/complications , HIV Infections/drug therapy , Humans , Lymphocyte Activation/drug effects , Male , Middle Aged , Prospective Studies , T-Lymphocytes/metabolism , Time FactorsABSTRACT
BACKGROUND: Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells. METHODS: We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug. RESULTS: We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR. CONCLUSIONS: These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , Monocytes/drug effects , Monocytes/physiology , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Adult , Antigen-Presenting Cells , Case-Control Studies , Cohort Studies , Dendritic Cells , Female , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Retrospective Studies , Ribavirin/administration & dosageABSTRACT
BACKGROUND: Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28(-)CD8(+) T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown. METHODS: We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28(-)CD8(+) T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals. RESULTS: Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28(-)CD8(+) T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28(-)CD8(+) T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6-15.9, P = .007). CONCLUSIONS: Abnormally low proportions of CD28(-)CD8(+) T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
Subject(s)
Anti-HIV Agents/pharmacology , CD28 Antigens/metabolism , CD57 Antigens/metabolism , CD8-Positive T-Lymphocytes/metabolism , HIV Infections/drug therapy , Adult , CD28 Antigens/genetics , CD57 Antigens/genetics , Female , HIV Infections/blood , HIV Infections/immunology , HIV Infections/mortality , Humans , Lymphocyte Count , MaleABSTRACT
BACKGROUND: Human immunodeficiency virus (HIV) infection-induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown. METHODS: We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the "KT ratio") in HIV-infected Ugandans before and during antiretroviral therapy (ART)-mediated viral suppression and its association with the rate of subsequent CD4(+) T-cell count recovery and mortality. RESULTS: Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4(+) T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4(+) T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4(+) T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4(+) T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016). CONCLUSIONS: The kynurenine pathway of tryptophan catabolism independently predicts poor CD4(+) T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.