ABSTRACT
BACKGROUND: Some risk factors for mother-to-child transmission (MTCT) of HIV have been identified. To further reduce MTCT, other risk factors were evaluated. MATERIALS AND METHODS: A retrospective study on early infant diagnosis was conducted. Two-sided chi-square test was used to assess associations with infant HIV status. RESULTS: A total of 15 233 HIV-infected mothers and 15 404 infants were recruited. MTCT rate was 9.34%. Only 3.8% of infants born to mothers on antiretroviral treatment were infected. Under nevirapine, 4.1% of infants were infected. MTCT increased with infant' age at testing. Younger mothers tend to transmit more HIV (P = 0.003). More children were infected in single pregnancies compared with multiple pregnancies, P < 0.001. There were more infections in male-female twins' sets (P = 0.037). CONCLUSIONS: Maternal age, type of pregnancy and twins' sets are new MTCT risk factors. Strategies to further decrease transmission through family planning, pre/post natal consultations and clinical practices are needed.
Subject(s)
Anti-HIV Agents/therapeutic use , Breast Feeding/adverse effects , HIV Infections/drug therapy , Infectious Disease Transmission, Vertical/prevention & control , Nevirapine/administration & dosage , Pregnancy Complications, Infectious/drug therapy , Adult , Antiretroviral Therapy, Highly Active , Cameroon/epidemiology , Female , HIV Infections/transmission , Humans , Infant , Infant, Newborn , Male , Maternal Age , Mothers , Pregnancy , Pregnancy, Multiple , Risk FactorsABSTRACT
Interleukin (IL)-7 is the main homeostatic regulator of CD4 T-lymphocytes (helper) at both central and peripheral levels. Upon activation by IL-7, several signaling pathways, mainly JAK/STAT, PI3K/Akt and MAPK, induce the expression of genes involved in T-cell differentiation, activation, and proliferation. We have analyzed the early events of CD4 T-cell activation by IL-7. We have shown that IL-7 in the first few min induces the formation of cholesterol-enriched membrane microdomains that compartmentalize its activated receptor and initiate its anchoring to the cytoskeleton, supporting the formation of the signaling complex, the signalosome, on the IL-7 receptor cytoplasmic domains. Here we describe by stimulated emission depletion microscopy the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated JAK/STAT signaling pathway. We image phospho-STAT5 and cytoskeleton components along IL-7 activation kinetics using appropriate inhibitors. We show that lipid raft inhibitors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation. Drug-induced disassembly of the cytoskeleton inhibits phospho-STAT5 formation, transport, and translocation into the nucleus that controls the transcription of genes involved in T-cell activation and proliferation. We fit together the results of these quantitative analyses and propose the following mechanism. Activated IL-7 receptors embedded in membrane microdomains induce actin-microfilament meshwork formation, anchoring microtubules that grow radially from rafted receptors to the nuclear membrane. STAT5 phosphorylated by signalosomes are loaded on kinesins and glide along the microtubules across the cytoplasm to reach the nucleus 2 min after IL-7 stimulation. Radial microtubules disappear 15 min later, while transversal microtubules, independent of phospho-STAT5 transport, begin to bud from the microtubule organization center.
Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Cytoskeleton/metabolism , Membrane Microdomains/metabolism , Receptors, Interleukin-7/metabolism , Actin Cytoskeleton/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/physiology , CD4-Positive T-Lymphocytes/ultrastructure , Cell Nucleus/metabolism , Cell Proliferation , Cells, Cultured , Cholera Toxin/immunology , Cytoskeleton/ultrastructure , Humans , Janus Kinase 1/metabolism , Janus Kinase 3/metabolism , Kinetics , Lymphocyte Activation , Membrane Microdomains/ultrastructure , Microtubules/metabolism , Phosphorylation , Protein Processing, Post-Translational , Protein Transport , Receptors, Interleukin-7/physiology , STAT5 Transcription Factor/metabolism , Signal TransductionABSTRACT
HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4(+) T cells were characterized by a higher frequency of gamma interferon (IFN-γ) production, perforin(+)/CD107a(+) expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer-positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-γ-producing CD4(+) T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-γ production, supporting the notion of a persistent immune dysfunction in HIV-specific CD4(+) T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions.
Subject(s)
HIV Infections/blood , HIV Infections/virology , Th1 Cells/virology , ADP-ribosyl Cyclase 1/biosynthesis , Adult , Aged , Anti-Retroviral Agents/pharmacology , CD4-Positive T-Lymphocytes/cytology , Cohort Studies , Cytokines/metabolism , Flow Cytometry/methods , Gene Products, gag/metabolism , Humans , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-17/metabolism , Interleukin-4/metabolism , Interleukins/metabolism , Leukocytes, Mononuclear/cytology , Lysosomal-Associated Membrane Protein 1/biosynthesis , Middle Aged , PhenotypeABSTRACT
HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vbeta repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-gamma responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vbeta repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , Gene Products, gag/immunology , HIV Infections/immunology , Receptors, Antigen, T-Cell/immunology , HIV/immunology , Humans , Lymphocyte Activation/immunology , Viral LoadABSTRACT
Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load and massive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers), and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , HIV Infections/immunology , HIV-1/immunology , HIV Infections/virology , Humans , Immunity, Innate/immunologyABSTRACT
The origin of the impaired CD4 T-cell response and immunodeficiency of HIV-infected patients is still only partially understood. We recently demonstrated that PLA2G1B phospholipase synergizes with the HIV gp41 envelope protein in HIV viremic plasma to induce large abnormal membrane microdomains (aMMDs) that trap and inactivate physiological receptors, such as those for IL-7. However, the mechanism of regulation of PLA2G1B activity by the cofactor gp41 is not known. Here, we developed an assay to directly follow PLA2G1B enzymatic activity on CD4 T-cell membranes. We demonstrated that gp41 directly binds to PLA2G1B and increases PLA2G1B enzymatic activity on CD4 membrane. Furthermore, we show that the conserved 3S sequence of gp41, known to bind to the innate sensor gC1qR, increases PLA2G1B activity in a gC1qR-dependent manner using gC1qR KO cells. The critical role of the 3S motif and gC1qR in the inhibition of CD4 T-cell function by the PLA2G1B/cofactor system in HIV-infected patients led us to screen additional microbial proteins for 3S-like motifs and to study other proteins known to bind to the gC1qR to further investigate the role of the PLA2G1B/cofactor system in other infectious diseases and carcinogenesis. We have thus extended the PLA2G1B/cofactor system to HCV and Staphylococcus aureus infections and additional pathologies where microbial proteins with 3S-like motifs also increase PLA2G1B enzymatic activity. Notably, the bacteria Porphyromonas gingivalis, which is associated with pancreatic ductal adenocarcinoma (PDAC), encodes such a cofactor protein and increased PLA2G1B activity in PDAC patient plasma inhibits the CD4 response to IL-7. Our findings identify PLA2G1B/cofactor system as a CD4 T-cell inhibitor. It involves the gC1qR and disease-specific cofactors which are gC1qR-binding proteins that can contain 3S-like motifs. This mechanism involved in HIV-1 immunodeficiency could play a role in pancreatic cancer and several other diseases. These observations suggest that the PLA2G1B/cofactor system is a general CD4 T-cell inhibitor and pave the way for further studies to better understand the role of CD4 T-cell anergy in infectious diseases and tumor escape.
Subject(s)
CD4-Positive T-Lymphocytes , Clonal Anergy , Group IB Phospholipases A2 , HIV Infections , Membrane Glycoproteins , Receptors, Complement , CD4-Positive T-Lymphocytes/metabolism , Carrier Proteins/metabolism , Group IB Phospholipases A2/metabolism , Humans , Interleukin-7/metabolism , Membrane Glycoproteins/metabolism , Protein Binding , Receptors, Complement/metabolismABSTRACT
Interleukin (IL)-7 is a central cytokine that controls homeostasis of the CD4 T lymphocyte pool. Here we show on human primary cells that IL-7 binds to preassembled receptors made up of proprietary chain IL-7Ralpha and the common chain gammac shared with IL-2, -4, -9, -15, and -21 receptors. Upon IL-7 binding, both chains are driven in cholesterol- and sphingomyelin-rich rafts where associated signaling proteins Jak1, Jak3, STAT1, -3, and -5 are found to be phosphorylated. Meanwhile the IL-7.IL-7R complex interacts with the cytoskeleton that halts its diffusion as measured by single molecule fluorescence autocorrelated spectroscopy monitored by microimaging. Comparative immunoprecipitations of IL-7Ralpha signaling complex from non-stimulated and IL-7-stimulated cells confirmed recruitment of proteins such as STATs, but many others were also identified by mass spectrometry from two-dimensional gels. Among recruited proteins, two-thirds are involved in cytoskeleton and raft formation. Thus, early events leading to IL-7 signal transduction involve its receptor compartmentalization into membrane nanodomains and cytoskeleton recruitment.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Compartmentation , Interleukin-7/metabolism , Receptors, Interleukin-7/metabolism , Signal Transduction , Binding Sites , Electrophoresis, Polyacrylamide Gel , Humans , Immunoprecipitation , Lymphocyte Activation , Mass Spectrometry , Spectrometry, Fluorescence , UltracentrifugationABSTRACT
A small minority of HIV-infected individuals, known as HIV controllers, is able to exert long-term control over HIV replication in the absence of treatment. Increasing evidence suggests that the adaptive immune system plays a critical role in this control but also that a combination of several host and/or viral factors, rather than a single cause, leads to this rare phenotype. Here, we review recent advances in the study of these remarkable individuals. We summarize the epidemiology and clinical characteristics of HIV controllers, and subsequently describe contributing roles of host genetic factors, innate and adaptive immune responses, and viral factors to this phenotype. We emphasize distinctive characteristics of HIV-specific CD4 T cell responses and of CD4 T cell subpopulations that are frequently found in HIV controllers. We discuss major controversies in the field and the relevance of the study of HIV controllers for the development of novel therapeutic strategies and vaccines.
Subject(s)
HIV Infections/immunology , HIV Infections/virology , HIV Long-Term Survivors , Adaptive Immunity , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Disease Models, Animal , Genome-Wide Association Study , HIV/immunology , HIV/pathogenicity , HIV/physiology , HIV Infections/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Humoral , Immunity, Innate , Immunity, Mucosal , Phenotype , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Th17 Cells/immunology , Th17 Cells/virology , Virus ReplicationABSTRACT
Interleukin-7 (IL-7) plays a central role in controlling the homeostasis of both naive and long-term-memory CD4(+) T cells. To better understand how human immunodeficiency virus (HIV) perturbs CD4(+) T-cell homeostasis, we performed a detailed analysis of IL-7R expression, IL-7 binding, and IL-7-dependent early and late signaling events in CD4(+) T-cell subsets from viremic and efficiently treated patients. HIV infection differentially affected the expression of IL-7 receptor (IL-7R) chains, with decreases in IL-7Ralpha/CD127 expression in the memory subset and increases in gammac/CD132 expression in all CD4(+) T cells. This resulted in preserved IL-7 binding in the naive compartment and decreased IL-7 binding in the memory compartment of viremic patients. Accordingly, the percentages of cells signaling in response to IL-7, as measured by pSTAT5 induction, were decreased in memory subsets, including conventional CD4(+) T cells and regulatory T cells. However, the levels of pSTAT5 induction per responding cell, as measured by pSTAT5 fluorescence intensity, were increased within all naive and memory CD4(+) T-cell subsets of viremic patients. The basal level of pSTAT5 was also increased, indicating a constitutive activation of the JAK/STAT5 pathway. IL-7 functional responses, as measured by Bcl-2, CD25, and Foxp3 induction, were impaired in viremic patient CD4(+) T cells, suggesting that chronic activation led to downstream defects in the STAT5 signaling pathway. Thus, HIV infection perturbs IL-7 responses at both receptor binding and signaling steps, which likely compromises the regenerative capacity of the CD4(+) T-cell pool and may contribute to CD4(+) T-cell depletion.
Subject(s)
CD4-Positive T-Lymphocytes/virology , HIV Infections/immunology , Interleukin-7/metabolism , Janus Kinases/metabolism , STAT5 Transcription Factor/metabolism , Adult , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/pathology , Case-Control Studies , Homeostasis , Humans , Middle Aged , Protein Binding , Signal Transduction , Viral LoadABSTRACT
IL-2 and IL-15 differentially control the development, activation and proliferation of human NK cells, although they share common signal-transducing receptor chains CD122 and common gamma. To explore this issue, we analyzed in detail the kinetics of cytokine receptor expression, cytokine binding, and signaling responses in human NK cells treated with common gamma-chain family cytokines. We provide evidence for the sequential expression of IL-15Ralpha and IL-2Ralpha at the surface of cytokine-stimulated human NK cells, independent of the cytokine used for stimulation (IL-2, IL-15, or IL-7). Binding experiments confirmed the switch of high-affinity receptor from IL-15R to IL-2R between 18 and 48 h after stimulation. Consequently, phospho-STAT5 signaling responses to IL-15 were efficient in human NK cells pretreated with cytokines for 18 h, but were abolished at 48 h. Functional NK cell responses to IL-15, including IFN-gamma secretion and CD107a expression, followed a similar pattern, indicating the physiological relevance of the cytokine receptor switch. Importantly, IL-15 complexed to soluble IL-15Ralpha preserved the capacity to activate cytokine-stimulated human NK cells at 48 h, suggesting that human NK cells remained competent for IL-15 trans-presentation, while they had become refractory to free diffusible IL-15. These findings define a common cytokine receptor expression program, which increases human NK cell sensitivity to free IL-15 in early activation and redirects responses toward IL-2 and trans-presented IL-15 at later stages. Such a program may prevent excessive human NK cell activation by effectors of innate immunity and regulate the transition between the innate and adaptive stages of immune responses.
Subject(s)
Gene Expression Regulation/immunology , Interleukin-15/immunology , Interleukin-2/immunology , Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Blotting, Western , Flow Cytometry , Humans , Immunoprecipitation , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-15/metabolism , Interleukin-2/metabolism , Killer Cells, Natural/metabolism , Lysosomal-Associated Membrane Protein 1/immunology , Lysosomal-Associated Membrane Protein 1/metabolism , Phosphorylation , Receptors, Cytokine/biosynthesis , Receptors, Cytokine/immunology , STAT5 Transcription Factor/immunology , STAT5 Transcription Factor/metabolismABSTRACT
BACKGROUND: Antibiotics have been shown to improve hidradenitis suppurativa (HS) patients but complete remission is rare using these treatments. OBJECTIVE: To assess the efficacy and safety of a combination of oral rifampin, moxifloxacin and metronidazole in long-lasting refractory HS. METHODS: We retrospectively studied 28 consecutive HS patients including 6, 10 and 12 Hurley stage 1, 2 and 3 patients, respectively. Complete remission, defined as a clearance of all inflammatory lesions including hypertrophic scars, was the main outcome criterion of the study. RESULTS: Complete remission was obtained in 16 patients, including 6/6, 8/10 and 2/12 patients with Hurley stage 1, 2 and 3, respectively (p=0.0004). The median duration of treatment to obtain complete remission was 2.4 (range 0.9-6.5) and 3.8 months (range 1.6-7.4) in stage 1 and 2 patients, respectively, and 6.2 and 12 months in the 2 stage 3 patients. Main adverse events of the treatments were gastrointestinal disorders (64% of patients) and vaginal candidiasis (35% of females). Reversible tendinopathy and hepatitis occurred in 4 and 1 patient, respectively. CONCLUSIONS: Complete remission of refractory HS can be obtained using broad-spectrum antibiotics and Hurley staging is a prognostic factor of response to the treatment.
Subject(s)
Anti-Infective Agents/therapeutic use , Antibiotics, Antitubercular/therapeutic use , Aza Compounds/therapeutic use , Hidradenitis Suppurativa/drug therapy , Metronidazole/therapeutic use , Quinolines/therapeutic use , Rifampin/therapeutic use , Adult , Anti-Infective Agents/adverse effects , Antibiotics, Antitubercular/adverse effects , Aza Compounds/adverse effects , Drug Therapy, Combination , Female , Fluoroquinolones , Hidradenitis Suppurativa/pathology , Humans , Kaplan-Meier Estimate , Logistic Models , Male , Metronidazole/adverse effects , Middle Aged , Moxifloxacin , Prognosis , Quinolines/adverse effects , Recurrence , Remission Induction , Retrospective Studies , Rifampin/adverse effects , Treatment Outcome , Young AdultABSTRACT
More than 30 million people are infected by HIV worldwide. The rate of progression to AIDS is variable. A newly identified category of patients, so-called HIV controllers, spontaneously control HIV replication for long periods. HIV controllers are defined as infected patients whose viral load remains below 400 RNA copies/ml of blood, without treatment, for at least five years. We have studied the immune system of these patients, and particularly their CD4 lymphocytes, that participate in the induction, intensity, quality and duration of immune responses. CD4 lymphocytes in patients who progress to AIDS are directly targeted by the virus and participate in the activation that leads to immune deficiency. Central memory CD4 cells exhibit unusual properties in HIV controllers. Apart from the fact that they persist in large numbers and secrete large amounts of interleukin-2, which serves as an autocrine factor for their own growth, central memory CD4 cells overexpress the CCR7 homing molecule that allows them to leave capillaries and rapidly enter lymph nodes, the site of effective immune responses. These CD4 lymphocytes also men multiply rapidly, and some of them express receptors with very high antigen avidity. The presence of these central memory CD4 cells and their characteristic properties may explain the remarkable stability observed in HIV controllers. We suspect that these lymphocytes react very rapidly and efficiently to any breakthrough in viral replication. The putative relationship between HIV controllers and patients who remain asymptomatic and uninfected despite repeated exposure to the virus is discussed. Our new findings should help to guide antiretroviral therapy and vaccination strategies.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/virology , HIV Long-Term Survivors , Humans , Viral LoadABSTRACT
The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Clonal Anergy , Group IB Phospholipases A2/immunology , HIV Infections/immunology , HIV-1/immunology , Lymphopenia/immunology , CD4-Positive T-Lymphocytes/pathology , Cytokines/immunology , Female , HIV Infections/pathology , Humans , Lymphopenia/pathology , MaleABSTRACT
Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n = 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4+ central memory T (T(CM)) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor alpha (IL-7Ralpha). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T(CM)-cell homing patterns. CD4+ effector memory T (T(EM))-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4+ T(EM)-cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7Ralpha expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1beta secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4+ T(CM)-cell compartment and signs of potent functional activation in the CD4+ T(EM)-cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Long-Term Survivors , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Adult , Aged , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/classification , Cytokines/metabolism , Female , HIV Infections/virology , HIV-1/immunology , Humans , Male , Middle AgedABSTRACT
The common gamma chain (gammac)-sharing cytokines (IL's-2, 4, 7, 9, 15, and 21) play a vital role in the survival, proliferation, differentiation and function of T lymphocytes. As such, disruption of their signaling pathways would be expected to have severe consequences on the integrity of the immune system. Indeed, it appears that the signaling network of these cytokines is both disrupted and exploited by HIV at various stages of infection. IL-2 secretion and signaling downstream of its receptor are impaired in T cells from chronically-infected HIV+ patients. Elevated plasma IL-7 levels and decreased IL-7Ralpha expression in patient T cells results in significantly decreased responsiveness to this critical cytokine. Interestingly, IL-2 and IL-15 are also able to render CD4+ T cells permissive to HIV infection through their influence on the activity of the APOBEC3G deaminase enzyme. Herein, we describe the current state of knowledge on how the gammac cytokine network is affected during HIV infection, with a focus on how this impairs CD4+ and CD8+ T cell function while also benefiting the virus itself. We also address the use of cytokines as adjuncts to highly active antiretroviral therapy to bolster immune reconstitution in infected patients.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , HIV Infections/immunology , HIV Infections/virology , Interleukin Receptor Common gamma Subunit/antagonists & inhibitors , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , HIV Infections/metabolism , HIV Infections/pathology , Humans , Interleukin Receptor Common gamma Subunit/metabolismABSTRACT
CD4 T lymphocytes play a central role in the pathogenesis of human immunodeficiency virus (HIV) infection. In viremic patients, these cells are direct targets for the virus: HIV multiplies intensely in this subpopulation during the acute phase of the disease and continues to propagate in these same cells during the clinical latency phase. Uninfected CD4 T lymphocytes are also indirectly affected during this second phase: they are activated, become anergic, then disappear by apoptosis, ultimately contributing to CD4 lymphopenia. Our studies have shown that dysfunction of the interleukin-2 system and its receptors largely explain the early immune deficiency seen in viremic patients. Later, blockade of the homeostatic interleukin-7/CD4 loop contributes to rendering this CD4 lymphopenia irreversible. Our studies suggest that the inflammatory reaction which accompanies this infection gives rise to a state of abnormal activation, with receptor desensitization to the main cytokines regulating CD4 lymphocyte functions and numbers. In the few rare patients who manage to control HIV in the absence of any treatment, the CD4 T cell compartment has a very characteristic configuration. We have shown that an extensive subpopulation of "central memory" CD4 T lymphocytes expresses large quantities of the CCR7 homing receptor and that this helps drive these lymphocytes to infected lymph nodes. Also, these "central memory" CD4 T lymphocytes produce large quantities of IL-2, that they use in an autocrine manner, stimulating their self-renewal and ensuring their long-term survival. Our studies have opened the door to cytokine-based immunotherapy and to the development of new drug- and vaccine-based strategies.
Subject(s)
CD4-Positive T-Lymphocytes/virology , HIV Infections/etiology , HIV/physiology , Acute Disease , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Autocrine Communication , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Chemotaxis, Leukocyte , Disease Progression , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/virology , HIV Long-Term Survivors , Humans , Immunologic Memory , Interleukin-2/physiology , Interleukin-7/blood , Interleukin-7/physiology , Lymphocyte Activation , Lymphopoiesis , Receptors, CCR7/physiology , Viremia/immunology , Viremia/virologyABSTRACT
Measurements of Bcl-2 and CD25 expression suggested that IL-7R function is modified in CD4 lymphocytes of untreated viraemic patients. The extent of IL-7R function restoration post-HAART was analysed. A positive linear relationship was demonstrated between IL-7Ralpha expression and the magnitude of IL-7-induced responses in healthy individuals, whereas this relationship is lost in HIV-infected patients, suggesting that viraemic patients suffer a receptor signaling transduction defect in IL-7R function. IL-7 responsiveness is only partly restored by HAART.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Interleukin-7/immunology , Receptors, Interleukin-7/immunology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Case-Control Studies , HIV Infections/drug therapy , Humans , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-7 Receptor alpha Subunit/immunology , Proto-Oncogene Proteins c-bcl-2/immunology , Viral LoadABSTRACT
1. Interleukin-2 (IL-2) has proinflammatory properties that limit its therapeutic use. Its side effects are mainly explained by the induction of a vascular leakage syndrome. Cytokines, as TNF-alpha and IL-1beta, and nitric oxide (NO) generated by IL-2-activated leukocytes play a role in this defect. 2. As the systemic release of these mediators inhibits neutrophil migration to a specific inflammatory site, we investigated now whether IL-2 administrated systemically inhibits the neutrophil recruitment to the inflamed peritoneum. The involvement of NO in the process was also addressed. 3. Using peritoneal neutrophils, we show that the intravenous treatment of the mice with IL-2 inhibits the neutrophil migration induced by carrageenin, LPS or fMLP. In confirmation, IL-2-treated mice showed a significant reduction in leukocyte rolling and adhesion in mesenteric microcirculation evaluated after carrageenin, LPS and fMLP injections. Aminoguanidine prevented the inhibitory effect of IL-2 on carrageenin-induced neutrophil migration, rolling and adhesion. In contrast, IL-2 failed to reduce the lung leukocyte infiltration induced by LPS. Therefore, IL-2 inhibition of neutrophil migration is organ specific. 4. Our results indicate that IL-2 administered systemically inhibits neutrophil recruitment to some inflammatory sites through a mechanism dependent on NO. The results also reinforce the needs to determine the mechanism by which patients treated with IL-2 show increased risks of infection.