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HIV-1 Infection (hiv-1 + infection)
Kinds of HIV-1 Infection Selected AbstractsMULTIPLE HIV-1 INFECTION OF CELLS AND THE EVOLUTIONARY DYNAMICS OF CYTOTOXIC T LYMPHOCYTE ESCAPE MUTANTSEVOLUTION, Issue 9 2009Dominik Wodarz Cytotoxic T lymphocytes (CTL) are an important branch of the immune system, killing virus-infected cells. Many viruses can mutate so that infected cells are not killed by CTL anymore. This escape can contribute to virus persistence and disease. A prominent example is HIV-1. The evolutionary dynamics of CTL escape mutants in vivo have been studied experimentally and mathematically, assuming that a cell can only be infected with one HIV particle at a time. However, according to data, multiple virus particles frequently infect the same cell, a process called coinfection. Here, we study the evolutionary dynamics of CTL escape mutants in the context of coinfection. A mathematical model suggests that an intermediate strength of the CTL response against the wild-type is most detrimental for an escape mutant, minimizing overall virus load and even leading to its extinction. A weaker or, paradoxically, stronger CTL response against the wild-type both lead to the persistence of the escape mutant and higher virus load. It is hypothesized that an intermediate strength of the CTL response, and thus the suboptimal virus suppression observed in HIV-1 infection, might be adaptive to minimize the impact of existing CTL escape mutants on overall virus load. [source] ORIGINAL ARTICLE: Analysis of Immunological Markers Associated with Pregnancy and HIV-1 Infection: Relevance in Perinatal Transmission in HIV-1-Infected Pregnant Women with Low Plasma Viral LoadAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2008Naresh Sachdeva Problem, In HIV-1-infected pregnant women with low plasma viral load, risk factors associated with perinatal HIV-1 transmission are not clearly understood. Method of study, We analyzed distribution of peripheral CD8 T-cell subsets, plasma cytokines and measured secretory leukocyte peptidase inhibitor (SLPI) and myeloid-related protein (MRP)-8 levels in whole-blood and cervico-vaginal fluid (CVF) specimens obtained from 35 HIV-1-infected pregnant women (group 1), 12 HIV-1-infected non-pregnant women (group 2) and 15 HIV-1 uninfected pregnant women (group 3). Results, The group 1 women had higher expression of CD38, human leukocyte antigen-DR and CD95 on CD8 T-cells and higher levels of plasma tumor necrosis factor-, and epidermal growth factor. CVF-SLPI levels were the highest in group-3, while MRP-8 levels were the highest in group 1 women in plasma and CVF (P < 0.01). Although there were no cases of perinatal HIV-1 transmission, group 1 women undergoing HIV-1-indicated cesarean section had lower levels of CVF-SLPI as compared with those undergoing normal vaginal delivery. Conclusion, Pregnancy contributes to the activation of peripheral CD8 T cells and increase in pro-inflammatory cytokines. Production of protective mucosal secretory factors such as SLPI is affected by HIV-1 infection in pregnant women and down-regulated SLPI levels may indirectly indicate a higher possibility of perinatal HIV-1 transmission. [source] Neurodevelopmental outcomes in children with HIV infection under 3 years of ageDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 8 2006C J Foster BA MBBS MRCPCH Following the introduction of combination antiretroviral therapy, children vertically infected with the human immunodeficiency virus (HIV-1) living in the developed world are surviving into adult life. This paper reviews the neurodevelopmental outcomes of 62 consecutively-presenting children with HIV-1 infection diagnosed before 3 years of age (32 males, 30 females; median age at presentation 6mo). Neurological and developmental data are presented with immunological and virological responses to antiretroviral therapy. Fourteen children (22%) had abnormal neurological signs and 25 (40%) demonstrated significant developmental delay on standardized developmental assessments. Children presenting with more severe HIV-1 disease and immune compromise had significantly more abnormal neurological signs and developmental delays than children presenting with milder HIV-1 symptomatology. Immune function, control of HIV-1 viral replication, and growth parameters improved with antiretroviral therapy (median age at last follow-up 7y 3mo); however, abnormal neurological signs and significant gross motor difficulties persisted. [source] Mixed cryoglobulinemia is associated with increased risk for death, or neoplasia in HIV-1 infectionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2001T. Kordossis Backround Cryoglobulinemia has been reported in several chronic infectious and autoimmune diseases, and in patients with HIV-1 infection. Cryoglobulinemia associated with hepatitis C virus infection is considered a risk factor for the development of neoplasia, especially B-cell non-Hodgkin lymphoma. This study was undertaken to investigate whether the presence of circulating cryoglobulins is associated with survival or development of neoplastic disease in HIV-1 infection. Design We evaluated 87 unselected consecutive HIV-1 infected patients for the presence of cryoglobulinemia and they were prospectively followed up for a median of 34 months, with clinic visits at 4-month intervals. None of the patients had neoplasia at study entry. Time-to-event analysis for death, neoplasm and B-cell lymphoproliferative disorder were performed with Cox proportional hazards models. Results Mixed cryoglobulinemia (types II and III) was detected in 24 (28%) of the 87 patients. During the follow up, 12 patients died and 8 developed neoplastic disease. Multivariate analysis showed that circulating cryoglobulins were an independent predictor of death [relative risk (RR), 4·97; 95% confidence intervals (CI), 1·26,19·63] and development of neoplasia (RR, 5·18; 95% CI, 1·23,21·83). In addition, cryoglobulinemia reached borderline significance as a predictor of lymphoproliferative disorder of B-cell origin (P = 0·08; RR, 4·53; 95% CI, 0·83,24·75). Conclusions Our results suggest that cryoglobulinemia is associated with an increased risk for death, neoplasia or development of lymphoproliferative disorder of B-cell origin, in HIV-1 infected patients. [source] Interactions between major histocompatibility complex class II surface expression and HIV: implications for pathogenesisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2001W. Kamp Although it has been almost 20 years since the first cases of acquired immunodeficiency syndrome (AIDS) were documented, the pathogenesis is still not completely understood. Interactions between major histocompatibility complex (MHC) Class I and human immunodeficiency virus (HIV), resulting in down-regulation of MHC-I surface expression, have been reported to contribute to pathogenesis by suppressing the host's immune response. Interactions between MHC Class II and HIV have also been described, but it is unclear how these contribute to the pathogenesis. MHC-II surface expression on HIV-infected monocytes and monocytic cell lines has been described to be increased as well as decreased when compared to uninfected control monocytes. HIV-specific mechanisms appear to down-regulate MHC-II expression on blood monocytes during HIV-1 infection, whereas host mechanisms up-regulate MHC-II expression in response to infection of blood monocytes as well as brain macrophages. A balance between these two may determine MHC-II expression levels in individual patients. Altogether, HIV seems to be able to benefit from both low and high levels of MHC-II surface expression. The first results in reduced immune surveillance of the host, allowing the virus to replicate faster; the second increases infectivity of the virus as a result of higher MHC-II density on macrophages and virion particles. [source] HIV-1 infection: new treatment paradigmsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001Y. Persidsky No abstract is available for this article. [source] Progressive CD127 down-regulation correlates with increased apoptosis of CD8 T cells during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2009Shu-Ye Zhang Abstract Chronic HIV-1 infection can induce a significant decrease in CD127 expression on CD8 T cells, but the underlying mechanisms and immunological consequences are unclear. In this study, we investigated CD127 expression on CD8 T cells from a total of 51 HIV-1-infected subjects and 16 healthy individuals and analyzed the association between CD127 expression and CD8 T-cell apoptosis in these HIV-1-infected subjects. We found that CD127 expression on total CD8 T cells was significantly down-regulated, which was correlated with the increased CD8 T-cell apoptosis and disease progression of chronic HIV-1 infection. The in vitro addition of IL-7 efficiently rescued the spontaneous apoptosis of CD8 T cells from HIV-1-infected individuals. IL-7 stimulation also transiently down-regulated CD127 expression, whereas some of the CD127, CD8 T cells regained CD127 expression soon after IL-7 was retracted from the incubation medium. Thus, IL-7 stimulation reduced apoptosis of both CD127+ and CD127,CD8 T cells to some degree. These data indicate that CD127 loss might impair IL-7 signaling and increase CD8 T-cell apoptosis during HIV-1 infection. This study, therefore, will extend the notion that IL-7 could be a good candidate for immunotherapy in HIV-1-infected patients. [source] Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Markus Moll Abstract Invariant CD1d-restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV-1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV-1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN-, in response to CD1d-restricted lipid antigen as compared with cells from uninfected control subjects. HIV-1 infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor (CD279) on the CD4, subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD-1-independent. Furthermore, the elevated PD-1 expression and the functional defects were not restored by anti-retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT-cell compartment in HIV-1-infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients. [source] B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2008Xicheng Wang Abstract Impaired myeloid dendritic cells (mDC) fail to elicit host antiviral immune responses, leading to disease progression in HIV-1 infection. However, mechanisms underlying mDC suppression remain elusive. In this study, we found that the T-cell co-stimulatory molecule programmed death-1 ligand-1 (B7-H1) is significantly up-regulated on peripheral mDC in HIV-1-infected typical progressors and AIDS patients, but is maintained at a relatively low level in long-term non-progressors. Successful immune reconstitution after highly active antiretroviral therapy, indicated by full suppression of HIV-1 replication and substantial increases of CD4 T-cell counts, correlated with a decrease in B7-H1 expression. Importantly, we also found that X4 HIV-1 isolates directly induced B7-H1 expression on mDC in vitro, while adding antiviral agents hampered this B7-H1 up-regulation. Blockade of B7-H1 in vitro strongly enhanced mDC-mediated allostimulatory capacity and IL-12 production. In contrast, B7-H1 ligation with soluble programmed death-1 (PD-1) reduced mDC maturation and IL-12 production but increased mDC apoptosis and IL-10 production. Thus, B7-H1 up-regulation may inhibit mDC-mediated immune response, thereby facilitating viral persistence and disease progression in HIV-1-infected patients. This study provides new evidence that B7-H1 inhibitory signaling may reversely mediate functional impairment of mDC in HIV-1 infection, which further supports the notion that B7-H1 blockade represents a novel therapeutic approach to this disease. [source] Site-directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Sarah Abstract Chemokine receptor CXCR6 mediates the chemotaxis and adhesion of leukocytes to soluble and membrane-anchored forms of CXCL16, and is an HIV-1 co-receptor. Here, we describe the effects of mutation of acidic extracellular CXCR6 residues on receptor function. Although most CXCR6 mutants examined were expressed at levels similar to wild-type (WT) CXCR6, an N-terminal E3Q mutant was poorly expressed, which may explain previously reported protective effects of a similar single nucleotide polymorphism, with respect to late-stage HIV-1 infection. In contrast to several other chemokine receptors, mutation of the CXCR6 N,terminus and inhibition of post-translational modifications of this region were without effect on receptor function. Likewise, N-terminal extension of CXCL16 resulted in a protein with decent potency and efficacy in chemotaxis and not, as anticipated, a CXCR6 antagonist. D176N and E274Q CXCR6 mutants were unable to interact with soluble CXCL16, suggesting a critical role for D176 and E274 in ligand binding. Intriguingly, although unable to interact with soluble CXCL16, the E274Q mutant could promote robust adhesion to membrane-anchored CXCL16, suggesting that soluble and membrane-bound forms of CXCL16 possess distinct conformations. Collectively, our data suggest a novel paradigm for the CXCR6:CXCL16 interaction, a finding which may impact the discovery of small-molecule antagonists of CXCR6. [source] Interaction between the CCR5 chemokine receptors and microbial HSP70EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Trevor Whittall Abstract Evidence is presented that the microbial 70-kD heat shock protein (HSP70) binds to CCR5 chemokine receptors in CCR5-transfected cell lines and in primary human cells. Significant CCR5-mediated calcium mobilization was stimulated by HSP70 and inhibited with TAK,779, which is a specific CCR5 antagonist. HSP70-mediated activation of the p38 MAPK phosphorylation signaling pathway was also demonstrated in CCR5-transfected HEK 293 cells. Direct binding of three extracellular peptides of CCR5 to HSP70 was demonstrated by surface plasmon resonance. Functional evidence of an interaction between HSP70, CCR5 and CD40 was shown by enhanced production of CCL5 by HEK 293 cells transfected with both CD40 and CCR5. Primary monocyte-derived immature DC stimulated with HSP70 produced IL-12 p40, which showed dose-dependent inhibition of >90% on treatment with both TAK 779 and anti-CD40 mAb. Stimulation of IL-12 p40 or TNF-, by HSP70 was related to the differential cell surface expression of CCR5 in primary human immature and mature DC, and those with the homozygous ,,32 CCR5 mutation. These findings may be of significance in the interaction between HSP70 and immune responses of CCR5+ T cells in HIV-1 infection, as well as in inflammatory bowel disease. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636551 [source] CD30 ligation differentially affects CXCR4-dependent HIV-1 replication and soluble CD30 secretion in non-Hodgkin cell lines and in ,,,,T,lymphocytesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2003Priscilla Biswas Abstract We studied whether signaling through CD30, a member of the TNF receptor family, affected acute infection with HIV-1, encompassing its entire replicative cycle. Several non-Hodgkin cell lines, targets of CXCR4-dependent (X4) HIV-1 infection, were positive for CD30 expression. CD30 ligation induced up-regulation of viral replication only in certain CD30+ cell lines. Enhancement ofX4 virus replication by CD30 engagement inversely correlated with both CD30 surface density and constitutive NF-,B activation. Conversely, expression of CD30, but not of other members of the TNF receptor family, was proportional to constitutive NF-,B binding. Concomitantly, secretion of soluble (s) CD30 increased in all cell lines by CD30 ligation. sCD30 release was enhanced by engagement of CD30 alone and, to a greater extent, by co-engagement of CD3 also in primary ,,,,T,lymphocytes, along with complementary modulations of their surface CD30 expression. sCD30-containing supernatant specifically inhibited HIV-1 expression induced by CD30 engagement in chronically infected ACH-2 T,cells; thus sCD30 may act as a negative feed-back molecule. In conclusion, we have delineated novel features of CD30 biology and underline the peculiar link of CD30 expression to constitutive NF-,B activation which is pivotal to both HIV replication and cell survival. [source] MULTIPLE HIV-1 INFECTION OF CELLS AND THE EVOLUTIONARY DYNAMICS OF CYTOTOXIC T LYMPHOCYTE ESCAPE MUTANTSEVOLUTION, Issue 9 2009Dominik Wodarz Cytotoxic T lymphocytes (CTL) are an important branch of the immune system, killing virus-infected cells. Many viruses can mutate so that infected cells are not killed by CTL anymore. This escape can contribute to virus persistence and disease. A prominent example is HIV-1. The evolutionary dynamics of CTL escape mutants in vivo have been studied experimentally and mathematically, assuming that a cell can only be infected with one HIV particle at a time. However, according to data, multiple virus particles frequently infect the same cell, a process called coinfection. Here, we study the evolutionary dynamics of CTL escape mutants in the context of coinfection. A mathematical model suggests that an intermediate strength of the CTL response against the wild-type is most detrimental for an escape mutant, minimizing overall virus load and even leading to its extinction. A weaker or, paradoxically, stronger CTL response against the wild-type both lead to the persistence of the escape mutant and higher virus load. It is hypothesized that an intermediate strength of the CTL response, and thus the suboptimal virus suppression observed in HIV-1 infection, might be adaptive to minimize the impact of existing CTL escape mutants on overall virus load. [source] Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolinFEBS JOURNAL, Issue 18 2005Elias A. Said The growth factor pleiotrophin (PTN) has been reported to bind heparan sulfate and nucleolin, two components of the cell surface implicated in the attachment of HIV-1 particles to cells. Here we show that PTN inhibits HIV-1 infection by its capacity to inhibit HIV-1 particle attachment to the surface of permissive cells. The ,-sheet domains of PTN appear to be implicated in this inhibitory effect on the HIV infection, in particular the domain containing amino acids 60,110. PTN binding to the cell surface is mediated by high and low affinity binding sites. Other inhibitors of HIV attachment known to bind specifically surface expressed nucleolin, such as the pseudopeptide HB-19 and the cytokine midkine prevent the binding of PTN to its low affinity-binding site. Confocal immunofluorescence laser microscopy revealed that the cross-linking of surface-bound PTN with a specific antibody results in the clustering of cell surface-expressed nucleolin and the colocalization of both PTN and nucleolin signals. Following its binding to surface-nucleolin, PTN is internalized by a temperature sensitive mechanism, a process which is inhibited by HB-19 and is independent of heparan and chondroitin sulfate proteoglycans. Nevertheless, proteoglycans might play a role in the concentration of PTN on the cell surface for a more efficient interaction with nucleolin. Our results demonstrate for the first time that PTN inhibits HIV infection and suggest that the cell surface-expressed nucleolin is a low affinity receptor for PTN binding to cells and it is also implicated in PTN entry into cells by an active process. [source] Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brainGLIA, Issue 2 2006Huanyu Dou Abstract The balance between astrocyte and microglia neuroprotection and neurotoxicity defines the tempo of neuronal dysfunction during HIV-1-associated dementia (HAD). Astrocytes maintain brain homeostasis and respond actively to brain damage by providing functional and nutritive neuronal support. In HAD, low-level, continuous infection of astrocytes occurs, but the functional consequences of thisinfection are poorly understood. To this end, human fetal astrocytes (HFA) and monocyte-derived macrophages (MDM) were infected with HIV-1DJV and HIV-1NL4-3 (neurotropic and lymphotropic strains respectively) and a pseudotyped Vesicular Stomatitis Virus (VSV/HIV-1NL4-3) prior to intracranial injection into the basal ganglia of severe combined immunodeficient mice. Neuropathological and immunohistochemical comparisons for inflammatory and neurotoxic activities were performed amongst the infected cell types at 7 or 14 days. HIV-1-infected MDM induced significant increases in Mac-1, glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1, and proinflammatory cytokine RNA and/or protein expression when compared with HSV/HIV-1- and HIV-1-infected HFA and sham-operated mice. Levels of neuron-specific nuclear protein, microtubule-associated protein 2, and neurofilament antigens were reduced significantly in the brain regions injected with human MDM infected with HIV-1DJV or VSV/HIV-1. We conclude that HIV-1 infection of astrocytes leads to limited neurodegeneration, underscoring the early and active role of macrophage-driven neurotoxicity in disease. © 2006 Wiley-Liss, Inc. [source] Dose-dependent long-term effects of Tat in the rat hippocampal formation: A design-based stereological studyHIPPOCAMPUS, Issue 4 2010Sylvia Fitting Abstract The human immunodeficiency virus type 1 (HIV-1) protein transactivator of transcription (Tat) is believed to play a critical role in mediating central nervous system (CNS) pathology in pediatric HIV-1 infection. Long-term neurotoxicity was investigated in a design-based stereology study following intrahippocampal injection of Tat on postnatal day (P)10, a time period that approximates the peak in the rats' rate of brain growth and mimics clinical HIV-1 CNS infection at labor/delivery. The goal was to examine the impact of P10 intrahippocampal Tat injection on the anatomy of the adult hippocampus (5 month) to gain a better understanding about how timing of infection influences the rate of progression of pediatric HIV-1 infection [cf. Fitting et al. (2008a) Hippocampus 18:135,147]. Male P10 Sprague-Dawley rats were bilaterally injected with vehicle or one of three different doses of Tat (5, 25, or 50 ,g). Unbiased stereological estimates were used to quantify total neuron number (Nissl stain) in five major subregions of the rat hippocampus: granular layer (GL), hilus of the dentate gyrus (DGH), cornu ammonis fields (CA)2/3, CA1, and subiculum (SUB). Glial cells (astrocytes and oligodendrocytes) were quantified in the DGH and SUB. No significant reduction of neuron number was noted for any of the five hippocampal subregions, in contrast to the very prominent reductions reported when Tat was administered on P1 [Fitting et al. (2008a) Hippocampus 18:135,147]. However, for glial cells, the number of astrocytes in the DGH and SUB as well as the number of oligodendrocytes in the DGH were linear dose dependently increased as a function of dose of Tat. In conjunction with previous stereological research [Fitting et al., (2008a) Hippocampus 18:135,147], the present data suggest that variability in the progression of pediatric HIV/acquired immunodeficiency syndrome (AIDS) may be better understood with the knowledge of the factor of timing of HIV-1 CNS infection. © 2009 Wiley-Liss, Inc. [source] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infectionHIV MEDICINE, Issue 10 2009PENTA Steering Committee PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: ,When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. ,What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained. [source] Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety reviewHIV MEDICINE, Issue 1 2007CL Cooper In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source] Successful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt's lymphomaHIV MEDICINE, Issue 1 2005C Lehmann Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are concerns not only about infectious and haematological complications in HIV-infected patients during intensive chemotherapy, but also about potential interactions between chemotherapy and highly active antiretroviral therapy (HAART). Current data on patients treated concomitantly with intensive chemotherapy and HAART are limited, and no data exist on patients with ARL suffering from active opportunistic infections. We report the case of a 38-year-old man with advanced HIV-1 infection, pulmonary tuberculosis and Burkitt's lymphoma. Intensive chemotherapy was administered in parallel with tuberculostatic therapy and HAART. Six months later, the patient achieved not only a complete remission of Burkitt's lymphoma and sustained viral suppression, but also a full recovery from tuberculosis. This case report provides some useful observations on the successful application of intensive chemotherapy in addition to tuberculostatic therapy and HAART in HIV-infected patients. [source] Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infectionHIV MEDICINE, Issue 2 2004G Hardy Objectives We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate this with the restoration of peripheral naïve T cells. Methods Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiatiated HAART demonstrated reconstitution of the naïve T-cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts (mean 82, range 9,160 cells/,L blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T-cell receptor excision circles (TRECs) in peripheral cells. Results In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naïve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2-month time point. Conclusions The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV-1 infected persons with low CD4 T-cell counts. [source] The selection and evolution of viral quasispecies in HIV-1 infected childrenHIV MEDICINE, Issue 1 2002P Nowak Objectives To analyse the diversity and divergence of the viral populations in three mother,child pairs in longitudinally obtained samples for up to 7 years. Methods Peripheral blood mononuclear cells were obtained from three mothers at delivery and three to four samples were obtained from each of their children from 1.5 months up to 78 months of age. The V3 region of HIV-1 was amplified by polymerase chain reaction, cloned and sequenced. HIV-1 DNA sequence comparisons were performed by phylogenetic analysis. Results The viral population was initially homogenous in two children but highly heterogeneous in one child. Three patterns of vertical transmission seemed to have occurred: transmission of the most prevalent maternal strain, of a minor maternal strain and of multiple maternal strains. In one child, a possible reappearance of a maternal sequence was observed at 34 months of age. Conclusions Children may become infected with the most prevalent maternal strain, a minor maternal variant or multiple maternal quasispecies. Maternal viral variants may reappear in children after several years of infection and could possibly be derived from a reservoir of founder quasispecies established during the children's primary HIV-1 infection. [source] Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-1 infectionIMMUNOLOGY, Issue 2 2008Kehmia Titanji Summary Human natural killer (NK) (CD3, CD56+) cells can be divided into two functionally distinct subsets, CD3, CD56dim and CD3, CD56bright. We analysed the distribution of NK cell subsets in primary and chronic human immunodeficiency virus-1 (HIV-1) infection, to determine if HIV infection stage may influence the subset distribution. In primary infection, contrary to chronic infection, the CD3, CD56dim subset was expanded compared to healthy controls. We also studied the effect of antiretroviral therapy administered early in infection and found that NK cell subset distribution was partially restored after 6 months of antiretroviral therapy in primary infection, but not normalized. Recently, NK cells have been divided into CD27, and CD27+ subsets with different migratory and functional capacity and CD27-mediated NK cell activation has been described in mice. We therefore investigated whether CD27 and/or CD70 (CD27 ligand) expression on NK cells, and thus the distribution of these novel NK subsets, was altered in HIV-1-infected patients. We found up-regulated expression of both CD27 and CD70 on NK cells of patients, resulting in higher proportions of CD27high and CD70high NK cells, and this phenomenon was more pronounced in chronic infection. Experiments conducted in vitro suggest that the high interleukin-7 levels found during HIV-1 infection may participate in up-regulation of CD70 on NK cell subsets. Imbalance of NK cell subsets and up-regulated expression of CD27 and CD70 initiated early in HIV-1 infection may indicate NK cell activation and intrinsic defects initiated by HIV-1 to disarm the innate immune response to the virus. [source] Distribution of CCR2 polymorphism in HIV-1-infected and healthy subjects in North IndiaINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2007G. Kaur Summary Substitution of V64I in CCR2 relates to delayed progression to AIDS and protects against HIV-1 infection. We examined the distribution of V64I in HIV-infected and healthy North Indian subjects. No significant difference in the allele or genotype distribution of CCR2 V64I polymorphism was observed, indicating that there is no association between CCR2 V64I polymorphism and susceptibility to HIV infection in North Indian population. [source] Nicotinamide phosphoribosyltransferase/sirtuin 1 pathway is involved in human immunodeficiency virus type 1 Tat-mediated long terminal repeat transactivationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2010Hong-Sheng Zhang Abstract Tat is a multifunctional transactivator encoded by human immunodeficiency virus type 1 (HIV-1). Tat transactivating activity is controlled by nicotinamide adenine nucleotide+ (NAD+)-dependent deacetylase sirtuin 1 (SIRT1). Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the conversion of nicotinamide into NAD+, which is crucial for SIRT1 activation. Thus, the effect of Nampt on Tat-regulated SIRT activity was studied in Hela-CD4-,-gal (MAGI) cells. We demonstrated that Tat caused NAD+ depletion and inhibited Nampt mRNA and protein expression in MAGI cells. Resveratrol reversed Tat-induced NAD+ depletion and inhibition of Nampt mRNA and protein expression. Further investigation revealed that Tat-induced inhibition of SIRT1 activity was potentiated in Nampt-knockdown by Nampt siRNA compared to treatment with Tat alone. Nampt siRNA potentiated Tat-induced HIV-1 transactivation in MAGI cells. Altogether, these results indicate that Nampt is critical in the regulation of Tat-induced inhibition of SIRT1 activity and long terminal repeat (LTR) transactivation. Nampt/SIRT1 pathway could be a novel therapeutic tool for the treatment of HIV-1 infection. J. Cell. Biochem. 110: 1464,1470, 2010. © 2010 Wiley-Liss, Inc. [source] Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2004Dr. Jinhai Wang Abstract Chemokine receptors CCR5 and CXCR4 are the major coreceptors of HIV-1 infection and also play fundamental roles in leukocyte trafficking, metastasis, angiogenesis, and embyogenesis. Here, we show that transfection of CCR5 into CXCR4 and CD4 expressing 3T3 cells enhances the cell surface level of CXCR4. In CCR5 high expressing cells, cell surface level of CXCR4 was incompletely modulated in the presence of the CXCR4 ligand CXCL12/SDF-1,. CCR5 was resistant to ligand-dependent modulation with the CCR5 ligand CCL5/RANTES. Confocal laser microscopy revealed that CCR5 was colocalized with CXCR4 on the cell surface. In CD4 expressing CCR5 and CXCR4 double positive NIH 3T3 cells, immunoprecipitation followed by Western blot analysis revealed that CCR5 was associated with CXCR4 and CD4. CXCR4 and CCR5 were not co-immunoprecipitated in cells expressing CCR5 and CXCR4 but without CD4 expression. Compared to NIH 3T3CD4 cells expressing CXCR4, the entry of an HIV-1 X4 isolate (HCF) into NIH 3T3CD4 expressing both CXCR4 and CCR5 was reduced. Our data indicate that chemokine receptors interact with each other, which may modulate chemokine,chemokine receptor interactions and HIV-1 coreceptor functions. Published 2004 Wiley-Liss, Inc. [source] Undetectable HIV-1 RNA load with the Cobas TaqMan v1.0 in a patient diagnosed at the time of primary HIV-1 infectionJOURNAL OF MEDICAL VIROLOGY, Issue 11 2010Jade Ghosn Abstract Diagnosis of primary HIV-1 infection is challenging due to the presence of a serological window; thus, HIV-1-RNA quantitation and/or measurement of p24 antigenemia are recommended in such cases. A patient was diagnosed at the time of primary HIV-1 infection, he harbored a CFR02_AG subtype virus; quantitation of plasma HIV-1-RNA yielded an undetectable result according to one commercial assay, while HIV-1-RNA was detectable when measured with three other assays. J. Med. Virol. 82:1816,1818, 2010. © 2010 Wiley-Liss, Inc. [source] Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection,,JOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Thomas Vollbrecht Abstract Excessive immune activation is a hallmark of chronic uncontrolled HIV infection. During the past years, growing evidence suggests that immune inhibitory signals also play an important role in progressive disease. However, the relationship between positive and negative immune signals on HIV-specific CD8 T cells has not been studied in detail so far in chronic HIV-1 infection. In this study, the expression of markers of positive (CD38) and negative (PD-1) immune signals on virus-specific CD8 T cells in chronic, untreated HIV-1 infection was evaluated using intracellular cytokine staining. Viral escape mutations were assessed by autologous virus sequence analysis and subsequent peptide titration assays. Single-epitope CD8 T-cell responses toward Gag, Pol, and Nef were compared in 12 HIV-1 controllers (viral load <5,000,cp/ml) and 12 HIV-1 progressors (viral load >50,000,cp/ml) and a highly significant increase of CD38/PD-1 co-expression on virus-specific CD8 T cells in progressors was found (P,<,0.0001). The level of CD38/PD-1 co-expression was independent of epitope specificity. Longitudinal follow-up revealed a clear drop in CD38/PD-1 co-expression on virus-specific CD8 T cells after the suppression of antigen following either viral escape mutation or the initiation of HAART (P,=,0.004). Antigen persistence with a fluctuating viral load revealed stable levels of CD38/PD-1 co-expression whereas significant rises in viral load were accompanied or even preceded by substantial increases in CD38/PD-1 co-expression. The CD38/PD-1 phenotype clearly distinguishes HIV-specific CD8 T-cell responses between controllers and progressors. Whether it plays a causative role in disease progression remains debatable. J. Med. Virol. 82:358,370, 2010. © 2010 Wiley-Liss, Inc. [source] Prevalence of persistent and latent viruses in untreated patients infected with HIV-1 from Ghana, West AfricaJOURNAL OF MEDICAL VIROLOGY, Issue 11 2009Lara Isobel Compston Abstract Only limited epidemiological data, pertaining to the prevalence of common persistent viruses has been reported in Ghana. This study was conducted to determine the prevalence of persistent viruses in individuals with untreated HIV-1 infection and uninfected blood donors. Paired plasma and cellular samples from HIV-negative blood donors, asymptomatic HIV and symptomatic/AIDS cohorts were screened by multiplex PCR then qPCR for parvovirus B19 (B19V), hepatitis B virus (HBV), GB virus-C (GBV-C), cytomegalovirus (CMV), Epstein,Barr virus (EBV), human herpesvirus-8 (HHV-8) and varicella-zoster virus (VZV). IgG antibodies specific to each target virus were tested to determine exposure rates. No evidence of viraemia was found for B19V and VZV in any group. Prevalence of GBV-C plasma viraemia was significantly higher in asymptomatic and symptomatic HIV infection (16.7%) and (16.2%) than in blood donors (4%) P,<,0.005. Occult HBV infection was significantly more frequent in symptomatic HIV infection (10.9%) compared to asymptomatic HIV (3.6%) and blood donors (1.6%) P,<,0.005. Although there was a high background of EBV viraemia in cellular fractions of blood donors (8.3%), it was significantly higher in asymptomatic (44.6%) and symptomatic HIV (14.6%) P,<,0.0001. For CMV, the significantly increased prevalence of viraemia was only observed in the plasma fraction of the symptomatic HIV-1/AIDS patients (7.6%) compared to asymptomatic individuals (1.8%) and blood donors (0.8%) P,,,0.001. The background seroprevalence in blood donors was high for B19V (,64%), HBV (,70%), CMV and EBV (,90%) and was significantly increased in HIV infections for HBV, CMV, VZV (symptomatic HIV), and HHV-8 (asymptomatic and symptomatic HIV). J. Med. Virol. 81:1860,1868, 2009. © 2009 Wiley-Liss, Inc. [source] Seroprevalence of Kaposi's sarcoma-associated herpesvirus and risk factors in Xinjiang, China,JOURNAL OF MEDICAL VIROLOGY, Issue 8 2009Bishi Fu Abstract Xinjiang, China is an endemic area for Kaposi's sarcoma (KS) but the seroprevalence of Kaposi's sarcoma-associated herpesvirus (KSHV) and risk factors remain undefined. In this study, antibodies to one KSHV latent protein (ORF73) and two KSHV lytic proteins (ORF65 and ORF-K8.1) were examined in 2,228 subjects from the general population and 37 subjects infected with HIV-1 in Xinjiang, and 560 subjects from the general population in Hubei, a low KS incidence region. The serostatus of a serum sample was defined based on positive results in any one of the three serologic assays. The seroprevalence of KSHV in the general population was higher in Xinjiang than in Hubei (19.2% vs. 9.5%; odds ratios [OR], 2.28; 95% confidence interval [CI], 1.68,3.08; P,<,0.001). Among the ethnic groups in Xinjiang, 68 (15.8%) Han, 182 (20.7%) Uygur, 140 (19.9%) Hazakh, 9 (33.3%) Xibo, and 29 (16.8%) Hui were KSHV-seropositive, respectively. Compared to the Han, the latter groups had an increase in the risk of KSHV of 62.2%, 63.8%, 180.1%, and 30.2% (P,=,0.003, 0.004, 0.018, and 0.286, respectively). Subjects aged <20, 20,50, and >50 had a seroprevalence of KSHV of 11.8%, 17.9%, and 24.6%, respectively. Compared to subjects aged <20, the latter groups had an increase in the risk of KSHV of 63.3% and 144.5% (P,=,0.009 and <0.001, respectively). Subjects infected with HIV-1 in Xinjiang had a seroprevalence of KSHV of 43.2%, and a 220% increase in the risk of KSHV compared to the general population (P,<,0.001). Similar results were obtained when the seroprevalence of KSHV was analyzed with any single or two of the three serologic assays alone. Genotyping identified three unique sequences clustered in the A clade. This study indicates that Xinjiang has a high seroprevalence of KSHV. Geographic location, ethnicity, age and HIV-1 infection are risk factors. Serologic and genotyping results suggest the introduction of KSHV into Xinjiang by specific ethnic groups. J. Med. Virol. 81:1422,1431, 2009. © 2009 Wiley-Liss, Inc. [source] Association of IL-4 589 C/T promoter and IL-4R,I50V receptor polymorphism with susceptibility to HIV-1 infection in North IndiansJOURNAL OF MEDICAL VIROLOGY, Issue 6 2009Animesh Chatterjee Abstract The clinical course and outcome of HIV-1 infection are highly variable among individuals. Interleukin 4 (IL-4) is a key T helper 2 cytokine with various immune-modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co-receptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 promoter 589 C/T and IL-4 R, I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV-1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV-1 exposed seronegative (HES), and 305 HIV-1 seronegative (HSN) individuals. The subjects were genotyped for IL-4 589 C/T promoter polymorphism and IL-4 R, I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL-4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL-4R, I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL-4R, I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P,=,0.000; OR,=,1.734) and HES (76.11% vs. 62.00%; P,=,0.007; OR,=,1.953). Homozygous IL-4R, I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P,=,0.002; OR,=,1.804) and HES (58.88% vs. 42.00%; P,=,0.038; OR,=,1.978). The present study for the first time suggests an association of IL-4R, I50 allele with increased likelihood of HIV-1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL-4R, polymorphism on the outcome of HIV-1 infection. J. Med. Virol. 81:959,965, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||