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Livio Azzoni,
Andrea S Foulkes, Emmanouil Papasavvas,
Angela M Mexas,
Kenneth M Lynn,
Karam Mounzer,
Pablo Tebas,
Jeffrey M Jacobson,
Ian Frank,
Una O'Doherty,
Jay Kostman,
Luis J Montaner
The Journal of Infectious Diseases 04/2013; · 6.41 Impact Factor
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Livio Azzoni,
Andrea S Foulkes, Emmanouil Papasavvas,
Angela M Mexas,
Kenneth M Lynn,
Karam Mounzer,
Pablo Tebas,
Jeffrey M Jacobson,
Ian Frank,
Michael P Busch,
Steven G Deeks,
Mary Carrington,
Una O'Doherty,
Jay Kostman,
Luis J Montaner
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ABSTRACT: Background. Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control HIV replication.Methods. 23 HIV-1 infected, virologically-suppressed subjects on ART (CD4 >450 cells/ml) were randomized to add Peg-IFN-α2A 180 (arm A) or 90 (arm B) μg/week to current ART. After 5 weeks, ART was interrupted and Peg-IFN-α2A continued for up to 12 weeks (primary endpoint) with option to continue to 24 weeks. Endpoints included virologic failure (viral load, VL ≥ 400 copies/ml) and adverse events. Residual VL and HIV-1 DNA integration were also assessed.Results. At week 12 of Peg-IFN-α2A monotherapy, viral suppression was observed in 9/20 (45%) subjects, a significantly greater proportion than expected (arm A p=0.0088; arm B p=0.0010; combined arms p<0.0001). Over 24 weeks, both arms had lower proportions of VL rebound than an historical control (arm A, p= 0.0046; arm B, p= 0.0011). Subjects who sustained VL < 400 copies/ml had decreased the levels of integrated HIV DNA (p= 0.0313), but increased residual VL (p=0.0078) when compared to subjects with endpoint failure.Conclusions. Peg-IFN-α2A immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immune-mediated approaches in HIV suppression and/or eradication.
The Journal of Infectious Diseases 10/2012; · 6.41 Impact Factor
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Angela M Mexas,
Erin H Graf,
Matthew J Pace,
Jianqing J Yu, Emmanouil Papasavvas,
Livio Azzoni,
Michael P Busch,
Michele Di Mascio,
Andrea S Foulkes,
Stephen A Migueles,
Luis J Montaner,
Una O'doherty
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ABSTRACT: OBJECTIVES:: Interest in targeting HIV reservoirs is fueling trials that may decrease reservoir size and/or induce viral replication. Therefore, we aimed to develop strategies to sensitively measure changes in these parameters in patients on and off ART. Achieving these goals may help evaluate the effects of future clinical trials. DESIGN:: To determine the relationship between measurements of total and integrated HIV DNA and their role as markers of reservoir size and ongoing replication, these parameters were measured during the first year of ART, during long-term effective ART, and during a clinical trial aimed at targeting reservoirs. METHODS:: Total and integrated HIV DNA were measured in patient samples using quantitative PCR techniques. CD4+T cell counts and plasma viremia were also monitored. RESULTS:: Unintegrated HIV DNA became undetectable during the first year of ART. Total and integrated HIV DNA levels were generally equal in well controlled patients on ART, and low-level plasma viremia correlated best with integration measures. Finally, patients who controlled plasma viremia (<400 copies/ml) during interferon-α monotherapy exhibited a decrease in the level of integrated but not total HIV DNA and a rise in the ratio of total to integrated HIV DNA over time. CONCLUSIONS:: Our findings suggest the appearance of unintegrated HIV DNA reflects residual HIV expression and de novo reverse transcription, providing insight into the mechanism by which interferon-α reduces the HIV reservoir. We conclude concurrent measurements of total and integrated HIV DNA provide information regarding reservoir size and ongoing replication in trials targeting HIV.
AIDS (London, England) 09/2012; · 4.91 Impact Factor
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ABSTRACT: Endothelial progenitor cells (EPCs) are involved in the endothelium repair. Low circulating EPC levels are predictive of cardiovascular events in HIV-negative subjects. The impact of HIV infection on EPCs, and the role of EPCs in HIV-associated cardiovascular disease, is not known. We hypothesized that circulating EPCs would be inversely associated with carotid artery intima-media thickness (c-IMT) changes in HIV-infected subjects.
EPCs (CD34(+)/KDR(+), CD133(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+)) were defined retrospectively by flow cytometry in cryopreserved peripheral blood mononuclear cells collected longitudinally from 66 chronic HIV-infected subjects and cross-sectionally from 50 at-risk HIV-negative subjects. The HIV-infected subjects participated in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort, were receiving antiretroviral therapy (59/66) and had two sequential measurements of c-IMT 1 year apart. Two distinct groups of HIV-infected subjects were identified a priori: rapid c-IMT progressors (subjects with rapid c-IMT progression, n=13, Δc-IMT>0.2 mm) and slow c-IMT progressors (subjects with slow or no c-IMT progression, n=53, Δc-IMT<0.2 mm).
Although cryopreservation reduced sensitivity of detection, EPC frequency in HIV-infected subjects was still significantly higher compared to at-risk HIV-negative subjects (CD34(+)/KDR(+); P=0.01) and correlated positively with CD4(+) T-cell count (CD34(+)/KDR(+), r=0.27; P=0.03). No association was found between the change of EPC frequencies over time (ΔEPC) and Δc-IMT or between EPC frequencies and c-IMT or Δc-IMT.
The lack of an association between EPCs and c-IMT in our cohort does not support HIV-associated reductions in EPC frequency as a cause of accelerated atherosclerosis.
Antiviral therapy 12/2011; 17(3):557-63. · 3.16 Impact Factor
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Livio Azzoni,
Andrea S Foulkes,
Cynthia Firnhaber,
Xiangfan Yin,
Nigel J Crowther,
Deborah Glencross,
Denise Lawrie,
Wendy Stevens, Emmanouil Papasavvas,
Ian Sanne,
Luis J Montaner
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ABSTRACT: The degree of immune reconstitution achieved in response to suppressive ART is associated with baseline individual characteristics, such as pre-treatment CD4 count, levels of viral replication, cellular activation, choice of treatment regimen and gender. However, the combined effect of these variables on long-term CD4 recovery remains elusive, and no single variable predicts treatment response. We sought to determine if adiposity and molecules associated with lipid metabolism may affect the response to ART and the degree of subsequent immune reconstitution, and to assess their ability to predict CD4 recovery.
We studied a cohort of 69 (48 females and 21 males) HIV-infected, treatment-naïve South African subjects initiating antiretroviral treatment (d4T, 3Tc and lopinavir/ritonavir). We collected information at baseline and six months after viral suppression, assessing anthropometric parameters, dual energy X-ray absorptiometry and magnetic resonance imaging scans, serum-based clinical laboratory tests and whole blood-based flow cytometry, and determined their role in predicting the increase in CD4 count in response to ART.
We present evidence that baseline CD4+ T cell count, viral load, CD8+ T cell activation (CD95 expression) and metabolic and anthropometric parameters linked to adiposity (LDL/HDL cholesterol ratio and waist/hip ratio) significantly contribute to variability in the extent of CD4 reconstitution (ΔCD4) after six months of continuous ART.
Our final model accounts for 44% of the variability in CD4+ T cell recovery in virally suppressed individuals, representing a workable predictive model of immune reconstitution.
Journal of the International AIDS Society 07/2011; 14:37. · 3.26 Impact Factor
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Daniel H Sterman,
Andrew Haas,
Edmund Moon,
Adriana Recio,
Daniel Schwed,
Anil Vachani,
Sharyn I Katz,
Colin T Gillespie,
Guanjun Cheng,
Jing Sun, Emmanouil Papasavvas,
Luis J Montaner,
Daniel F Heitjan,
Leslie Litzky,
Joseph Friedberg,
Melissa Culligan,
Carl H June,
Richard G Carroll,
Steven M Albelda
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ABSTRACT: New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).
American Journal of Respiratory and Critical Care Medicine 06/2011; 184(12):1395-9. · 11.08 Impact Factor
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Emmanouil Papasavvas,
Livio Azzoni,
Andrea Foulkes,
Avy Violari,
Mark F Cotton,
Maxwell Pistilli,
Griffin Reynolds,
Xiangfan Yin,
Deborah K Glencross,
Wendy S Stevens,
James A McIntyre,
Luis J Montaner
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ABSTRACT: The effect of early versus deferred antiretroviral treatment (ART) on plasma concentration of lipopolysaccharide (LPS) and host LPS-binding molecules in human immunodeficiency virus (HIV)-infected infants up to 1 year of age was investigated.
We evaluated 54 perinatally HIV-infected and 22 HIV-exposed uninfected infants (controls) at the first and second semester of life. All HIV-infected infants had a baseline CD4 of ≥ 25%, participated in the Comprehensive International Program of Research on AIDS Children with HIV Early Antiretroviral Therapy trial in South Africa, and were randomized in the following groups: group 1 (n = 20), ART deferred until CD4 < 25% or severe HIV disease; and group 2 (n = 34), ART initiation within 6 to 12 weeks of age. LPS, endotoxin-core antibodies, soluble CD14 (sCD14), and LPS-binding protein (LBP) were measured in cryopreserved plasma. T-cell activation was measured in fresh whole blood.
At the first semester, LPS concentration was higher in HIV-infected infants than in controls; sCD14, LBP, and T-cell activation were higher in group 1 than in group 2 and controls. Although LPS was not correlated with study variables, viral load was positively associated with sCD14, LBP, or endotoxin-core antibodies. At the second semester, LPS was not detectable and elevated host LPS-control molecules values were sustained in all groups and in conjunction with ART in all HIV-infected infants.
Although plasma concentration of LPS was higher in perinatally HIV-infected infants 0 to 6 months of age than in controls independent of ART initiation strategy, concentration of LPS-control molecules was higher in infants with deferred ART, suggesting the presence of increased microbial translocation in HIV-infected infants with sustained early viral replication.
The Pediatric Infectious Disease Journal 05/2011; 30(10):877-82. · 3.58 Impact Factor
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AIDS research and human retroviruses 10/2010; 26(10):1047-9. · 2.18 Impact Factor
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Andrea D Raymond,
Bethsebah Gekonge,
Malavika S Giri,
Aidan Hancock, Emmanouil Papasavvas,
Jihed Chehimi,
Andrew V Kossenkov,
Andrew V Kossevkov,
Calen Nicols,
Malik Yousef,
Karam Mounzer,
Jane Shull,
Jay Kostman,
Louise Showe,
Luis J Montaner
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ABSTRACT: Circulating monocytes exhibit an apoptotic resistance phenotype during HIV viremia in association with increased MT expression. MTs are known to play an important role in zinc metabolism and immune function. We now show, in a cross-sectional study using peripheral monocytes, that expression of MT1 isoforms E, G, H, and X is increased significantly in circulating monocyte cells from HIV+ subjects during chronic viremic episodes as compared with uninfected subjects. This increase in expression is also observed during acute viremia following interruption of suppressive ART. Circulating monocytes from HIV+ donors were also found to have elevated zinc importer gene Zip8 expression in conjunction with elevated intracellular zinc levels in contrast to CD4(+)T-lymphocytes. In vitro HIV-1 infection studies with elutriated MDM confirm a direct relation between HIV-1 infection and increased MDM MT1 (isoform G) gene expression and increased intracellular zinc levels. A direct link between elevated zinc levels and apoptosis resistance was established using a cell-permeable zinc chelator TPEN, which reversed apoptosis resistance effectively in monocytes from HIV-infected to levels comparable with uninfected controls. Taken together, increases in MT gene expression and intracellular zinc levels may contribute directly to maintenance of an immune-activated monocyte by mediating an increased resistance to apoptosis during active HIV-1 viremia.
Journal of leukocyte biology 09/2010; 88(3):589-96. · 4.99 Impact Factor
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Jihed Chehimi, Emmanouil Papasavvas,
Costin Tomescu,
Bethsebah Gekonge,
Shaheed Abdulhaqq,
Andrea Raymond,
Aidan Hancock,
Kavita Vinekar,
Craig Carty,
Griffin Reynolds,
Maxwell Pistilli,
Karam Mounzer,
Jay Kostman,
Luis J Montaner
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ABSTRACT: The function of plasmacytoid dendritic cells (PDC) in chronic human immunodeficiency virus type 1 (HIV-1) infection remains controversial with regard to its potential for sustained alpha interferon (IFN-alpha) production and induction of PDC-dependent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity of HIV-infected cells. We address these areas by a study of chronically HIV-1-infected subjects followed through antiretroviral therapy (ART) interruption and by testing PDC cytolytic function against autologous HIV-infected CD4(+) T cells. Rebound in viremia induced by therapy interruption showed a positive association between TRAIL and viral load or T-cell activation, but comparable levels of plasma IFN-alpha/beta were found in viremic ART-treated and control subjects. While PDC from HIV-infected subjects expressed less interferon regulator factor 7 (IRF-7) and produced significantly less IFN-alpha upon Toll-like receptor 7/9 (TLR7/9) engagement than controls, membrane TRAIL expression in PDC from HIV(+) subjects was increased. Moreover, no significant increase in death receptor 5 (DR5) expression was seen in CD4(+) T cells from viremic HIV(+) subjects compared to controls or following in vitro infection/exposure to infectious and noninfectious virus or exogenous IFN-alpha, respectively. Although activated PDC killed the DR5-expressing HIV-infected Sup-T1 cell line, PDC did not lyse primary autologous HIV(+) CD4(+) T cells yet could provide accessory help for NK cells in killing HIV-infected autologous CD4(+) T cells. Taken together, our data show a lack of sustained high levels of soluble IFN-alpha in chronic HIV-1 infection in vivo and document a lack of direct PDC cytolytic activity against autologous infected or uninfected CD4(+) T cells.
Journal of Virology 03/2010; 84(6):2762-73. · 5.40 Impact Factor
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Livio Azzoni,
Nigel J Crowther,
Cynthia Firnhaber,
Andrea S Foulkes,
Xiangfan Yin,
Deborah Glencross,
Robert Gross,
Mitch D Kaplan, Emmanouil Papasavvas,
Doreen Schulze,
Wendy Stevens,
Tessa van der Merwe,
Rita Waisberg,
Ian Sanne,
Luis J Montaner
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ABSTRACT: Advanced HIV infection can result in lipoatrophy and wasting, even in the absence of ongoing opportunistic infections, suggesting that HIV may directly affect adipose tissue amount and distribution.
We assessed the relationship of fat (measured using anthropometry, DEXA, MRI scans) or markers related to glucose and lipid metabolism with viral load in a cross-sectional sample of 83 antiretroviral-naïve HIV-1-infected South African women. A multivariable linear model was fitted to log10VL to assess the combined effect of these variables.
In addition to higher T cell activation, women with viral load greater than the population median had lower waist circumference, body mass index and subcutaneous abdominal fat, as well as lower serum leptin. We demonstrate that leptin serum levels are inversely associated with viral replication, independent of the amount of adipose tissue. This association is maintained after adjusting for multiple variables associated with disease progression (i.e., cellular activation and innate immunity effector levels).
Our results demonstrate that serum leptin levels are inversely associated with viral replication, independent of disease progression: we postulate that leptin may affect viral replication.
Journal of the International AIDS Society 01/2010; 13:33. · 3.26 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2009; 50(3):334-5. · 4.43 Impact Factor
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Emmanouil Papasavvas,
Maxwell Pistilli,
Griffin Reynolds,
Robert Bucki,
Livio Azzoni,
Jihed Chehimi,
Paul A Janmey,
Mark J DiNubile,
Joe Ondercin,
Jay R Kostman,
Karam C Mounzer,
Luis J Montaner
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ABSTRACT: Increased circulating levels of lipopolysaccharide (LPS) have been demonstrated in HIV-1-infected progressors. We investigated the effect of antiretroviral therapy (ART) interruptions on plasma LPS levels.
Overall, 77 individuals participated in this study (51 HIV-positive and 26 healthy). Ten out of 51 HIV-positive participants were viremic ART-naive patients and 41 out of 51 were chronically suppressed patients on ART (three or more drugs, CD4 cell count more than 400 cells/microl, HIV-1 RNA less than 500 copies/ml for more than 8 months, less than 50 copies/ml at recruitment) undergoing therapy interruption. The limulus amebocyte assay was used to measure plasma LPS levels; enzyme-linked immunosorbent assay to measure plasma levels of endotoxin-core antibodies (EndoCAb), soluble (s)CD14, LPS-binding protein and IFN-alpha; immunoblotting to measure plasma gelsolin levels; and same day whole blood flow cytometry to measure levels of T-cell-activation markers (CD8/CD38, CD8/HLA-DR and CD3/CD95).
Increases in viremia and T-cell-activation markers were observed during therapy interruptions. During short-term therapy interruptions of less than 12 weeks, no change in LPS levels was found, whereas negative associations between viral load and LPS levels (Spearman's Rho = -0.612, P = 0.0152), viral load and EndoCAb change (DeltaEndoCAb, correlation = -0.502, P = 0.0204), and between DeltaLPS and DeltaEndoCAb (correlation = -0.851, P = 0.0073) were observed. In contrast, increased LPS (P = 0.0171) and sCD14 (P < 0.0001) levels were observed during long-term therapy interruption of more than 12 weeks compared with levels during ART, together with no association between LPS and viral load or EndoCAb. No association between immune activation and LPS was evident at any time point.
Increased plasma LPS levels were observed only after more than 12 weeks of ART interruption, despite presence of LPS-controlling host mechanisms.
AIDS (London, England) 01/2009; 23(3):369-75. · 4.91 Impact Factor
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ABSTRACT: We investigated the association between plasma HIV-1 RNA, immune activation, and polyclonal T cell function in viremic subjects whether on or off antiretroviral therapy (ART). The surface expression of activation/functional molecules on T cells and monocytes as well as cytokine secretion and T cell proliferation were assessed in 23 HIV-1(-) and 79 HIV-1(+)-infected subjects with different levels of viral suppression and CD4(+) T cell count >250 cells/mm(3) for >6 months. Viral replication was associated with increased T cell and monocyte activation irrespective of ART. In subjects with a detectable viral load on ART, we found a positive association with anti-CD3/CD28-induced T cell proliferation compared to patients with undetectable viral load (<400 copies/ml). No difference among groups was observed for anti-CD3/CD28-mediated IFN-gamma responses. The presence of an unexpected positive association between polyclonal T cell proliferation and viral load in subjects with levels of T cell IFN-gamma responses comparable to those of uninfected subjects is of potential relevance to an increase in T cell activation response before the loss of polyclonal cytokine secretion and proliferation observed with disease progression. This finding suggests that T cell hyperresponsiveness may play a role in the pathogenesis of immune comorbidities on ART.
AIDS research and human retroviruses 10/2008; 24(9):1203-8. · 2.18 Impact Factor
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Emmanouil Papasavvas,
Livio Azzoni,
Maxwell Pistilli,
Aidan Hancock,
Griffin Reynolds,
Cecile Gallo,
Joe Ondercin,
Jay R Kostman,
Karam Mounzer,
Jane Shull,
Luis J Montaner
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ABSTRACT: We investigated the effect of short viremic episodes on soluble markers associated with endothelial stress and cardiovascular disease risk in chronically HIV-1-infected patients followed during continuous antiretroviral therapy, antiretroviral therapy interruption and antiretroviral therapy resumption.
We assessed changes in plasma levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 by enzyme-linked immunosorbent assay, as well as T-cell activation (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+) by flow cytometry, in 36 chronically HIV-1-infected patients participating in a randomized study. Patients were divided into the following three groups: a, on continuous antiretroviral therapy; b, on a 6-week antiretroviral therapy interruption; or c, on antiretroviral therapy interruption extended to the achievement of viral set point.
Although all measurements remained stable over a 40-week follow-up on antiretroviral therapy, plasma levels of soluble vascular cell adhesion molecule-1 (P < 0.0001) and soluble intercellular adhesion molecule-1 (P = 0.003) increased during treatment interruption in correlation with viral rebound and T-cell activation. No significant changes in von Willebrand factor were observed in any of the groups. After resuming antiretroviral therapy, soluble vascular cell adhesion molecule-1 levels remained elevated even after achievement of viral suppression to less than 50 copies/ml.
The prompt rise in plasma soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1 upon viral rebound suggests an acute increase in endothelial stress upon treatment interruption, which may persists after viral resuppression of virus. Thus, viral replication during short-term treatment interruption may increase the overall cardiovascular risk during and beyond treatment interruption.
AIDS (London, England) 06/2008; 22(10):1153-61. · 4.91 Impact Factor
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Emmanouil Papasavvas,
Jay R Kostman,
Brian Thiel,
Maxwell Pistilli,
Agnieszka Mackiewicz,
Andrea Foulkes,
Robert Gross,
Kimberly A Jordan,
Douglas F Nixon,
Robert Grant,
Jean-Francois Poulin,
Joseph M McCune,
Karam Mounzer,
Luis J Montaner
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ABSTRACT: The impact of transient viral load blips on anti-HIV-1 immune responses and on HIV-1 rebound following treatment interruption (TI) is not known. Clinical and immunological parameters were measured during 40 weeks of antiretroviral therapy (ART) and following TI in an observational cohort of 16 chronically HIV-1-infected subjects with or without observed viral load blips during ART. During therapy, blips in seven subjects were associated with higher anti-HIV-1 (p24) CD4+ T cell lymphoproliferative responses (p = 0.04), without a significant difference in T cell activation or total anti-HIV-1 CD8+ T cell interferon-gamma (IFN-gamma) responses when compared to nine matched non-blippers. Therapy interruption resulted in a significantly higher viral rebound in blippers by 8 week despite retention of higher lymphoproliferative p24 responses (p = 0.01) and a rise in CD3+ T cell activation (p = 0.04) and anti-HIV-1 CD8+ T cell responses in blippers by week 4 when compared to non-blippers. Past week 4 of interruption, therapy re-initiation criteria were also met by a higher frequency in blippers by week 14 (p < 0.04) with no difference between groups by week 24. These data support that blippers have higher anti-HIV lymphoproliferative responses while on ART but experience equal to higher viral rebound as compared to matched non-blippers upon TI.
Journal of Clinical Immunology 02/2006; 26(1):40-54. · 3.08 Impact Factor
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ABSTRACT: We show in this study that acute exposure of PBMCs derived from HIV-infected subjects to IL-13 results in increased recall T cell lymphoproliferative responses against HIV-1 p24 (n = 30, p < 0.0001) and other recall Ags (influenza, n = 43, p < 0.0001; purified protein derivative tuberculin, n = 6, p = 0.0299). This effect is due to a mechanism that acutely targets APC function in the adherent monocyte subset, as shown by the expansion of CD4(+) T cell responses following coculture of IL-13-treated enriched CD14(+) monocytes with donor-matched enriched CD4(+) T cells and Ag. Exposure to IL-13 over 18-72 h resulted in a significant enhancement of monocyte endocytosis (n = 11, p = 0.0005), CD86 expression (n = 12, p = 0.001), and a significant decrease in spontaneous apoptosis (n = 8, p = 0.008). Moreover, IL-13 exposure induced a significant decrease of significantly elevated constitutive levels of PBMC-secreted TNF-alpha (n = 14, p < 0.001) and IL-10 (n = 29, p < 0.001) within 18 h of exposure ex vivo, also reflected by decreased gene expression in the adherent cell population. Our data show that IL-13 is able to acutely enhance the function of the CD14(+) cell subset toward supporting Ag-specific cell-mediated responses in chronic HIV-1 infection.
The Journal of Immunology 11/2005; 175(8):5532-40. · 5.79 Impact Factor
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Emmanouil Papasavvas,
Jay R Kostman,
Karam Mounzer,
Robert M Grant,
Robert Gross,
Cele Gallo,
Livio Azzoni,
Andrea Foulkes,
Brian Thiel,
Maxwell Pistilli,
Agnieszka Mackiewicz,
Jane Shull,
Luis J Montaner
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ABSTRACT: Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms.
Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1-8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4-8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen.
Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted.
PLoS Medicine 12/2004; 1(3):e64. · 16.27 Impact Factor
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ABSTRACT: To determine the effect of treatment interruptions (TI) on the evolution and persistence of drug-resistant viruses in chronically HIV-1-infected suppressed patients.
The emergence of viral resistance to combination antiretroviral therapy was monitored in 11 suppressed chronically HIV-1-infected patients undergoing from one up to four sequential TI (a total of 25 TI), by genotyping of the virus for known mutations in the genes for protease and reverse transcriptase. Resistance assays were performed at the first viral rebound > 100 copies/ml.
All subjects achieved resuppression of HIV-1 under the same antiretroviral therapy, regardless of the number of TI. Five of eleven patients showed no development of resistance. In the remaining six patients, the following patterns of mutations associated with viral resistance were found: one mutation (K70R), which was observed in one patient during the 1st TI and persisted during follow-up; two mutations (L90M, M184V), which were observed in four patients during the 1st TI and were intermittently present or lost following extended TI, treatment reinitiation and/or during subsequent TI; and evolution of two mutations (M184V, K219E) observed in two patients. These two mutations were not present during the 1st TI and were subsequently lost following therapy reinitiation or during the next TI.
Detection of drug resistance during TI by virus genotyping assays does not predict failure to resuppress after antiretroviral therapy reinitiation nor persistence of a resistant viral population during extended interruptions or subsequent TI.
AIDS 11/2003; 17(16):2337-43. · 6.24 Impact Factor
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Emmanouil Papasavvas,
Johan K Sandberg,
Richard Rutstein,
Elizabeth C Moore,
Agnieszka Mackiewicz,
Brian Thiel,
Maxwell Pistilli,
Rayford R June,
Kimberly A Jordan,
Robert Gross,
Vernon C Maino,
Douglas F Nixon,
Luis J Montaner
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[hide abstract]
ABSTRACT: The present study assessed antiviral T cell immune responses in 48 human immunodeficiency virus (HIV)-infected children with a stable or decreasing CD4(+) T cell counts and different levels of viral control, in the presence or absence of antiretroviral therapy. Children with full (<40 copies/mL) or partial (<50,000 copies/mL) virus suppression and with a history of stable CD4(+) T cell counts had significantly increased levels of anti-HIV CD4(+) T cell lymphoproliferative responses, lower levels of CD38(+), and higher CD8(+)/CD28(+) T cell percentage, compared with those in treated children with a lack of virus suppression (>50,000 copies/mL). Levels of anti-HIV CD8(+) T cell activity, although higher in treated children with a lack of virus suppression, were not significantly different between the groups. Although levels of anti-HIV CD4(+) and CD8(+) T cell responses were not associated, these levels of responses were associated with the percentage of specific T cell subsets. Overall, a history of stable CD4(+) T cell counts, as a result of therapy that imparted full or partial virus suppression, was associated with increased levels of anti-HIV CD4(+) T helper responses and decreased T cell activation.
The Journal of Infectious Diseases 10/2003; 188(6):873-82. · 6.41 Impact Factor
