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Find video protocols related to scientific articles indexed in Pubmed.
Virological failure and HIV-1 drug resistance mutations among naive and antiretroviral pre-treated patients entering the ESTHER program of Calmette Hospital in Cambodia.
PLoS ONE
PUBLISHED: 08-28-2014
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In resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes.
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Reduction of death receptor 5 expression and apoptosis of CD4+ T cells from HIV controllers.
Clin. Immunol.
PUBLISHED: 08-07-2014
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TNF-related apoptosis ligand (TRAIL) induces apoptosis of HIV-1-exposed CD4 T cells expressing the death receptor 5 (DR5) in vitro and has been associated with reduced CD4 T cell number in viremic HIV-1-infected patients. Alterations of the TRAIL/DR5 apoptotic pathway could be involved in the absence of massive CD4 T cell depletion in HIV-1-infected controllers (HIC). We studied here apoptosis of CD4 T cells from HIV-infected progressors and controllers. Reduced apoptosis of CD4 T cells from HIC was observed upon HIV stimulation. This lower apoptosis correlated with a deficiency of DR5 cell surface expression by CD4 T cells upon HIV-1 stimulation. The significant lower apoptosis observed in CD4 T cells after HIV exposure, associated with lower expression of membrane DR5 could explain the better survival of HIV-specific CD4 T cells from HIV controllers. The levels of DR5 cell surface expression on CD4 T cells could represent a new prognostic marker.
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Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag-protease genes.
J. Antimicrob. Chemother.
PUBLISHED: 08-04-2014
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Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping.
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Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial.
Clin. Infect. Dis.
PUBLISHED: 04-23-2014
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Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival.
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Immunohematologic tolerance of chronic transfusion exchanges with erythrocytapheresis in sickle cell disease.
Transfusion
PUBLISHED: 02-24-2014
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Sickle cell disease (SCD) has become a major public health issue. Hydroxyurea and red blood cell (RBC) transfusion are the cornerstone treatments. Erythrocytapheresis (ECP) is an automated method for transfusion exchange. Given that ECP requires more blood than conventional transfusion, there is concern about alloimmunization and hemolytic transfusion reactions. We evaluate the incidence of hemolytic transfusion reactions and alloimmunization rates in patients receiving conventional blood transfusions and in patients participating in long-term blood exchange programs with ECP.
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Successful outcome of a corticodependent henoch-schönlein purpura adult with rituximab.
Case Rep Med
PUBLISHED: 02-23-2014
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Henoch-Schönlein purpura (HSP) is a systemic vasculitis involving small vessels with deposition of immunoglobulin A (IgA) complexes, usually affecting children. Compared with children, HSP in adults is more severe and frequently associated with cancer. We report the case of a 49-year-old woman with medical history of kidney transplantation for segmental glomerular hyalinosis. Eight years after the transplantation, while taking combined immunosuppressive therapy with tacrolimus and azathioprine indicated for the prevention against transplant rejection, she developed a Henoch-Schönlein purpura. Vasculitis involves skin and sciatic peroneal nerve and she received systemic corticosteroid treatment. Because of four relapses and corticosteroid dependence, the patient was treated with rituximab (two intravenous infusions of 1000?mg given two weeks apart). Successful outcome was observed along two years of follow-up. This new case of successful use of rituximab in HSP promotes more investigations of this treatment in clinical trials.
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CD4+ cell count recovery in naïve patients initiating cART, who achieved and maintained plasma HIV-RNA suppression.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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A key objective of combined antiretroviral therapy (cART) is to reach and maintain high CD4 cell counts to provide long-term protection against AIDS-defining opportunistic infections and malignancies, as well as other comorbidities. However, a high proportion of patients present late for care. Our objective was to assess CD4 cell count recovery up to seven years in naïve patients initiating cART with at least three drugs in usual clinical care.
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Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up.
Yoland Schoindre, Moez Jallouli, Marie-Laure Tanguy, Pascale Ghillani, Lionel Galicier, Olivier Aumaître, Camille Francès, Véronique Le Guern, Frédéric Lioté, Amar Smail, Nicolas Limal, Laurent Perard, Hélène Desmurs-Clavel, Du Le Thi Huong, Bouchra Asli, Jean-Emmanuel Kahn, Laurent Sailler, Félix Ackermann, Thomas Papo, Karim Sacre, Olivier Fain, Jérôme Stirnemann, Patrice Cacoub, Gaëlle Leroux, Judith Cohen-Bittan, Jean-Sébastien Hulot, Philippe Lechat, Lucile Musset, Jean-Charles Piette, Zahir Amoura, Jean-Claude Souberbielle, Nathalie Costedoat-Chalumeau, Astudillo Leonardo, Belizna Cristina, Belmatoug Nadia, Benveniste Olivier, Benyamine Audrey, Bezanahary Holly, Blanco Patrick, Bletry Olivier, Bodaghi Bahram, Bourgeois Pierre, Brihaye Benoît, Chatelus Emmanuel, Damade Richard, Daugas Eric, De-Gennes Christian, Delfraissy Jean-François, Delluc Céline, Delluc Aurélien, Duhaut Pierre, Dupuy Alain, Durieu Isabelle, Ea Hang-Korng, Farge Dominique, Funck-Brentano Christian, Gandjbakhch Frédérique, Gellen-Dautremer Justine, Godeau Bertrand, Goujard Cécile, Grandpeix Catherine, Grange Claire, Grimaldi Lamiae, Guettrot Gaëlle, Guillevin Loïc, Hachulla Eric, Harle Jean-Robert, Haroche Julien, Hausfater Pierre, Jouquan Jean, Kaplanski Gilles, Keshtmand Homa, Khellaf Mehdi, Lambotte Olivier, Launay David, Levesque Hervé, Lidove Olivier, Liozon Eric, Ly Kim, Mahevas Matthieu, Mariampillai Kubéraka, Mariette Xavier, Mathian Alexis, Mazodier Karin, Michel Marc, Morel Nathalie, Mouthon Luc, Ngack Rokiya, Ninet Jacques, Oksenhendler Eric, Pellegrin Jean-Luc, Peyr Olivier, Piette Anne-Marie, Poindron Vincent, Pourrat Jacques, Roux Fabienne, Saadoun David, Sahali Sabrinel, Saint-Marcoux Bernadette, Sarrot-Reynauld Françoise, Sellam Jérémie, Sene Damien, Serratrice Jacques, Seve Pascal, Sibilia Jean, Simon Claude, Sordet Christelle, Terrier Benjamin, Trad Salim, Viallard Jean-François, Vidal Elisabeth, Wechsler Bertrand, Weiller Pierre-Jean, Zahr Noël.
Lupus Sci Med
PUBLISHED: 01-01-2014
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Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups.
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Past, present and future: 30 years of HIV research.
Nat. Rev. Microbiol.
PUBLISHED: 10-28-2013
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This year marks the thirtieth anniversary of the publication of the study that first reported the isolation of HIV-1. In this Timeline article, we provide a historical perspective of some of the major milestones in HIV science, highlighting how translational research has affected treatment and prevention of HIV. Finally, we discuss some of the current research directions and the scientific challenges ahead, in particular in the search for a cure for HIV.
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Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial.
AIDS
PUBLISHED: 10-08-2013
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To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).
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Long-term immunogenicity of two doses of 2009 A/H1N1v vaccine with and without AS03(A) adjuvant in HIV-1-infected adults.
AIDS
PUBLISHED: 06-19-2013
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In immunocompromised patients, alternative schedules more immunogenic than the standard influenza vaccine regimen are necessary to enhance and prolong vaccine efficacy. We previously reported that the AS03A-adjuvanted 2009 A/H1N1v vaccine yielded a higher short-term immune response than the nonadjuvanted one in HIV-1-infected adults. This study reports the long-term persistence of the immune response.
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High Antibody-Dependent Cellular Cytotoxicity Responses Are Correlated with Strong CD8 T Cell Viral Suppressive Activity but Not with B57 Status in HIV-1 Elite Controllers.
PLoS ONE
PUBLISHED: 01-01-2013
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The role of Antibody-dependent cellular cytotoxicity (ADCC) responses in HIV-1 controllers is still unclear due to the heterogeneity of these patients. We analyzed 67 HIV-1 controllers and found significantly higher levels of ADCC antibodies in controllers versus viremic subjects (p?=?0.017). Moreover, multivariate analysis revealed significantly higher ADCC titers in HLA B57- controllers compared to HLA-B57+ ones (p?=?0.0086). These data suggest a role for ADCC in immune control of HIV, especially in HLA B57 negative controllers.
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Is clinical practice concordant with the changes in guidelines for antiretroviral therapy initiation during primary and chronic HIV-1 infection? The ANRS PRIMO and COPANA cohorts.
PLoS ONE
PUBLISHED: 01-01-2013
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Guidelines for initiating HIV treatment are regularly revised. We explored how physicians in France have applied these evolving guidelines for ART initiation over the last decade in two different situations: chronic (CHI) and primary HIV-1 infection (PHI), since specific recommendations for PHI are also provided in France.
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Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.
N. Engl. J. Med.
PUBLISHED: 10-21-2011
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Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy.
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HIV infection perturbs interleukin-7 signaling at the step of STAT5 nuclear relocalization.
AIDS
PUBLISHED: 07-01-2011
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Interleukin-7 (IL-7) responses are impaired in CD4(+) T cells from HIV-infected patients, which may play a significant role in the loss of CD4(+) T-cell homeostasis. We set to investigate the nature of IL-7-dependent signaling defects in patients with progressive HIV-1 infection.
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Polymorphism in Gag gene cleavage sites of HIV-1 non-B subtype and virological outcome of a first-line lopinavir/ritonavir single drug regimen.
PLoS ONE
PUBLISHED: 06-23-2011
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Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (p?=?0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial.
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Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy.
PLoS ONE
PUBLISHED: 05-17-2011
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Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery.
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Interferon-alpha triggers B cell effector 1 (Be1) commitment.
PLoS ONE
PUBLISHED: 04-02-2011
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B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-? play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-? triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-? gene imprinting factors. IFN-? primed naive B-cells for IFN-? production and increased IFN-? gene responsiveness to IL-12. IFN-? continues this polarization by re-inducing T-bet and up-regulating IL-12R?2 expression. IFN-? and IFN-? therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-?, IFN-? and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.
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High efficacy of lopinavir/r-based second-line antiretroviral treatment after 24 months of follow up at ESTHER/Calmette Hospital in Phnom Penh, Cambodia.
J Int AIDS Soc
PUBLISHED: 03-26-2011
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The number of patients on second-line highly active antiretroviral therapy (HAART) regimens is increasing in resource-limited settings. We describe the outcomes after 24 months for patients on LPV/r-based second-line regimens followed up by the ESTHER programme in Phnom Penh, Cambodia.
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CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory.
PLoS ONE
PUBLISHED: 03-14-2011
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There are few large published studies of HIV controllers with long-term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers.
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Trends in unsafe sex and influence of viral load among patients followed since primary HIV infection, 2000-2009.
AIDS
PUBLISHED: 03-02-2011
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In the current context of increasing unsafe sex, HIV incidence may have evolved, depending on HIV prevalence in sexual networks and, among HIV-infected persons who practice unsafe sex, on their infectivity and partners HIV serostatus. We examined calendar trends in sexual behaviours at risk of HIV-1 transmission (SBR) among 967 adults followed since primary HIV infection (ANRS PRIMO cohort) and relationship with current treatments and viral load.
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Short communication: three years follow-up of first-line antiretroviral therapy in cambodia: negative impact of prior antiretroviral treatment.
AIDS Res. Hum. Retroviruses
PUBLISHED: 01-17-2011
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There are few long-term data on ART-experienced patients in resource-limited settings. We performed a cross-sectional study of HIV-infected patients included in the ESTHER program in Calmette hospital, Phnom Penh, Cambodia, after 36 ± 3 months of cART. Therapeutic, clinical, and immunovirological outcomes were compared between patients who stated they were ART-naive (naive group), dual nucleoside reverse-transcriptase inhibitor (two-NRTI group), or fixed-dose combination of stavudine/lamivudine/nevirapine experienced (three-drug group) at entry to the program. A logistic regression model was used to evaluate the factors associated with virological failure (PCR HIV > 250 copies/ml). Among the 256 patients included in the analysis, 148 (58%) were ART naive while 50 (20%) had previously received two NRTIs and 58 (22%) three drugs. At entry to the program, all the patients received two NRTIs and one nonnucleoside reverse-transcriptase inhibitor (NNRTI). At evaluation, 46 patients (18%) were switched to a protease inhibitor-based regimen (9%, 32%, and 29% of the naive, two-NRTI, and three-drug groups; p < 0.0001). The median CD4 cell count increase was 180/?l overall (IQR: 96-276) and was higher in ART-naive than ART-experienced patients. In the intent-to-treat analysis, virological success was achieved in 83.5%, 67%, and 69% of the naive, two-NRTI, and three-drug groups, respectively (p = 0.002). Factors associated with virological failure were suboptimal previous ART exposure and WHO immunological failure criteria. The long-term efficacy of first-line cART is maintained in Cambodia. In ART-experienced patients, viral load monitoring needs to be available to establish early virological failure and preserve the potency of second line regimens.
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Fat tissue distribution changes in HIV-infected patients treated with lopinavir/ritonavir. Results of the MONARK trial.
Curr. HIV Res.
PUBLISHED: 01-05-2011
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Given the decline in mortality among HIV-infected patients, it has become increasingly important to consider delayed disease-related and/or anti-HIV therapy-related adverse effects, such as lipodystrophy, when choosing initial therapy. Data from the MONARK trial allowed for comparison of the potential lipodystrophic effects of lopinavir/ritonavir (LPV/r) monotherapy with those of triple therapy with LPV/r plus zidovudine (ZDV) and lamivudine (3TC). This was a randomized, open-label, multinational study that included 136 antiretroviral-naive HIV-infected patients. A portion of study patients underwent evaluations of limb and trunk fat tissue by dual-energy x-ray absorptiometry at baseline and after 48 weeks of treatment (and 96 weeks in some patients). Sixty-three patients had paired absorptiometry data at baseline and week 48 (13 patients at week 96). At week 48, median change in limb fat was -63 g on LPV/r monotherapy versus -703 g on LPV/r + ZDV/3TC triple therapy (p=0.014). The proportion of patients with fat loss (>20% loss in limb fat) was significantly lower with LPV/r monotherapy (4.9% versus 27.3%; p=0.018). Changes in trunk fat did not differ significantly between treatments. Nonetheless, limb fat and trunk fat varied in the same direction with both treatments. The decrease in arm lean mass was also significantly less in patients receiving LPV/r monotherapy. Only treatment type emerged as a significant predictor of fat loss (odds ratio, 7.06; 95% CI, 1.11-78.69). These results suggest that LPV/r, and possibly other protease inhibitors, may not be the main contributor to lipoatrophy in HIV-infected patients receiving triple therapy.
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Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication.
J Perinat Med
PUBLISHED: 12-13-2010
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To determine rate of and risk factors for birth defects in infants born to HIV-infected women receiving nucleoside and protease inhibitor antiretroviral (ARV) therapy.
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Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen.
Antivir. Ther. (Lond.)
PUBLISHED: 11-03-2010
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Triple combination therapy based on a ritonavir (RTV)-boosted protease inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) has improved outcomes in HIV type-1 (HIV-1)-infected patients. For patients unable to tolerate these regimens, alternative therapeutic approaches are needed.
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Impact of 48 week lopinavir/ritonavir monotherapy on blood cell-associated HIV-1-DNA in the MONARK trial.
J. Antimicrob. Chemother.
PUBLISHED: 03-18-2010
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To study the impact of protease inhibitor monotherapy on the HIV-1 blood reservoir in 72 antiretroviral-naive patients.
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Cellular CD4 T cell responses to the diphtheria-derived carrier protein of conjugated pneumococcal vaccine and antibody response to pneumococcal vaccination in HIV-infected adults.
Clin. Infect. Dis.
PUBLISHED: 03-10-2010
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The French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac trial showed that a strategy combining a 7-valent pneumococcal conjugate vaccine (PCV) prime at week 0 followed by a 23-valent pneumococcal polysaccharide vaccine (PPV) boost at week 4 enhances the frequency and magnitude of immunoglobulin (Ig) G responses against Streptococcus pneumoniae polysaccharides (SPPs) compared with PPV alone. CD4 T cell responses specific to the diphtheria-derived carrier protein CRM(197) were evaluated.
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HIV controller CD4+ T cells respond to minimal amounts of Gag antigen due to high TCR avidity.
PLoS Pathog.
PUBLISHED: 01-20-2010
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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.
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Targeted vs. systematic early antiviral treatment against A(H1N1)v influenza with neuraminidase inhibitors in patients with influenza-like symptoms: clinical and economic impact.
PLoS Curr
PUBLISHED: 10-26-2009
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Capitalizing on available data, we used a decision model to estimate the clinical and economic outcomes associated with early initiation of treatment with neuraminidase inhibitors in all patients with influenza-like illnesses ( ILI ) (systematic strategy) vs. only those at high risk of complications (targeted strategy). Systematic treatment of ILI during an A(H1N1)v influenza epidemic wave is both effective and cost-effective. Patients who present to care with ILI during an A(H1N1)v influenza epidemic wave should initiate treatment with neuraminidase inhibitors, regardless of risk status. Administering neuraminidase inhibitors between epidemic waves, when the probability of influenza is low, is less effective and cost-effective.
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Genomewide association study of a rapid progression cohort identifies new susceptibility alleles for AIDS (ANRS Genomewide Association Study 03).
J. Infect. Dis.
PUBLISHED: 09-17-2009
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Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology.
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Spontaneous control of viral replication during primary HIV infection: when is "HIV controller" status established?
Clin. Infect. Dis.
PUBLISHED: 08-18-2009
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Eight patients in the ANRS PRIMO cohort experienced early spontaneous viral control. Viral control was established a median of 6.2 months after primary human immunodeficiency virus type 1 infection and lasted a median of 4.1 years. Seven of the patients initially had detectable viral replication. For 4 patients, viral control was lost during follow-up.
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Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses.
J. Immunol.
PUBLISHED: 06-05-2009
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"HIV controllers" (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8(+) T cell responses. Accordingly, we have recently shown that CD8(+) T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4(+) T cells, suggesting a crucial role of this response in vivo. Knowledge of the mechanisms underlying the CD8(+) T cell antiviral activity might help to develop effective T cell-based vaccines. In the present work, we further characterized the HIV-suppressive capacity of CD8(+) T cells in 19 HICs. CD8(+) T cells from 14 of the 19 HICs showed strong HIV-suppressive capacity ex vivo. This capacity was stable over time and was partially effective even on other primate lentiviruses. HIV-suppressive capacity of CD8(+) T cells correlated strongly with the frequency of HIV-specific CD8(+) T cells, and in particular of Gag-specific CD8(+) T cells. We also identified five HICs who had weak HIV-suppressive CD8(+) T cell capacities and HIV-specific CD8(+) T cell responses. Among these five HICs, at least three had highly in vitro replicative viruses, suggesting that the control of viremia in these patients is not due to replication-defective viruses. These results, on the one hand, suggest the importance of Gag responses in the antiviral potency of CD8(+) T cells from HICs and, on the other hand, propose that other host mechanisms may contribute to restraining HIV infection in HICs.
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Identification and biochemical characterization of human plasma soluble IL-7R: lower concentrations in HIV-1-infected patients.
J. Immunol.
PUBLISHED: 06-05-2009
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The IL-7R alpha-chain and the common gamma-chain (gamma(c)) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Ralpha and sgamma(c)) that are detected and assayed by Western blotting, showing that the levels of sIL-7Ralpha are higher than the levels of sgamma(c) (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Ralpha is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Ralpha and sgamma(c) are present as heterocomplexes and sgamma(c) was found to be mainly associated with sIL-7Ralpha. The affinities of two IL-7 binding sites (K(d) = 35 +/- 8 pM and K(d) = 3 +/- 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Ralpha/sgamma(c) complex retains high affinity for IL-7. sIL-7Ralpha mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p > 0.714) variation in sgamma(c) levels and a significant (p < 0.0014) 2-fold decrease in plasma sIL-7Ralpha levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Ralpha levels did not show any obvious relationship.
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HIV infection impairs CCR7-dependent T-cell chemotaxis independent of CCR7 expression.
AIDS
PUBLISHED: 05-21-2009
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CCR7, a chemokine receptor expressed at high levels on naive and central memory T cells, is essential for T-cell recirculation into secondary lymphoid organs. We investigated CCR7 expression and chemotactic function in patient T cells, to gain further insights into mechanisms of T-cell dysfunction in HIV infection.
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Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy.
Antimicrob. Agents Chemother.
PUBLISHED: 05-18-2009
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The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society-USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.
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No evidence of a change in HIV-1 virulence since 1996 in France.
AIDS
PUBLISHED: 05-09-2009
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We investigated temporal trends in the CD4 cell count and in plasma HIV RNA and total HIV DNA levels measured at the time of primary HIV infection, as proxies for HIV-1 virulence, taking changes in patient characteristics into account.
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Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers.
AIDS
PUBLISHED: 05-06-2009
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To determine the spectrum of antiviral antibodies in HIV-1-infected individuals in whom viral replication is spontaneously undetectable, termed HIV controllers (HICs).
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Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection.
J. Infect.
PUBLISHED: 04-08-2009
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Immune reconstitution after initiation of antiretroviral therapy may unmask a latent infection. We report a case of disseminated Histoplasma capsulatum capsulatum infection associated with a hemophagocytic syndrome in an HIV-infected patient, three weeks after initiation of antiretroviral therapy. The immune reconstitution inflammatory syndrome might be a risk factor for hemophagocytosis.
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Prognostic factors for virological response in antiretroviral therapy-naive patients in the MONARK Trial randomized to ritonavir-boosted lopinavir alone.
Antivir. Ther. (Lond.)
PUBLISHED: 03-27-2009
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MONARK is a pilot randomized trial comparing the safety and efficacy of lopinavir/ritonavir (LPV/r) monotherapy to a standard triple-drug regimen as initial therapy. The primary endpoint was virological response (VR) defined as viral load (VL)<400 copies/ml at week 24 and VL<50 copies/ml at week 48. The objective of this study was to determine prognostic factors of VR in patients receiving LPV/r monotherapy.
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Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment.
J. Clin. Invest.
PUBLISHED: 01-28-2009
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HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART-treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/microl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 microg/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-gamma and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.
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Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02).
J. Infect. Dis.
PUBLISHED: 01-01-2009
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To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P=6.79x10(-10); odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P=3.02x10(-19)) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.
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HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy.
Antivir. Ther. (Lond.)
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The occurrence of viral control after interruption of an antiretroviral treatment (ART) initiated during primary HIV-1 infection (PHI) is rare and the frequency and predictive factors of such a control are unknown.
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HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term.
J. Virol.
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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-?) 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-?-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-? 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.
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Plasmacytoid dendritic cells (pDCs) from HIV controllers produce interferon-? and differentiate into functional killer pDCs under HIV activation.
J. Infect. Dis.
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Human immunodeficiency virus (HIV) controllers spontaneously control viremia and CD4 T-cell depletion in contrast to viremic patients. After HIV exposure, plasmacytoid dendritic cells (pDCs) produce high levels of interferon alpha (IFN-?) and express the apoptotic ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand). Simian models have shown that prolonged high levels of IFN-? production could be responsible for AIDS progression.
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Risk Factors for Hepatitis C Transmission in HIV Patients, Hepacam Study, ANRS 12267 Cambodia.
AIDS Behav
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In 2009, we conducted a case-control study to explore the routes of HCV transmission in people living with HIV/AIDS (PLHIV) in Cambodia. Cases were HCV/HIV co-infected patients (who tested RT-PCR positive for HCV-RNA or had confirmed presence of HCV antibodies) (n = 44). Controls were HIV mono-infected patients, with no HCV antibodies (n = 160). They were recruited among the PLHIV presenting at one national reference centre of HIV/AIDS. Multivariate analysis showed that factors associated with the co-infection were the age older than 50 years (OR 5.4, 95 % confidence interval (CI) 1.5-19.6), the exposure to multiple parenteral infusions before the year 2000 (OR 3.4, 95 % CI 1.5-7.6), to surgery (OR 2.6, 95 % CI 1.2-5.7) and to fibroscopy (OR 2.4, 95 % CI 1.0-5.7). These results show the need to implement HCV screening in PLHIV, to support the implementation of national infection control guidelines, and to reinforce public awareness on the risks linked to parenteral medications.
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