Publications by authors named "Mohamed-Rachid Boulassel"

56 Publications

Low-Level Viremia Predicts Virological Failure in HIV-Infected Omani Patients Receiving Antiretroviral Therapy.

J Int Assoc Provid AIDS Care 2020 Jan-Dec;19:2325958220979817

Department of Hematology, 37611Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.

Background: The implication and clinical significance of low-level viremia (LLV) in HIV patients are still not clear. This study aimed to characterize the clinical outcomes and to evaluate whether LLV could predict future virological failure in a well-defined cohort of HIV-infected Omani patients attending a large HIV clinic.

Methods: Patients on regular antiretroviral therapy (ART) for at least 12 months, and had at least 2 HIV RNA measurements 1 year after starting ART, were prospectively enrolled in a cohort study. LLV was defined as plasma HIV RNA between 50-200 copies/mL that persists after at least 2 consecutive measurements after 12 months of ART. Multivariate Cox proportional hazards regression model was used to measure the association among virological failure, LLV and potential predictors.

Results: After 12 months of starting ART, 60 patients (40%) had undetectable viral load (UVL) < 50 copies/mL, while 37 patients (24%) had LLV and 53 patients (35%) had primary virological failure > 200 copies/mL. The incidence rates of subsequent secondary virological failure for UVL and LLV groups, were 3 and 7 cases per 1000 patient-months, respectively. Compared to UVL group, LLV group had increased risk of subsequent secondary virological failure with hazard ratio of (4.437 [95% CI, 1.26-15.55]; p = 0.02). Age, duration of HIV infection, pretreatment HIV RNA level, pretreatment CD4 cell count, and ART adherent were associated with subsequent secondary virological failure.

Conclusion: Collectively, Omani HIV patients with LLV were at a higher risk for HIV virological failure, and should be monitored closely. Further studies are need to assess whether ART modification in LLV patients would lower the risk of virological failure.
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http://dx.doi.org/10.1177/2325958220979817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783682PMC
December 2020

Respiratory Viral Infections in Sickle Cell Anemia: Special Emphasis on H1N1 Co-infection.

Oman Med J 2020 Nov 7;35(6):e197. Epub 2020 Nov 7.

Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.

Objectives: Patients with sickle cell anemia (SCA) are immunocompromised and at an increased risk of developing infections. Our aim was to establish the clinical, laboratory, and radiological manifestations of respiratory viral infections in SCA at Sultan Qaboos University Hospital (SQUH), Oman and assess its impact on disease morbidity and mortality, with special emphasis on H1N1.

Methods: We undertook a retrospective study in SCA patients with respiratory viral infections following up at the hematology department at SQUH. We collected demographic data and clinical, radiological, and laboratory parameters.

Results: In 84 SCA patients with 109 admission episodes for vaso-occlusive crisis (VOC), molecular diagnostic techniques confirmed 125 respiratory viral infections. Rhinovirus was the most prevalent infection (35.8%), whereas H1N1 virus infection was seen only in 10.1%. Laboratory investigations revealed a significant fall in mean hemoglobin levels, mean white blood cell, and platelet counts from baseline, whereas there was a significant rise in the mean lymphocyte and retic count, serum lactate dehydrogenase, and C-reactive protein levels during infective episodes ( < 0.050, Wilcoxon signed rank test). One-third (32.1%) of the VOC episodes progressed to acute chest syndrome (ACS), but in the H1N1 cohort, only two episodes of ACS was seen (18.2%).

Conclusions: Rhinovirus was the commonest respiratory virus infections in SCA patients, whereas parainfluenza 3 was associated with a significant adverse outcome. H1N1 was associated with a mild course. ACS was seen in approximately one-third of this group of patients.
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http://dx.doi.org/10.5001/omj.2020.89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648876PMC
November 2020

Students' Perceived Benefits of Integrating a BSc in Health Sciences within a Medical Degree at Sultan Qaboos University.

Sultan Qaboos Univ Med J 2020 May 28;20(2):e187-e193. Epub 2020 Jun 28.

Department of Medicine, Sultan Qaboos University, Muscat, Oman.

Objectives: After completing the pre-clinical phase of a Doctor of Medicine (MD) curriculum, undergraduate medical students may choose to add a Bachelor of Science (BSc) degree in health sciences to their MD degree. Limited data exists on the motives behind students' decisions to undertake such intercalated degrees. Hence, this study aimed to identify the factors that influence students in making this choice.

Methods: Undergraduate students who chose the research-based academic track of the intercalated phase of the BSc programme at the College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman, between 2014-2018 were enrolled. A standardised and validated self-explanatory questionnaire examining motivations to join the intercalated phase was administered to all students in the first week of enrolment.

Results: Over a five-year period, out of 557 eligible students, 18 (3%) were enrolled in the intercalated phase and all completed the questionnaire. The mean age was 22 ± 1.5 years and the majority (83%) were female. Out of the 18 students, 10 (55%) had taken the university's foundation programme. A total of 45% of students chose to intercalate out of their own interest, regardless of career ambitions. The main reasons to intercalate were an opportunity to enhance research experience, alignment with long-term career goals and a chance to publish in indexed journals.

Conclusion: Despite the benefits of obtaining an additional degree, a relatively small proportion of MD students were attracted to the intercalated phase. A better presentation of the BSc degree is needed to help students make a more informed decision.
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http://dx.doi.org/10.18295/squmj.2020.20.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328834PMC
May 2020

The Value of Programmed Death Ligand 1 Expression in Cancer Patients Treated with Neoadjuvant Chemotherapy.

Sultan Qaboos Univ Med J 2019 Nov 22;19(4):e277-e283. Epub 2019 Dec 22.

Department of Biochemistry, Sultan Qaboos University, Muscat, Oman.

Programmed death ligand 1 (PD-L1) is an inhibitory molecule expressed by cancer cells to supress T-cell activity and escape anti-tumour immunity. The role of PD-L1 in cancer has been studied extensively as it is considered an important immune checkpoint against immune over-activation through its interaction with Programmed death receptor 1 (PD-1) expressed on activated lymphocytes. PD-L1 expression was found to be enhanced by chemotherapy through different proliferation pathways. However, the predictive and prognostic value for PD-L1 expression in cancer patients treated with neoadjuvant chemotherapy (NAC) is not yet established. This review focused on the potential effects of chemotherapy on PD-L1 expression and the role of PD-L1 as a prognostic and predictive marker in NAC-treated cancer patients. In addition, the potential use of this marker in clinical practice is discussed.
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http://dx.doi.org/10.18295/squmj.2019.19.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930029PMC
November 2019

Elevated levels of circulating invariant natural killer cell subsets are skewed toward Th2-like phenotype in children with sickle cell disease.

Clin Immunol 2020 01 11;210:108308. Epub 2019 Nov 11.

Department of Child Health, Sultan Qaboos University Hospital, College of Medicine and Health Sciences, Oman.

Invariant natural killer T (iNKT) cells are being considered as potential targets for immunotherapeutic strategies in a variety of conditions including sickle cell disease (SCD). However, relatively little is known about the fate of iNKT cell subsets in children with SCD. Herein, quantitative and qualitative analyses of circulating iNKT cell subsets were carried out in 120 children in steady state and 30 healthy controls. Children with SCD displayed significantly elevated levels of circulating iNKT cell subsets with a preferential polarization toward Th2-like cells. The known SCD modifiers did not influence levels of iNKT cell subsets, except that children carrying the Bantu haplotype exhibited elevated levels of CD4iNKT cells, and to a lesser degree CD8iNKT cells. Collectively, these findings indicate that circulating iNKT cell subsets are significantly increased in children with SCD, and highlight the existence of imbalanced production of cytokines toward Th2-like phenotype, which seems to be associated with genetic polymorphisms.
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http://dx.doi.org/10.1016/j.clim.2019.108308DOI Listing
January 2020

Comparative Analysis of two Methods of Measuring Antiretroviral Therapy Adherence in HIV-Infected Omani Patients.

J Int Assoc Provid AIDS Care 2019 Jan-Dec;18:2325958219867316

3 Department of Hematology, Sultan Qaboos University Hospital, Sib, Sultanate of Oman.

Background: Antiretroviral therapy (ART) adherence is crucial to achieve HIV suppression and to prolong survival of HIV-infected patients. Although monitoring of ART adherence is standard of HIV care, there is yet no optimal method to measure ART adherence. Therefore, it is essential to compare the effectiveness of different adherence measurement tools to predict HIV suppression.

Methods: In this study, we measured ART adherence using pharmacy refill prescription and self-reported adherence questionnaire. Both the methods were compared for predicting HIV suppression in adult Omani HIV-infected patients attending the outpatient clinics at Sultan Qaboos University Hospital.

Results: A total of 141 HIV-infected patients were included. The pharmacy refill-based measure showed a median adherence rate of 98.90% (interquartile range [IQR]: 86%-99.45%). The self-report adherence questionnaire revealed a median adherence rate of 100% (IQR: 75-100). A significant positive correlation was found between the adherence rates measured by the 2 methods ( = 0.32, = .01). The pharmacy refill and self-report questionnaire adherence measures were both negatively correlated with plasma HIV RNA levels ( = -0.20, = .01 and = -0.26, = .04, respectively).

Conclusion: Collectively, these findings suggest that pharmacy refill measure could serve as a valid and practical tool of ART adherence in routine clinical practice.
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http://dx.doi.org/10.1177/2325958219867316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900587PMC
July 2020

Levels of regulatory T cells and invariant natural killer cells and their associations with regulatory B cells in patients with non-Hodgkin lymphoma.

Mol Clin Oncol 2018 Dec 2;9(6):677-682. Epub 2018 Oct 2.

Department of Haematology, Sultan Qaboos University Hospital, College of Medicine and Health Sciences, Muscat 123, Sultanate of Oman.

Due to their immunoregulatory properties, several specialized cell subsets, including regulatory T (Treg), invariant natural killer T (iNKT) and regulatory B (Breg) cells, are involved in the pathogenesis of non-Hodgkin lymphoma (NHL). However, the interaction between various cells remains to be elucidated. The aim of the present study was to evaluate the levels of Treg, iNKT and Breg cell subsets and their interrelationships in the peripheral blood (PB) and bone marrow (BM) of patients with B-cell NHL who received rituximab-based regimens and achieved a complete remission. A total of 20 patients and 20 healthy age- and sex-matched controls were prospectively enrolled for investigation of Treg, iNKT and Breg cell subsets in PB and BM by flow cytometry and cell culture. Prior to administration of combination chemotherapy with rituximab, the patients had lower levels of Breg cells and, to a lesser degree, Treg cells, but not iNKT cells, in PB compared with controls. Compartmental differences in the levels of Treg and Breg cell subsets, but not iNKT cells, were observed between PB and BM, suggesting an increase in trafficking through the blood of these regulatory cell subsets to the marrow. Following complete remission, the levels of circulating Treg, iNKT and Breg cell subsets increased. The levels of Treg cells were not significantly associated with iNKT and Breg cell subsets, although negative correlations were observed. Taken together, these results may provide new insights into the potential role of regulatory cell subsets in patients with B-cell NHL. However, whether the observed differences between PB and BM may affect clinical outcomes requires further investigation.
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http://dx.doi.org/10.3892/mco.2018.1732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256168PMC
December 2018

Hemoglobin F as a predictor of health-related quality of life in children with sickle cell anemia.

Qual Life Res 2019 Feb 22;28(2):473-479. Epub 2018 Oct 22.

Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.

Purpose: As treatment options for children with sickle cell anemia (SCA) continue to expand survival, evaluation of factors associated with health-related quality of life (HRQoL) is becoming an important aspect for further improving clinical management. Although the general features of SCA are similar, factors influencing HRQoL within a country may differ from those of other countries, therefore this study aimed to explore factors affecting HRQoL in children with SCA living in the Sultanate of Oman.

Methods: This was a cross-sectional study in which the PedsQL™ Sickle Cell Disease Module was used to evaluate the overall HRQoL in children with SCA. The socio-demographic data, clinical, and treatment outcomes were collected. Univariate and multivariate linear regression analyses were used to identify predictors of HRQoL.

Results: A total of 123 children with SCA, aged from 2 to 16 years were enrolled. The mean total HRQoL score was 52 ± 15% (9-94), where Worry II scale recorded the highest score. The multiple regression analysis revealed that the only predictors of total HRQoL score were hemoglobin F (B = 0.64, 95% confidence interval [CI] 0.149-1.118, P = 0.009) and to a lesser degree white blood cell count (B = - 0.99, 95% CI - 1.761 to - 0.198, P = 0.01), independently of other study parameters such as age, gender, spleen status, and hydroxyurea therapy.

Conclusions: Collectively, these findings indicated that hemoglobin F out-weighted white blood cell count in predicting HRQoL in Omani children with SCA. Recognition of these factors could help health professionals to develop effective strategies to improve the overall HRQoL in these young patients.
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http://dx.doi.org/10.1007/s11136-018-2031-0DOI Listing
February 2019

Does sickle cell disease have a psychosomatic component? A particular focus on anxiety and depression.

Life Sci 2018 Oct 29;210:96-105. Epub 2018 Aug 29.

Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; Department of Hematology, Sultan Qaboos University Hospital, College of Medicine and Health Sciences, Muscat, Oman.

Sickle cell disease, an early-age genetic condition, encompasses a range of blood disorders with severe complications. This disease is characterized by the synthesis of abnormal hemoglobin molecules, which tend to polymerize due to their low solubility upon deoxygenation in the peripheral capillary beds, resulting in sickle-like red blood cells. Sickled cells lose their normal functioning and hemodynamic properties, leading to chronic fatigue as well as to episodes of painful crises. Over the last two decades, a growing body of clinical evidence has pointed out that these somatic complaints can give rise to neuropsychiatric disorders, among which anxiety and depression are the most common, that worsen the health-related quality of life in patients. At first glance, this somatic influence may be unsurprising, as both anxiety and depressive signs are prevalent in almost all chronic diseases. However, in the case of a genetic condition such as sickle cell disease whose somatic disturbances are predetermined, the fact that mood disorders can increase fatigue and pain through a psychosomatic component has attracted increasing attention. In this review, we address the hypothesis of a psychosomatic component in patients with sickle cell disease by underlining the most relevant clinical studies that have highlighted the existence of a bidirectional link between physical and psychological sequelae, which are reported to be relieved not only by pharmacological cotreatments but also by the concomitant application of cognitive behavioral therapy.
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http://dx.doi.org/10.1016/j.lfs.2018.08.066DOI Listing
October 2018

Regulatory B Cells Are Functionally Impaired in Patients Having Hemophilia A With Inhibitors.

Clin Appl Thromb Hemost 2018 May 10;24(4):618-624. Epub 2017 Apr 10.

2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.

Development of inhibitors remains a major clinical complication in patients with hemophilia A receiving replacement therapy with factor VIII (FVIII). Understanding the immune mechanisms involved in the development of inhibitors can provide valuable information about pathways to human tolerance. Recent evidence indicates that B regulatory (Breg) cells play a pivotal role in controlling the production of antibodies (Abs) while promoting follicular T helper (Tfh) cells and monocytes, expressing the low-density lipoprotein receptor-related protein (LRP/CD91), which is involved in FVIII intake from the circulation. We studied circulating levels of Breg cells along with Tfh cells and the expression of LRP/CD91 on monocytes in patients with hemophilia A using 8-color flow cytometry and cell culture. Compared to healthy controls, patients with hemophilia A with inhibitors showed a severe reduction in levels of Breg cells and produced less interleukin-10 when activated via the CD40 signaling pathway. In addition, patients with hemophilia A with inhibitors exhibited an overexpression of LPR/CD91 on monocytes and normal levels of Tfh cells. Levels of Breg cells were not significantly related to LPR/CD91 although negative associations were evidenced. Collectively, these results provide new insights into the role of Breg cells and LPR/CD91 in the development of inhibitors in patients with hemophilia A.
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http://dx.doi.org/10.1177/1076029617702244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714706PMC
May 2018

and Epstein-Barr Virus Co-Infection in a Patient with Hemophagocytosis.

Infect Dis Rep 2016 Dec 31;8(4):6545. Epub 2016 Dec 31.

Department of Hematology; Department of Allied Health Sciences, Sultan Qaboos University, Sultanate of Oman.

The authors describe a rare case of a 27- year old previously healthy male presenting with high grade fever, pancytopenia, hepatosplenomegaly, high levels of ferritin and triglyceride, suggesting a diagnosis of hemophagocytic lymphohistiocytosis (HLH) syndrome. Other investigations showed a positive serology and high Epstein-Barr virus (EBV) viremia. The diagnosis of a visceral leishmaniasis was confirmed by bone morrow biopsy, which showed Leishman-Donovan bodies and evidence of HLH. The patient received liposomal amphotericin B and he had a complete resolution of his symptoms and clearance of EBV viremia. This case of HLH associated with visceral leishmaniasis and EBV co-infection raises the question about the significance of EBV in patients with HLH. The treatment of actual etiological agent can lead to complete cure while using current recommend chemotherapy for HLH-related EBV in a patient with hidden infection may have deleterious effects.
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http://dx.doi.org/10.4081/idr.2016.6545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226040PMC
December 2016

Accuracy of Platelet Counting by Optical and Impedance Methods in Patients with Thrombocytopaenia and Microcytosis.

Sultan Qaboos Univ Med J 2015 Nov 23;15(4):e463-8. Epub 2015 Nov 23.

Haematology, College of Medicine & Health Sciences, Sultan Qaboos University;

Objectives: Obtaining accurate platelet counts in microcytic blood samples is challenging, even with the most reliable automated haematology analysers. The CELL-DYN(™) Sapphire (Abbott Laboratories, Chicago, Illinois, USA) analyser uses both optical density and electronic impedance methods for platelet counting. This study aimed to evaluate the accuracy of optical density and electrical impedance methods in determining true platelet counts in thrombocytopaenic samples with microcytosis as defined by low mean corpuscular volume (MCV) of red blood cells. Additionally, the impact of microcytosis on platelet count accuracy was evaluated.

Methods: This study was carried out between February and December 2014 at the Haematology Laboratory of the Sultan Qaboos University Hospital in Muscat, Oman. Blood samples were collected and analysed from 189 patients with thrombocytopaenia and MCV values of <76 femtolitres. Platelet counts were tested using both optical and impedance methods. Stained peripheral blood films for each sample were then reviewed as a reference method to confirm platelet counts.

Results: The platelet counts estimated by the impedance method were on average 30% higher than those estimated by the optical method (P <0.001). The estimated intraclass correlation coefficient was 0.52 (95% confidence interval: 0.41-0.62), indicating moderate reliability between the methods. The degree of agreement between methods ranged from -85.5 to 24.3 with an estimated bias of -30, suggesting that these methods generate different platelet results.

Conclusion: The impedance method significantly overestimated platelet counts in microcytic and thrombocytopaenic blood samples. Further attention is therefore needed to improve the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis.
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http://dx.doi.org/10.18295/squmj.2015.15.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664089PMC
November 2015

Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

J Immunol 2013 Sep 5;191(5):2194-204. Epub 2013 Aug 5.

Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Saint-Luc, Montreal, Quebec H2X 1P1, Canada.

Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor programmed death (PD)-1 on HIV-1-specific CD4(+) and CD8(+) T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. In this study, we show that PD-1 is upregulated on all T cell subsets, including naive, central memory, and transitional memory T cells in HIV-1-infected subjects. PD-1 is expressed at similar levels on most CD4(+) T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression is dramatically increased in CD8(+) T cells during the transition from acute to chronic infection, and this is associated with reduced levels of cell proliferation. The failure to downregulate expression of PD-1 in most T cells during chronic HIV-1 infection is associated with persistent alterations in the distribution of T cell subsets and is associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection.
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http://dx.doi.org/10.4049/jimmunol.1200646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815464PMC
September 2013

HLA-DO increases bacterial superantigen binding to human MHC molecules by inhibiting dissociation of class II-associated invariant chain peptides.

Hum Immunol 2013 Oct 10;74(10):1280-7. Epub 2013 Jun 10.

Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, H3C 3J7, Canada.

HLA-DO (H2-O in mice) is an intracellular non-classical MHC class II molecule (MHCII). It forms a stable complex with HLA-DM (H2-M in mice) and shapes the MHC class II-associated peptide repertoire. Here, we tested the impact of HLA-DO and H2-O on the binding of superantigens (SAgs), which has been shown previously to be sensitive to the structural nature of the class II-bound peptides. We found that the binding of staphylococcal enterotoxin (SE) A and B, as well as toxic shock syndrome toxin 1 (TSST-1), was similar on the HLA-DO(+) human B cell lines 721.45 and its HLA-DO(-) counterpart. However, overexpressing HLA-DO in MHC class II(+) HeLa cells (HeLa-CIITA-DO) improved binding of SEA and TSST-1. Accordingly, knocking down HLA-DO expression using specific siRNAs decreased SEA and TSST-1 binding. We tested directly the impact of the class II-associated invariant chain peptide (CLIP), which dissociation from MHC class II molecules is inhibited by overexpressed HLA-DO. Loading of synthetic CLIP on HLA-DR(+) cells increased SEA and TSST-1 binding. Accordingly, knocking down HLA-DM had a similar effect. In mice, H2-O deficiency had no impact on SAgs binding to isolated splenocytes. Altogether, our results demonstrate that the sensitivity of SAgs to the MHCII-associated peptide has physiological basis and that the effect of HLA-DO on SEA and TSST-1 is mediated through the inhibition of CLIP release.
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http://dx.doi.org/10.1016/j.humimm.2013.05.010DOI Listing
October 2013

Multiple cycles of rituximab therapy in chronic refractory immune thrombocytopenia: a case report with a 10-year follow-up.

Am J Ther 2013 Mar-Apr;20(2):219-22

Division of Hematology, Department of Medicine Royal Victoria Hospital, McGill University Heath Centre, Montreal, Quebec, Canada.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated low platelet counts often leading to mucocutaneous bleeding. Administration of rituximab was shown to increase platelet counts in patients relapsing chronic ITP. However, duration of response with rituximab and the long-term benefit remains unknown. Herein, the authors presented a case of a 36-year-old splenectomised man with a relapsing ITP who received a total of 10 cycles of rituximab over the last decade with the concomitant assessments of circulating B cells. The data show that rituximab can be an effective therapy over 10 years, and monitoring B cells may help to herald ITP recurrence.
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http://dx.doi.org/10.1097/MJT.0b013e318258905eDOI Listing
August 2013

Immunotherapy for B-Cell Neoplasms using T Cells expressing Chimeric Antigen Receptors: From antigen choice to clinical implementation.

Sultan Qaboos Univ Med J 2012 Aug 15;12(3):273-85. Epub 2012 Jul 15.

Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada; ; Department of Haematology, College of Medicine & Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman;

Immunotherapy with T cells expressing chimeric antigen receptors (CAR) is being evaluated as a potential treatment for B-cell neoplasms. In recent clinical trials it has shown promising results. As the number of potential candidate antigens expands, the choice of suitable target antigens becomes more challenging to design studies and to assess optimal efficacy of CAR. Careful evaluation of candidate target antigens is required to ensure that T cells expressing CAR will preferentially kill malignant cells with a minimal toxicity against normal tissues. B cells express specific surface antigens that can theoretically act as targets for CAR design. Although many of these antigens can stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a challenge. Only targeted B-cell antigens CD19 and CD20 have been tested in clinical trials. This article reviews exploitable B cell surface antigens for CAR design and examines obstacles that could interfere with the identification of potentially useful cellular targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529661PMC
http://dx.doi.org/10.12816/0003140DOI Listing
August 2012

Autologous HIV-1 clade-B Nef peptides elicit increased frequency, breadth and function of CD8+ T-cells compared to consensus peptides.

PLoS One 2012 19;7(11):e49562. Epub 2012 Nov 19.

Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM) Saint-Luc, Montréal, Québec, Canada.

Objective: To determine the function and phenotype of CD8(+) T-cells targeting consensus and autologous sequences of entire HIV-1 Nef protein.

Methods: Multiparameter flow cytometry-based analysis was used to evaluate the responses of two treatment naïve HIV-infected individuals, during primary and the chronic phases of infection.

Results: A greater breadth and magnitude of CD8 IFN-γ responses to autologous compared to clade-B consensus peptides was observed in both subjects. Cross recognition between autologous and consensus peptides decreased in both subjects during progression from primary to chronic infection. The frequencies of TEMRA and TEM CD8(+) T-cells targeting autologous peptides were higher than those targeting consensus peptides and were more polyfunctional (IFN-γ(+) Gr-B(+) CD107a(+)).

Conclusions: Our data indicate superior sensitivity and specificity of autologous peptides. The functional and maturational aspects of "real" versus "cross-recognized" responses were also found to differ, highlighting the importance of a sequence-specific approach towards understanding HIV immune response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049562PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501503PMC
May 2013

CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.

PLoS Pathog 2012 16;8(8):e1002840. Epub 2012 Aug 16.

Caprion/ImmuneCarta Services, Montreal, Quebec, Canada.

Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.
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http://dx.doi.org/10.1371/journal.ppat.1002840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420930PMC
December 2012

A new cellular weapon to kill leukaemic B-cells.

Sultan Qaboos Univ Med J 2012 May 9;12(2):137-9. Epub 2012 Apr 9.

Division of Hematology, Royal Victoria Hospital, McGill University Health Centre.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327559PMC
http://dx.doi.org/10.12816/0003105DOI Listing
May 2012

The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin β7 but not CCR6 and regulated by retinoic acid.

PLoS One 2012 28;7(3):e32964. Epub 2012 Mar 28.

Department of Microbiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.

CD4(+) T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8(+) T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8(+) and CD4(+) T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a "signature" for HIV-specific but not CMV-specific CD4(+) T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8(+) T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4(+) versus CD8(+) T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8(+) T-cells may colocalize in excess with CD4(+) T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6(+)CD4(+) T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8(+) T-cells to migrate in the vicinity of CCR6(+)CD4(+) T-cells may facilitate HIV replication and dissemination at mucosal sites.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032964PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314661PMC
August 2012

CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy.

J Clin Virol 2012 Jan 22;53(1):29-32. Epub 2011 Oct 22.

Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

Background: The level of HIV-1 integrated DNA in CD4 T cells was reported to predict the evolution of untreated HIV-1 infection independently of CD4 cell counts or plasma HIV-1 RNA levels. However, the relevance of reservoir level while on efficient antiretroviral therapy (ART) is still unknown.

Objectives: To evaluate factors that may contribute to the establishment and maintenance of HIV-1 reservoir size in ART-treated HIV-1-infected adults with complete suppression of viremia.

Study Design: 35 subjects receiving ART with plasma HIV-1 RNA below the limit of detection for an average duration of 3.2 years were studied. A highly sensitive PCR was used to assess HIV-1 integrated DNA levels in sorted CD4 T cells.

Results: The mean HIV-1 integrated DNA was 300±7copies/10(6) CD4 cells (range 10-1408). In univariate analysis, the levels of HIV-1 proviral DNA appeared to be independent of duration of HIV-1-infection, duration on ART, time since HIV-1 viral load was undetectable, delay between HIV-1 infection and starting ART, or viral load before starting ART. Conversely, CD4 T cell nadir, CD4/CD8 ratio and, to lesser degree, CD4 T cell counts were inversely associated with HIV-1 proviral DNA levels. In multivariate analysis, only CD4 T cell nadir significantly predicted levels of HIV-1 proviral DNA (P=0.025).

Conclusions: CD4 T cell nadir strongly predicted reservoir size independently of other factors in HIV-1-infected adults with complete suppression of viremia. Collectively, these results indicate that the extent of CD4 T cell depletion before ART drives the size of the viral reservoir after prolonged therapy.
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http://dx.doi.org/10.1016/j.jcv.2011.09.018DOI Listing
January 2012

Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis.

J Clin Invest 2011 Oct 19;121(10):3877-88. Epub 2011 Sep 19.

Vaccine and Gene Therapy Institute - Florida, Port St. Lucie, Florida, USA.

Loss of memory B cells occurs from the onset of HIV-1 infection and persists into the chronic stages of infection. Lack of survival of these cells, even in subjects being treated, could primarily be the consequence of an altered local microenvironment induced by HIV infection. In this study we showed that memory B cell survival was significantly decreased in aviremic successfully treated (ST) subjects compared with subjects who control viral load as a result of natural immunity (elite controller [EC]) or with uninfected control (HIV-) subjects. The lower survival levels observed in memory B cells from ST subjects were the result of disrupted IL-2 signaling that led to increased transcriptional activity of Foxo3a and increased expression of its proapoptotic target TRAIL. Notably, memory B cell survival in ST subjects was significantly enhanced by the addition of exogenous IL-2 in a Foxo3a-dependent manner. We further showed that Foxo3a silencing by siRNA resulted in decreased expression of TRAIL and apoptosis levels in memory B cells from ST subjects. Our results thus establish a direct role for Foxo3a/TRAIL signaling in the persistence of memory B cells and provide a mechanism for the reduced survival of memory B cells during HIV infection. This knowledge could be exploited for the development of therapeutic and preventative HIV vaccines.
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http://dx.doi.org/10.1172/JCI59211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195482PMC
October 2011

T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers.

AIDS Res Ther 2011 Jun 16;8(1):20. Epub 2011 Jun 16.

Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

Background: Elite controllers (EC) are a rare subset of HIV infected individuals who control viral load below 50 copies/ml of plasma without treatment.

Methods: Thirty four EC were studied. The slope of CD4 count change was available for 25 of these subjects. We assessed immune activation by measuring the percent of CD38+HLA-DR+CD8+ T cells in the EC group and comparing it with that in 24 treatment-naïve HIV disease progressors and 13 HIV uninfected healthy controls.

Results: Compared to HIV uninfected subjects, EC had higher percentages of CD38+HLA-DR+CD8+ T cells (p < 0.001) that was lower than that observed in progressors (p < 0.01). Fifteen of 25 EC had a slope of CD4 count change that was not significantly different from 0 while 3 had a positive and 7 a negative CD4 count slope. Immune activation did not distinguish EC subsets with stable/increasing versus declining CD4 counts.

Conclusions: Elevated immune activation in ECs is not associated with a faster rate of CD4 decline.
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http://dx.doi.org/10.1186/1742-6405-8-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131237PMC
June 2011

Relative contribution of HIV-specific functional lymphocyte subsets restricted by protective and non-protective HLA alleles.

Viral Immunol 2011 Jun;24(3):189-98

National Immune Monitoring Laboratory (NIML), Genome Québec, Montreal, Québec, Canada.

Expression of major histocompatibility complex (MHC) class I alleles such as B*57 and B*27 are associated with slow HIV disease progression. HIV-specific immune responses in slow progressors (SP) are characterized by a poly-functional profile. We previously observed within infected subjects that HIV peptide-specific responses could differ from each other in their functional composition. We investigate here whether responses restricted by MHC class I alleles associated with slow disease progression have a more poly-functional profile than responses restricted by other alleles. We stimulated peripheral blood mononuclear cells (PBMCs) isolated from 36 chronically HIV-infected individuals with a panel of optimal peptides restricted by the HLA alleles expressed by each subject, and assessed the contribution of single IL-2-, single IFN-γ-, and IFN-γ/IL-2-secreting lymphocytes to the total response measured using a dual color ELISPOT assay. The contribution of functional subsets to responses restricted by HLA B*57/B*27 was similar in SP and progressors. For responses restricted by other MHC class I alleles, dual IFN-γ/IL-2-secreting lymphocytes contributed significantly more to the total response in SP than progressors. Within SP subjects, peptides restricted by both B*57/B*27 and other alleles stimulated responses with similar functional profiles. In progressors, peptides restricted by B*57/B*27 stimulated responses composed of a significantly greater proportion of IFN-γ/IL-2-secreting cells than peptides restricted by other alleles. Within progressors, the contribution of IFN-γ/IL-2-secreting lymphocytes was greater to epitopes restricted by protective HLA alleles compared with responses restricted by other alleles. HLA haplotypes influence the relative functional composition of HIV-specific responses.
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http://dx.doi.org/10.1089/vim.2010.0117DOI Listing
June 2011

Forced expression of HLA-DM at the surface of dendritic cells increases loading of synthetic peptides on MHC class II molecules and modulates T cell responses.

J Immunol 2011 Jul 27;187(1):74-81. Epub 2011 May 27.

Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.

Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR(+) cells resulted in increased loading of the exogenously supplied HA(307-318) peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL(48-61) and of the tumor Ag-derived gp100(174-190) peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY(-) and DMY(+) mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide-MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.
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http://dx.doi.org/10.4049/jimmunol.1002747DOI Listing
July 2011

Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57.

J Virol 2011 Jun 6;85(12):5949-60. Epub 2011 Apr 6.

Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
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http://dx.doi.org/10.1128/JVI.02652-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126301PMC
June 2011

Memory CCR6+CD4+ T cells are preferential targets for productive HIV type 1 infection regardless of their expression of integrin β7.

J Immunol 2011 Apr 11;186(8):4618-30. Epub 2011 Mar 11.

Department of Microbiology and Immunology, University of Montreal, Montreal, H3C 3J7 Quebec, Canada.

HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4(+) T cells. CCR6(+) T cells have the potential to migrate into the GALT via the gut-homing integrin α(4)β(7), a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β(7) are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6(+) T cell permissiveness to infection. We demonstrated that β(7)(-)R6(+) and β(7)(+)R6(+) compared with β(7)(-)R6(-) and β(7)(+)R6(-) T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α(4) and β(7) coexpression in both CCR6(+) and CCR6(-) T cells, but increased HIV permissiveness selectively in CCR6(+) T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin β(7), is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β(7) to regulate cell migration into the GALT and bind HIV-gp120, CCR6(+) T cells coexpressing integrin β(7) and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6(+) T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6(+) T cells.
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http://dx.doi.org/10.4049/jimmunol.1004151DOI Listing
April 2011

IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication.

J Leukoc Biol 2010 May 26;87(5):857-67. Epub 2010 Jan 26.

Laboratory of Innate Immunity, CHU-Sainte-Justine Research Center, McGill University, Montreal, Canada.

IL-21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV-infected persons. In this study, we have investigated how exogenous IL-21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT-3, MAPK, and Akt to enhance NK cell functions; the STAT-3 activation plays a key role in constitutive and IL-21-mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl-2 and Bcl-X(L) and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV-specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV-infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV-1 replication; and the cytokine-activated NK cells inhibit viral replication in cocultured, HIV-infected, autologous CD4(+) T cells in a perforin- and LFA-1-dependent manner. These data suggest that IL-21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV-infected patients.
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http://dx.doi.org/10.1189/jlb.1009701DOI Listing
May 2010

HIV-1 causes an imbalance in the production of interleukin-18 and its natural antagonist in HIV-infected individuals: implications for enhanced viral replication.

J Infect Dis 2010 Feb;201(4):608-17

Laboratory of Innate Immunity, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Quebec, Canada.

Background: Concentrations of interleukin (IL)-18 increase in the circulation of human immunodeficiency virus (HIV)-infected persons. However, nothing is known concerning the regulation of IL-18-binding protein (IL-18BP), which neutralizes IL-18 in vivo. This issue is addressed in the present study.

Methods: Serum samples obtained from healthy subjects and HIV-infected patients were analyzed by enzyme-linked immunosorbent assay to determine their IL-18 and IL-18BP contents. Human monocyte-derived macrophages (MDMs) were infected in vitro with HIV type 1 (HIV-1), and the production of these 2 cytokines by these cells was measured. Finally, we determined the effect of IL-18 on HIV-1 replication in human cells.

Results: In contrast to IL-18 levels, IL-18BP levels decreased in the serum of HIV-infected patients. This decrease resulted in enhanced levels of free IL-18 in the serum of such patients. The infection increased production of IL-18 but decreased that of IL-18BP in MDMs. IL-10 and transforming growth factor-beta, concentrations of which are increased in HIV-infected persons, also decreased production of IL-18BP by human MDMs. Finally, recombinant human IL-18 enhanced HIV-1 replication in human CD4(+) T cells.

Conclusions: Production of IL-18 and its antagonist becomes imbalanced in HIV-1-infected persons. The infection and the cytokine milieu play a role in this decreased production. The increased biological activities of IL-18 may enhance viral replication in human CD4(+) T cells.
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http://dx.doi.org/10.1086/650314DOI Listing
February 2010