Although natalizumab (anti-4 integrin) represents an effective therapy for relapsing remitting mu... more Although natalizumab (anti-4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (0), 1-12 (12), 13-24 (24), 25-36 (36), and over 36 ( > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the 0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared...
A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononucle... more A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononuclear cells (PBMCs), and plasma samples from naïve seropositive patients was conducted. One hundred patients were enrolled in this study. Of the 100 patients, 36 had a primary or recent infection (P-RI), 31 had an early chronic infection (>350 CD4 cells) (ECI), and 33 had a late chronic infection (LCI). All 3 compartments were sampled in a subset of 33 participants, while the remaining 67 patients provided plasma samples and PBMCs only. Seventy-seven patients harbored the R5 virus in plasma samples and had a significantly higher median and percentage of CD4 + T cells than patients with X4 virus (437 and 281 cells/μl, respectively; P = 0.0086; 20.6% and 18.6%, respectively). The X4 strain was detected more frequently in patients with LCI than in patients with P-RI or ECI (39.3%, 19.4%, and 9.6%, respectively; P = 0.0063). PBMC and plasma tropism was concordant in 90 patients, and 73 had t...
The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the rela... more The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCVspecific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8 + memory and effector cells was observed after 12 and 24 months of treatment. CD4 + and CD8 + T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8 + effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8 + T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.
In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been as... more In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been associated with the occurrence of progressive multifocal leukoencephalopathy (PML) caused by human polyomavirus JC (JCV). Here, we have shown a significant correlation between patients with JC viruria and positive JC-specific antibody response and patients without JCV-specific antibodies after 1 year of natalizumab (p=0.0006). Furthermore, JCV-specific quantitative PCR on urine and plasma samples, collected at the enrollment (t0) and every 4 months (t1, t2, t3) in the first year and at two time points (t4 and t5) in the second year of natalizumab treatment, indicated the prevalence of JC viremia rather than JC viruria only in the second year of treatment (p=0.04). Moreover, the analysis of JCV non-coding control region (NCCR) sequences in peripheral blood mononuclear cells of patients with JC-specific antibodies after 12 natalizumab infusions (t3) revealed the presence of rearranged sequences, whereas the prevalence of genotypes 1A, 1B, and 4 was detected in these patients by VP1 sequence analysis. In summary, JC viruria evaluation seems to be useful to identify early those patients who do not already develop a humoral immune response against JCV. It may also be interesting to study the JCV NCCR rearrangements since they could give us new insights on the onset of neuro-invasive viral variants.
Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-... more Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-2, and plays important immunoregulatory functions during HIV disease. To evaluate the role of IL-15 in HIV infection the following patients were studied: 18 antiretroviral-naive patients with advanced disease; 19 patients with continuous viral suppression and immunological response after 48-120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with evidence of virological and immunological HAART treatment failure. Nineteen healthy blood donors were included as controls. The production of IL-15 by human peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium avium complex, the priming effect of IL-15 on IFN-gamma production from purified CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta-chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the present work IL-15 production by human peripheral blood monocytes was significantly increased in HIV-infected patients with long-term virological and immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+) and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART. Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune response of HIV-infected patients by augmenting and/or modulating IFN-gamma production and beta-chemokine release. These data about functional properties of IL-15 could provide new implications for immune-based therapies in HIV infection.
CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a pr... more CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation (CIA). Here, we found that both apoptotic epitope (AE)-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper-1-like signature program in chronic (c)HCV infection. However, AE-specific CD8(+) T cells produced tumor necrosis factor (TNF)-α and interleukin-2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations acquiring high levels of programmed death-1 receptor expression. Contextually, only AE-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Taken together, these data suggest that AE-specific CD8(+) T cells can sustain CIA by their capacity to produce TNF-α and be resistant to in...
Introduction: During HIV infection the severe depletion of intestinal CD4 + T-cells is associated... more Introduction: During HIV infection the severe depletion of intestinal CD4 + T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4 + T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers. Methods: This longitudinal single-arm pilot study evaluates CD4 + T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4 + T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4 + Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA. Results: Eight months of cART increased intestinal CD4 + and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4 + T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4 + T-cell recovery. Conclusion: Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4 + T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4 + and of CD8 + T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
CD8 + T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a pri... more CD8 + T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope–specific and hepatitis C virus (HCV)– specific CD8 + T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA + cell subsets expressing a dysfunctional T-helper 1–like signature program in chronic HCV infection. However, apoptotic epitope–specific CD8 + T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8 + T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope–specific CD8 + T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8 + T cells, apoptotic epitope–specific CD8 + T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection.
prior to the prescribing of anti-TNF agents and monitoring for infection during treatment are rec... more prior to the prescribing of anti-TNF agents and monitoring for infection during treatment are recommended. The feasibility of novel screening tools, including QuantiFERON-TB Gold In-Tube (QFT-GIT), remains unclear in the setting of immunosuppression. The aim of this study was to evaluate the usefulness of serial QFT-GIT during biologic therapy to assess whether dynamic changes in IFN-γ levels may be helpful in identifying reactivation of LTBI or newly acquired TB. We conducted a prospective study on patient candidates to TNF inhibitors. QFT-GIT was performed at baseline and after 3 and 6 months since biologic onset. A further follow-up period of 6 months was observed. Among patients enrolled (n0119; F069 %; median age047 years, range 18-80), 24 had at least 1 risk factor for LTBI. Ninetysix were taking immunosuppressants at the time of TB testing. At baseline, 5 patients displayed positive, 93 negative, and 21 indeterminate QFT-GIT results. We observed QFT-GIT conversions and reversions in 12 patients with LTBI and in 73 without LTBI. QFT-GIT results changed of 28 % at month 3 and of 21 % at month 6; the greatest change was observed in patients with indeterminate results that became negative (15 %; p < 0.02). No TB cases were detected. In conclusion, the routine use of both QFT-GIT and TST at screening seems not to give any advantage in the setting of patients awaiting biologics. In addition, the feasibility of serial QFT-GIT during biologic therapy needs definition since changes in IFN-γ levels may occur without a pathologic connotation.
The incidence of invasive candidaemia is increasing all over the world, mainly in critically ill ... more The incidence of invasive candidaemia is increasing all over the world, mainly in critically ill and immunocompromised patients. A shift to non-albicans species and a growing antimycotic resistance have been noticed. We analyzed the different Candida species isolated from bloodstream infections and the related antifungal susceptibility pattern over a three year period at Policlinico Umberto I of Rome. 7574 blood cultures were tested from 2009 to 2011 . The overall incidence of invasive candidaemia during the three years under study was about 4.75% with a marked increase from 2009 to 2011 (3.85% to 7.5%). The species isolated were the following: C. albicans 37.6% and non-albicans 62.4% (C. krusei 30.2%, C. glabrata 21.7%, C. parapsilosis 5.6%, C. tropicalis 3.8% and C. lusitaniae 1.1%). C. albicans showed a growing resistance to amphotericin B (from 0% in 2009 to 6.6% in 2011) and voriconazole (from 0% in 2009 to 13.4% in 2011). C. krusei exhibited a raising resistance to amphoterici...
30 patients with HIV infection were enrolled to evaluate the clinical efficacy and toxicity of zi... more 30 patients with HIV infection were enrolled to evaluate the clinical efficacy and toxicity of zidovudine (AZT), 0.5 g/day p.o. (Group A) vs. AZT 0.5 g/day p.o. plus intravenous immunoglobulins (IVIG), 0.4 g/kg of body weight for three consecutive days, followed by one treatment of 0.6 g/kg of body weight every fourth week (Group B), over a period of one year. The study was open and randomized. The treatment groups were compared using the following study variables: 1) type of infections, recurrences and severity; 2) change in CD4+ T and CD8+ T cell count; 3) change in platelet count; 4) change in TNF alpha serum levels; 5) the probability of not developing an opportunistic infection over a period of 12 months. Patients from Group B developed less pathological events in comparison to Group A. No significative differences were evident with regard to values of T cell subsets obtained before and after treatment in each group and between the two groups. On the contrary, in 12 out of 15 patients from Group B there was a significant increase in platelet count. In both groups there was a significant decrease of mean serum levels of TNF alpha when a comparison was made between time 12 vs. time 6. However, when data were expressed as single values, in three subjects from Group B TNF alpha was still detectable by time 12 vs. 9 individuals in Group A. The cumulative probabilities of developing an opportunistic infection over the 12 months of treatment in the Group A subjects were significantly higher than in the Group B subjects (p less than 0.01). Adverse effects--nausea and gastric pain--were reported for 3 individuals (20%) from Group A and 4 patients (26%) from Group B. In conclusion, patients treated with AZT are especially likely to benefit from IVIG prophylaxis.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, Jan 15, 2015
Infections due to carbapenemase-producing Klebsiella pneumoniae represent an emerging threat due ... more Infections due to carbapenemase-producing Klebsiella pneumoniae represent an emerging threat due to the high mortality rate and lack of valid antimicrobial combinations, especially when the strain is colistin-resistant. We report a case of bloodstream infection due to pandrug-resistant K. pneumoniae treated successfully with an innovative regimen comprising a combination of colistin plus double carbapenem, along with an in vitro analysis showing the synergistic and bactericidal effect.
The aim of our study was to assess knowledge, attitudes, and practices (KAP) regarding HIV/AIDS i... more The aim of our study was to assess knowledge, attitudes, and practices (KAP) regarding HIV/AIDS in the city of Kribi, southern region of Cameroon. In November 2012, a questionnaire composed of 20 items was administered by trained staff from the Biomedical Sciences Department of the University of Dschang to 200 students selected from four population groups: high school students, local traders, tourism personnel (staff of bars, restaurants, hotels, nightclubs), and motorcycle taxi drivers. A cluster sampling method was used to select the first three groups while motorcycle taxi drivers were selected by the method of all comers. KAP regarding HIV/AIDS was found to be fragmentary in the studied population. Only 6.5% systematically uses condoms, 59% believe that AIDS can be cured by traditional medicine and religious faith and 40.9% developed stigmatizing behaviour toward HIV infected people. Among participants there is a wide discrepancy between knowledge and social behaviours toward HI...
International Journal of Antimicrobial Agents, 2009
Background: Unsatisfactory results of infectious endocarditis (IE) treatment are often determined... more Background: Unsatisfactory results of infectious endocarditis (IE) treatment are often determined by late diagnosis. Clinical polymorphism of the disease and development of immunopathologic features require differentiation with different diseases including wide spectrum of rheumatic ones. Methods: Complex examination and treatment of 50 patients with IE hospitalized in the Institute of Rheumatology was performed. There were 26 male and 24 female aged 16 to 68 years (mean age 41.4±14.8 years). Primary IE was diagnosed in 30%, secondary IE in 70% of patients. Hemoculture was positive in 48% of cases. Results. 44 from 50 of patients had different laboratory immune disturbances. Rheumatoid factor (72%), circulating immune complexes (59.2%), hypergammaglobulinemia (58%) and anti-DNA antibodies (57%) were the most frequent of them. Cryoglobulinemia (44%) and antinuclear factor (35%) were less frequent. 88% of patients with IE had clinical immunopathologic signs including musculoskeletal pathology (60%), urinary changes (30%), nephritis (28%), vasculitis (18%), myocarditis (12%), pleuritis (8%). Musculoskeletal pathology included arthralgia (38%), arthritis (20%), tendonitis and enthesitis (18%), myalgia (14%), back pain (12%). Nephritis was significantly more prevalent in patients older than 50 years of age (p = 0.03). It was associated with cryoglobulinemia (p = 0.04), antinuclear factor (p = 0.04), high level of rheumatoid factor (p = 0.03) and staphylococcal etiology of IE (p = 0.04). Circulating immune complexes elevation was significantly more frequent in patients with vasculitis (p = 0.007). Musculoskeletal pathology, myocarditis, pericarditis and pleuritis were not associated with laboratory signs of immunopathology. Conclusion: In case of IE suspicion additional examination should be performed aimed to early disclosure of immunopathologic features.
Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limi... more Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limited due to the high level of resistance to other antimicrobial classes including polymixins. The double-carbapenem regimen has been recently considered a possible therapeutic strategy; however, only case series have examined the clinical and microbiological effectiveness of this innovative combination. To evaluate the in-vivo efficacy and the in-vitro activity of the combination ertapenem plus meropenem in patients with infections due to CR-Kp in whom the use of colistin was not indicated, we performed a retrospective, observational study over a 2-years period. In-vitro synergy was evaluated throughout checkerboard and killing studies. A total of 15 subjects were included in the study, with sepsis, severe sepsis and septic shock found in 2 (13.3%), 5 (33.3%) and 1 (6.7%) patients, respectively. Overall, the clinical/microbiological response was 12/15 (80%). The absence of response at 5-days was associated with the presence of ≥2 infected sites (OR: 28.50, p=0.03), colistin-resistance (OR: 24.20, p=0.02) and CR-Kp bacteremia (OR: 29.00, p=0.03) whereas the occurrence of CR-Kp bacteremia was only associated with the presence of ≥2 infected sites (OR: 40.00, p=0.01). Synergy was observed in 11/14 (78.6%) isolates throughout checkerboard method whereas in killing studies 12/14 (85.7%) and 14/14 (100%) strains were synergic and bactericidal at 24h at concentrations of 1xMIC MEM+1xMIC ERT and 2xMIC MEM+1xMIC ERT, respectively, with a significant decrease of log CFU/mL compared to other combinations (p<0.0001). The double-carbapenem regimen showed in-vivo and in-vitro effectiveness in patients with CR-Kp infections.
Results obtained clearly indicated a significantly higher expression of plasma membrane GD3 conte... more Results obtained clearly indicated a significantly higher expression of plasma membrane GD3 content in lymphocytes from HIV-infected patients with respect to healthy controls. These HIV-induced perturbations of glycosphingolipid metabolism could be detected in all stages of the disease, including asymptomatic individuals. In addition, a significant percentage of patients showing disease progression displayed in serum samples an increased presence of anti-GD3 antibodies. Interestingly, ex vivo studies of lymphocytes from patients with HIV infection also indicated that GD3 expression is strictly associated with annexin V binding, an early marker of apoptosis. Moreover, cytofluorimetric analysis showed that virtually all anti-p24 Ab-positive cells were also immunolabeled with anti-GD3 antibodies. Accordingly, in vitro studies showed a significant redistribution and increase in GD3 expression in cultured U937 cells chronically infected with HIV-1 with respect to uninfected counterparts. In conclusion, our data clearly indicate that a significant increase in GD3 content in HIV-infected lymphocytes can occur and that this GD3 overexpression is paralleled by the presence of anti-GD3 antibodies in the plasma of patients. This is the first demonstration that disialoganglioside GD3, independent of the therapeutic schedule employed, can be considered as one of the early markers of HIV infection and can contribute to the early events leading to T cell depletion by apoptosis.
Although natalizumab (anti-4 integrin) represents an effective therapy for relapsing remitting mu... more Although natalizumab (anti-4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (0), 1-12 (12), 13-24 (24), 25-36 (36), and over 36 ( > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the 0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared...
A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononucle... more A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononuclear cells (PBMCs), and plasma samples from naïve seropositive patients was conducted. One hundred patients were enrolled in this study. Of the 100 patients, 36 had a primary or recent infection (P-RI), 31 had an early chronic infection (>350 CD4 cells) (ECI), and 33 had a late chronic infection (LCI). All 3 compartments were sampled in a subset of 33 participants, while the remaining 67 patients provided plasma samples and PBMCs only. Seventy-seven patients harbored the R5 virus in plasma samples and had a significantly higher median and percentage of CD4 + T cells than patients with X4 virus (437 and 281 cells/μl, respectively; P = 0.0086; 20.6% and 18.6%, respectively). The X4 strain was detected more frequently in patients with LCI than in patients with P-RI or ECI (39.3%, 19.4%, and 9.6%, respectively; P = 0.0063). PBMC and plasma tropism was concordant in 90 patients, and 73 had t...
The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the rela... more The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCVspecific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8 + memory and effector cells was observed after 12 and 24 months of treatment. CD4 + and CD8 + T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8 + effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8 + T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.
In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been as... more In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been associated with the occurrence of progressive multifocal leukoencephalopathy (PML) caused by human polyomavirus JC (JCV). Here, we have shown a significant correlation between patients with JC viruria and positive JC-specific antibody response and patients without JCV-specific antibodies after 1 year of natalizumab (p=0.0006). Furthermore, JCV-specific quantitative PCR on urine and plasma samples, collected at the enrollment (t0) and every 4 months (t1, t2, t3) in the first year and at two time points (t4 and t5) in the second year of natalizumab treatment, indicated the prevalence of JC viremia rather than JC viruria only in the second year of treatment (p=0.04). Moreover, the analysis of JCV non-coding control region (NCCR) sequences in peripheral blood mononuclear cells of patients with JC-specific antibodies after 12 natalizumab infusions (t3) revealed the presence of rearranged sequences, whereas the prevalence of genotypes 1A, 1B, and 4 was detected in these patients by VP1 sequence analysis. In summary, JC viruria evaluation seems to be useful to identify early those patients who do not already develop a humoral immune response against JCV. It may also be interesting to study the JCV NCCR rearrangements since they could give us new insights on the onset of neuro-invasive viral variants.
Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-... more Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-2, and plays important immunoregulatory functions during HIV disease. To evaluate the role of IL-15 in HIV infection the following patients were studied: 18 antiretroviral-naive patients with advanced disease; 19 patients with continuous viral suppression and immunological response after 48-120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with evidence of virological and immunological HAART treatment failure. Nineteen healthy blood donors were included as controls. The production of IL-15 by human peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium avium complex, the priming effect of IL-15 on IFN-gamma production from purified CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta-chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the present work IL-15 production by human peripheral blood monocytes was significantly increased in HIV-infected patients with long-term virological and immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+) and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART. Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune response of HIV-infected patients by augmenting and/or modulating IFN-gamma production and beta-chemokine release. These data about functional properties of IL-15 could provide new implications for immune-based therapies in HIV infection.
CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a pr... more CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation (CIA). Here, we found that both apoptotic epitope (AE)-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper-1-like signature program in chronic (c)HCV infection. However, AE-specific CD8(+) T cells produced tumor necrosis factor (TNF)-α and interleukin-2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations acquiring high levels of programmed death-1 receptor expression. Contextually, only AE-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Taken together, these data suggest that AE-specific CD8(+) T cells can sustain CIA by their capacity to produce TNF-α and be resistant to in...
Introduction: During HIV infection the severe depletion of intestinal CD4 + T-cells is associated... more Introduction: During HIV infection the severe depletion of intestinal CD4 + T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4 + T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers. Methods: This longitudinal single-arm pilot study evaluates CD4 + T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4 + T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4 + Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA. Results: Eight months of cART increased intestinal CD4 + and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4 + T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4 + T-cell recovery. Conclusion: Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4 + T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4 + and of CD8 + T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
CD8 + T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a pri... more CD8 + T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope–specific and hepatitis C virus (HCV)– specific CD8 + T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA + cell subsets expressing a dysfunctional T-helper 1–like signature program in chronic HCV infection. However, apoptotic epitope–specific CD8 + T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8 + T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope–specific CD8 + T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8 + T cells, apoptotic epitope–specific CD8 + T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection.
prior to the prescribing of anti-TNF agents and monitoring for infection during treatment are rec... more prior to the prescribing of anti-TNF agents and monitoring for infection during treatment are recommended. The feasibility of novel screening tools, including QuantiFERON-TB Gold In-Tube (QFT-GIT), remains unclear in the setting of immunosuppression. The aim of this study was to evaluate the usefulness of serial QFT-GIT during biologic therapy to assess whether dynamic changes in IFN-γ levels may be helpful in identifying reactivation of LTBI or newly acquired TB. We conducted a prospective study on patient candidates to TNF inhibitors. QFT-GIT was performed at baseline and after 3 and 6 months since biologic onset. A further follow-up period of 6 months was observed. Among patients enrolled (n0119; F069 %; median age047 years, range 18-80), 24 had at least 1 risk factor for LTBI. Ninetysix were taking immunosuppressants at the time of TB testing. At baseline, 5 patients displayed positive, 93 negative, and 21 indeterminate QFT-GIT results. We observed QFT-GIT conversions and reversions in 12 patients with LTBI and in 73 without LTBI. QFT-GIT results changed of 28 % at month 3 and of 21 % at month 6; the greatest change was observed in patients with indeterminate results that became negative (15 %; p < 0.02). No TB cases were detected. In conclusion, the routine use of both QFT-GIT and TST at screening seems not to give any advantage in the setting of patients awaiting biologics. In addition, the feasibility of serial QFT-GIT during biologic therapy needs definition since changes in IFN-γ levels may occur without a pathologic connotation.
The incidence of invasive candidaemia is increasing all over the world, mainly in critically ill ... more The incidence of invasive candidaemia is increasing all over the world, mainly in critically ill and immunocompromised patients. A shift to non-albicans species and a growing antimycotic resistance have been noticed. We analyzed the different Candida species isolated from bloodstream infections and the related antifungal susceptibility pattern over a three year period at Policlinico Umberto I of Rome. 7574 blood cultures were tested from 2009 to 2011 . The overall incidence of invasive candidaemia during the three years under study was about 4.75% with a marked increase from 2009 to 2011 (3.85% to 7.5%). The species isolated were the following: C. albicans 37.6% and non-albicans 62.4% (C. krusei 30.2%, C. glabrata 21.7%, C. parapsilosis 5.6%, C. tropicalis 3.8% and C. lusitaniae 1.1%). C. albicans showed a growing resistance to amphotericin B (from 0% in 2009 to 6.6% in 2011) and voriconazole (from 0% in 2009 to 13.4% in 2011). C. krusei exhibited a raising resistance to amphoterici...
30 patients with HIV infection were enrolled to evaluate the clinical efficacy and toxicity of zi... more 30 patients with HIV infection were enrolled to evaluate the clinical efficacy and toxicity of zidovudine (AZT), 0.5 g/day p.o. (Group A) vs. AZT 0.5 g/day p.o. plus intravenous immunoglobulins (IVIG), 0.4 g/kg of body weight for three consecutive days, followed by one treatment of 0.6 g/kg of body weight every fourth week (Group B), over a period of one year. The study was open and randomized. The treatment groups were compared using the following study variables: 1) type of infections, recurrences and severity; 2) change in CD4+ T and CD8+ T cell count; 3) change in platelet count; 4) change in TNF alpha serum levels; 5) the probability of not developing an opportunistic infection over a period of 12 months. Patients from Group B developed less pathological events in comparison to Group A. No significative differences were evident with regard to values of T cell subsets obtained before and after treatment in each group and between the two groups. On the contrary, in 12 out of 15 patients from Group B there was a significant increase in platelet count. In both groups there was a significant decrease of mean serum levels of TNF alpha when a comparison was made between time 12 vs. time 6. However, when data were expressed as single values, in three subjects from Group B TNF alpha was still detectable by time 12 vs. 9 individuals in Group A. The cumulative probabilities of developing an opportunistic infection over the 12 months of treatment in the Group A subjects were significantly higher than in the Group B subjects (p less than 0.01). Adverse effects--nausea and gastric pain--were reported for 3 individuals (20%) from Group A and 4 patients (26%) from Group B. In conclusion, patients treated with AZT are especially likely to benefit from IVIG prophylaxis.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, Jan 15, 2015
Infections due to carbapenemase-producing Klebsiella pneumoniae represent an emerging threat due ... more Infections due to carbapenemase-producing Klebsiella pneumoniae represent an emerging threat due to the high mortality rate and lack of valid antimicrobial combinations, especially when the strain is colistin-resistant. We report a case of bloodstream infection due to pandrug-resistant K. pneumoniae treated successfully with an innovative regimen comprising a combination of colistin plus double carbapenem, along with an in vitro analysis showing the synergistic and bactericidal effect.
The aim of our study was to assess knowledge, attitudes, and practices (KAP) regarding HIV/AIDS i... more The aim of our study was to assess knowledge, attitudes, and practices (KAP) regarding HIV/AIDS in the city of Kribi, southern region of Cameroon. In November 2012, a questionnaire composed of 20 items was administered by trained staff from the Biomedical Sciences Department of the University of Dschang to 200 students selected from four population groups: high school students, local traders, tourism personnel (staff of bars, restaurants, hotels, nightclubs), and motorcycle taxi drivers. A cluster sampling method was used to select the first three groups while motorcycle taxi drivers were selected by the method of all comers. KAP regarding HIV/AIDS was found to be fragmentary in the studied population. Only 6.5% systematically uses condoms, 59% believe that AIDS can be cured by traditional medicine and religious faith and 40.9% developed stigmatizing behaviour toward HIV infected people. Among participants there is a wide discrepancy between knowledge and social behaviours toward HI...
International Journal of Antimicrobial Agents, 2009
Background: Unsatisfactory results of infectious endocarditis (IE) treatment are often determined... more Background: Unsatisfactory results of infectious endocarditis (IE) treatment are often determined by late diagnosis. Clinical polymorphism of the disease and development of immunopathologic features require differentiation with different diseases including wide spectrum of rheumatic ones. Methods: Complex examination and treatment of 50 patients with IE hospitalized in the Institute of Rheumatology was performed. There were 26 male and 24 female aged 16 to 68 years (mean age 41.4±14.8 years). Primary IE was diagnosed in 30%, secondary IE in 70% of patients. Hemoculture was positive in 48% of cases. Results. 44 from 50 of patients had different laboratory immune disturbances. Rheumatoid factor (72%), circulating immune complexes (59.2%), hypergammaglobulinemia (58%) and anti-DNA antibodies (57%) were the most frequent of them. Cryoglobulinemia (44%) and antinuclear factor (35%) were less frequent. 88% of patients with IE had clinical immunopathologic signs including musculoskeletal pathology (60%), urinary changes (30%), nephritis (28%), vasculitis (18%), myocarditis (12%), pleuritis (8%). Musculoskeletal pathology included arthralgia (38%), arthritis (20%), tendonitis and enthesitis (18%), myalgia (14%), back pain (12%). Nephritis was significantly more prevalent in patients older than 50 years of age (p = 0.03). It was associated with cryoglobulinemia (p = 0.04), antinuclear factor (p = 0.04), high level of rheumatoid factor (p = 0.03) and staphylococcal etiology of IE (p = 0.04). Circulating immune complexes elevation was significantly more frequent in patients with vasculitis (p = 0.007). Musculoskeletal pathology, myocarditis, pericarditis and pleuritis were not associated with laboratory signs of immunopathology. Conclusion: In case of IE suspicion additional examination should be performed aimed to early disclosure of immunopathologic features.
Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limi... more Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limited due to the high level of resistance to other antimicrobial classes including polymixins. The double-carbapenem regimen has been recently considered a possible therapeutic strategy; however, only case series have examined the clinical and microbiological effectiveness of this innovative combination. To evaluate the in-vivo efficacy and the in-vitro activity of the combination ertapenem plus meropenem in patients with infections due to CR-Kp in whom the use of colistin was not indicated, we performed a retrospective, observational study over a 2-years period. In-vitro synergy was evaluated throughout checkerboard and killing studies. A total of 15 subjects were included in the study, with sepsis, severe sepsis and septic shock found in 2 (13.3%), 5 (33.3%) and 1 (6.7%) patients, respectively. Overall, the clinical/microbiological response was 12/15 (80%). The absence of response at 5-days was associated with the presence of ≥2 infected sites (OR: 28.50, p=0.03), colistin-resistance (OR: 24.20, p=0.02) and CR-Kp bacteremia (OR: 29.00, p=0.03) whereas the occurrence of CR-Kp bacteremia was only associated with the presence of ≥2 infected sites (OR: 40.00, p=0.01). Synergy was observed in 11/14 (78.6%) isolates throughout checkerboard method whereas in killing studies 12/14 (85.7%) and 14/14 (100%) strains were synergic and bactericidal at 24h at concentrations of 1xMIC MEM+1xMIC ERT and 2xMIC MEM+1xMIC ERT, respectively, with a significant decrease of log CFU/mL compared to other combinations (p<0.0001). The double-carbapenem regimen showed in-vivo and in-vitro effectiveness in patients with CR-Kp infections.
Results obtained clearly indicated a significantly higher expression of plasma membrane GD3 conte... more Results obtained clearly indicated a significantly higher expression of plasma membrane GD3 content in lymphocytes from HIV-infected patients with respect to healthy controls. These HIV-induced perturbations of glycosphingolipid metabolism could be detected in all stages of the disease, including asymptomatic individuals. In addition, a significant percentage of patients showing disease progression displayed in serum samples an increased presence of anti-GD3 antibodies. Interestingly, ex vivo studies of lymphocytes from patients with HIV infection also indicated that GD3 expression is strictly associated with annexin V binding, an early marker of apoptosis. Moreover, cytofluorimetric analysis showed that virtually all anti-p24 Ab-positive cells were also immunolabeled with anti-GD3 antibodies. Accordingly, in vitro studies showed a significant redistribution and increase in GD3 expression in cultured U937 cells chronically infected with HIV-1 with respect to uninfected counterparts. In conclusion, our data clearly indicate that a significant increase in GD3 content in HIV-infected lymphocytes can occur and that this GD3 overexpression is paralleled by the presence of anti-GD3 antibodies in the plasma of patients. This is the first demonstration that disialoganglioside GD3, independent of the therapeutic schedule employed, can be considered as one of the early markers of HIV infection and can contribute to the early events leading to T cell depletion by apoptosis.
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