Search

RationaleThere are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation.ObjectiveEvaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia.MethodsA randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021.Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days.Main Outcome MeasurementsPrimary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days.Main ResultsPre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2levels at or below the median value (≤60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with ≤60% FIO2 at baseline that no longer required supplemental oxygen (≥24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed.ConclusionsPost-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen (≤60% FiO2). Further studies are warranted.Trial registration numberNCT04467840

Objective The aim of this study was to explore weight gain in people with HIV (PWH) at least 65 years of age who switch to a DTG based regimen (DTG-s) vs. remaining INSTI-naive (INSTI-n) on stable ART. Methods This was a longitudinal prospective study of PWH from the GEPPO cohort. At the beginning of the observational period, participants were INSTI-naives (INSTI-n). During follow-up, they were divided in two groups: INSTI-n vs. dolutegravir-switchers (DTG-s) with no further change in ART. Body weight was assessed at baseline and at last follow-up visit. Significant weight gain was defined as an increase at least 5% of baseline weight from the first to the last visit. ART regimens were collected at each patients' visit. Kaplan--Meier curves were drawn to assess time to reach a weight gain more than 5%. Results Out of 568 PWH (83.1% men, median age 69.5 years), 427 (75%) were INSTI-n and 141 (25%) DTG-s. After an average follow-up of 2.6 (±0.8) years, no significant change in body weight was observed both among INSTI-n [delta weight = 0.02 (±7.5), P = 0.633] and DTG-s [delta weight = -0.04 (±5.2), P = 0.755]. Weight gain was also not significantly different between study groups (9.3% in INSTI-n and 15.1% in DTG-S: P = 0.175). No significant differences in time to achieve a weight gain greater or equal than 5% of baseline weight emerged in INSTI-n vs. DTG-s (P = 0.93), two-drug regimens (2DR) vs. three-drug regimens (3DR) (P = 0.56) or TAF vs. TDF (P = 0.56). Conclusion Results from a large Italian cohort did not show a significant weight gain associated with switch to DTG in PWH 65 years of age or older. This finding emerged also when comparing 3DR vs. 2DR and TAF exposed and unexposed geriatric PWH.

Objective To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation. Design This is an analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more. Methods The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves. Results Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p Conclusions The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.

The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, p = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients’ survival was also significant compared with the controls (p = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47–7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.

A 64-year-old woman presented to our emergency department during the outbreak of the covid-19 emergency in Italy with syncope, anosmia, mild dyspnoea and atypical chest and dorsal pain. A chest CT scan showed an acute type B aortic dissection (ATBAD) and bilateral lung involvement with ground-glass opacity, compatible with interstitial pneumonia. Nasopharyngeal swabs resulted positive for SARS-CoV-2. For the persistence of chest pain, despite the analgesic therapy, we decided to treat her with a TEVAR. Patient's chest and back pain resolved during the first few days after the procedure. No surgical or respiratory complications occurred and the patient was discharged 14 days after surgery.By performing the operation under local anesthesia, it was possible to limit both the staff inside the operatory room and droplet/aerosol release. Since we had to perform the operation in a hemodynamics room, thanks to the limited extension of the endoprosthesis and the good caliber of the right vertebral artery we were able to reduce the risk of spinal cord ischemia despite the lack of a revascularization of the left subclavian artery.A minimally invasive total endovascular approach allows, through local anesthesia and percutaneous access, to avoid surgical cut down and orotracheal intubation. This, combined with a defined management protocol for infected patients, seems to be a reasonable way to perform endovascular aortic procedures in urgent setting, even in a SARSCoV- 2 positive patient.COVID-19, Dissection, TEVAR.Nel marzo 2020 una donna di 64 anni si è presentata presso il nostro pronto soccorso con sincope, anosmia, lieve dispnea e dolore toracico. Riferiva inoltre febbricola nei giorni precedenti, ma al momento del ricovero era apiretica e la sua saturazione di ossigeno in aria ambiente era 93%. Una TC del torace (eseguita per escludere una tromboembolia polmonare) ha evidenziato una dissezione aortica acuta di tipo B e una polmonite interstiziale bilaterale, con successiva positività del tampone naso-faringeo per SARS-CoV-2. La dissezione aortica era estesa longitudinalmente per circa 6 cm, con un tear di entrata situato subito distalmente rispetto all’origine dell’arteria succlavia sinistra. Come per tutte le sindromi aortiche acute, la paziente è stata trasferita in terapia intensiva per monitoraggio invasivo della pressione arteriosa; in questo caso è stata pianificata una stanza singola con isolamento da contatto e per droplets. Secondo il protocollo interno è stata impostata una terapia antivirale ed una profilassi antibiotica ed antitrombotica. La somministrazione di ossigeno a basso flusso attraverso occhialini nasali era sufficiente per mantenere una saturazione94%. Una scansione TC dopo 24 ore non ha mostrato cambiamenti nell’estensione della dissezione, ma la paziente continuava a riferire dolore toracico nonostante la terapia analgesica per cui è stato deciso di sottoporla a trattamento chirurgico. In anestesia locale (senza intubazione oro-tracheale e con un anestesista in stand-by fuori dalla stanza) ed utilizzando una sala di emodinamica (per la indisponibilità delle sale operatorie, trasformate in terapia intensiva per i pazienti COVID-19) la lesione è stata esclusa mediante il posizionamento di una endoprotesi toracica con copertura intenzionale dell’origine della succlavia di sinistra senza rivascolarizzazione. L’angiografia finale ha mostrato la completa esclusione della dissezione e l’assenza di endoleak. In base al nostro protocollo infettivologico, per l’intera durata della procedura alla paziente è stata applicata una mascherina chirurgica al fine di limitare la diffusione di droplets e l’ossigenoterapia è stata somministrata tramite occhialini nasali. Il personale presente all’interno della sala di emodinamica è stato ridotto al minimo (tre chirurghi vascolari ed un infermiere di sala operatoria) per abbattere il rischio infettivo e l’impiego di dispositivi di protezione individuale. Oltre alla divisa, al camice piombato ed agli occhiali schermati, il personale presente nella stanza era dotato di un doppio camice chirurgico, due paia di guanti, visiera protettiva, maschera FFP2 e copri scarpe. La procedura si è svolta regolarmente e circa 6 ore dopo il termine la paziente è stata trasferita nel reparto di malattie infettive. Non si sono verificate complicanze chirurgiche né respiratorie e la paziente è stata dimessa in quattordicesima giornata post-operatoria. Al fine di evitare la mobilizzazione della paziente al di fuori del reparto di malattie infettive e data la risoluzione delle algie toraciche ed il decorso post-operatorio favorevole, il controllo angio-TC non è stato eseguito durante il ricovero ma è stato programmato a distanza di circa sei mesi dall’intervento.

Objectives This retrospective study evaluates the effect of maraviroc, the first CCR5 receptor antagonist, on non-AIDS-related comorbidity incidence and its impact on inflammatory and lipid parameters. Methods Seventy-four HIV patients on maraviroc treatment were compared with 312 patients never exposed to maraviroc (matched for sex, age and CD4 nadir). Results At baseline (T0), maraviroc patients presented a longer duration of HIV infection, a higher prevalence of comorbidities and a greater frequency of polypharmacy. Non-AIDS-defining disease incidence was lower in the maraviroc group than in the non-maraviroc group (without achieving statistical significance). Except triglycerides (TGL), which dropped only in the maraviroc group, inflammatory and immunological parameters did not significantly change in either group by the end of the study period (T3). At T3, high-sensitivity C-reactive protein (hsCRP) and high-density lipoprotein were inversely correlated in both groups (Spearman’s rho: maraviroc −0.30, P = 0.05; non-maraviroc −0.23, P = 0.0003). Only in the non-maraviroc group was the positive correlation between hsCRP and lipids observed both at T0 (hsCRP/low-density lipoprotein (LDL) +0.17, P = 0.004; hsCRP/total cholesterol +0.20, P = 0.0007; hsCRP/TGL +0.12, P = 0.04) and T3 (hsCRP/LDL +0.26, P Conclusions These data suggest a possible protective role of maraviroc in the incidence of non-AIDS-related comorbidities in a population with longer-lasting infection and allow us to hypothesize its role in the modulation of lipid-dependent inflammation.

Background Geriatric Patients Living with HIV/AIDS (GEPPO) is a new prospective observational multicentre cohort consisting of all the HIV-positive geriatric patients being treated at 10 clinics in Italy, and HIV-negative controls attending a single geriatric clinic. The aim of this analysis of the GEPPO cohort was to compare prevalence and risk factors of individual non-communicable diseases (NCD), multi-morbidity (MM) and polypharmacy (PP) amongst HIV positive and HIV negative controls at enrolment into the GEPPO cohort. Methods This cross-sectional study was conducted between June 2015 and May 2016. The duration of HIV infection was subdivided into three intervals: 20 years. The NCD diagnoses were based on guidelines defined criteria, including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease, dyslipidaemia, chronic obstructive pulmonary disease. MM was classified as the presence of two or more co-morbidities. The medications prescribed for the treatment of comorbidities were collected in both HIV positive and HIV negative group from patient files and were categorized using the Anatomical Therapeutic Chemical (ATC) classification. PP was defined as the presence of five or more drug components other than anti-retroviral agents. Results The study involved a total of 1573 patient: 1258 HIV positive and 315 HIV negative). The prevalence of individual comorbidities was similar in the two groups with the exception of dyslipidaemia, which was more frequent in the HIV-positive patients (p

Burkholderia cepacia complex (Bcc) includes several phenotypically similar but genotypically distinct gram-negative bacteria (GNB) that can colonize the respiratory tract of Cystic Fibrosis (CF) patients. Pathogens are difficult to treat due to intrinsic resistance to multiple antibiotics and are associated to a more rapid decline in lung function and to increased mortality, particularly after lung transplantation. For all these reasons, chronic infection by Burkholderia (B) cenocepacia is presently considered a relative or absolute contraindication in almost all lung transplant centres. We report the case of a young adult CF patient chronically colonized by B multivorans genomovar II, with diabetes and end-stage renal disease treated with renal replacement therapy: a few months after lung transplantation, she developed post-surgery B multivorans bacteremia and multiple brain abscesses. This severe infection did not improve despite multiple standard antibiotic regimen. The introduction of ceftazidime-avibactam, a new β-lactam/ β-lactamase inhibitor combination resulted in clinical recovery and in radiological and biochemical improvement.

BACKGROUND Adults aging with HIV are at greater risk for several comorbidities. The CD4 cell count and CD4/CD8 ratio often fail to normalize in elderly patients despite prolonged antiretroviral therapy; this has been associated with concomitant diseases and poor prognosis. METHODS A cross-sectional analysis in antiretroviral-treated HIV-positive patients aged 65 years and older. The aim of the study was to describe the predictors of normalized T-cell subsets ("nT", CD4/CD8 ratio ≥1 and CD4 ≥500 cells/μL) in a cohort of geriatric HIV-positive patients and its association with HIV-associated non-AIDS conditions (HANA). RESULTS One thousand ninety-two patients were included: nT was observed in 340 patients (31.1%). Multivariate binary logistic analysis showed that plasma HIV RNA

Pasteurella spp is the most frequently pathogen isolated from infected wound inflicted by domestic animal bites. Here we present a case of isolation of Pasteurella pneumotropica like organism from knee mega prosthesis infection occurred in 63 years old female.

Background:It has been suggested that probiotics modulate atopic dermatitis (AD) progression, but no data are actually available on their mechanisms of action and on their ability to act as immunomodulators in this pathology.Objective:The aim of this randomized double-blinded active treatment versus

Despite optimal suppression of HIV replication, restoration of CD4+ T cells is not always achieved in antiretroviral therapy–treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4+ T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14+ cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4+ (CD4+/Ki67+) and CD14+ (CD14+/CD69+) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4+ T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.

Sublingual immunotherapy (SLIT) is an alternate route of administration of allergen-specific immunotherapy with an improved safety profile; to clarify the immune mechanisms elicited by this therapy, we analyzed the clinical and immunologic effects of SLIT in patients with a clinical history of ragweed sensitization. To analyze possible difference among immunotherapeutic protocols, we also compared patients receiving preseasonal, seasonal, or prolonged sublingual therapy (≥3 y); patients receiving symptomatic therapy alone were enrolled as well in the study. Clinical and immunological parameters were measured twice in and out of the pollination period. Clinical benefits, as measured by the visual analog scale for symptoms and for use of drugs, were evident in all three groups of individuals receiving immunotherapy, but were significantly better in patients undergoing prolonged SLIT. Immunologically, SLIT resulted in increased IL-10 production, programmed cell death ligand 1 expression, and concentration of allergen-specific IgG4, as well as in the reduction of CD80 and CD86 expression and IL-4 production. SLIT, thus, is associated with modulation of programmed cell death ligand 1 expression and IL-10 synthesis and favors the production of allergen-specific IgG4. These effects are evident from the first pollen season, independently from therapeutic regimen (preseasonal or seasonal) even if a prolonged treatment is necessary to obtain full clinical efficacy. A more detailed understanding of the interaction of allergen and APCs within the oral mucosa will allow improved targeting of allergy vaccine.

Persistently reduced CD4(+) T-lymphocyte counts in the face of undetectable HIV viremia are seen in a sizable percentage of HIV-infected patients undergoing antiretroviral therapy (ART). We analyzed the immune correlates of this phenomenon.Sixty-seven HIV-infected patients with undetectable viremia (50 copies/microl) after more than 7 years of ART were enrolled in the study and divided into two groups (CD4 cell counts500 cells/microl or500 cells/microl). Duration of HIV infection (16 years) was comparable. Peripheral blood mononuclear cell were stimulated with gag+env or with cytomegalovirus peptides. Activated T cells (Ki67(+)), Treg lymphocytes (CD4(+)/CD25high/Foxp3+), divided into naive and activated cells based on PD1 expression, interleukin (IL)-10 and transforming growth factor (TGF)-beta production, annexin V, activation of caspases 8 and 9, Toll-like receptor (TLR)2 and TLR4 expression on immune cells, and plasma lipopolysaccharide (LPS) concentration were analyzed.CD4(+)/Ki67(+) T cells; plasma LPS; total, naive, and activated Treg; TLR2-expressing and TLR4-expressing Treg; IL-10 production; and early and late apoptotic CD4 T cells, were significantly increased in patients with undetectable viremia and CD4 cell counts less than 500 cells/microl after more than 7 years of ART. As previously shown, CD4 nadir were also lower in these individuals. Immune activation, LPS concentration, Treg, and degree of apoptosis were negatively correlated with CD4 cell counts.Lack of CD4 recovery in individuals in whom ART suppresses HIV replication is associated with complex immune alterations. Immune activation, likely driven by altered gut permeability and resulting in augmented Treg activity could play a pivotal role in this process.

HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV-infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen-allergic HAART-treated HIV-positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes©) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom-medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT-treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro-immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated.

After the introduction of highly active antiretroviral treatment, the course of HIV infection turned into a chronic disease and most of HIV-positive patients will soon be over 50 years old. This paper reviews the multiple aspects that physicians have to face while taking care of HIV-positive ageing patients including the definitions of frailty and the prevalence and risk factors of concomitant diseases. From a therapeutic point of view pharmacokinetic changes and antiretroviral-specific toxicities associated with ageing are discussed; finally therapeutic approaches to frailty are reviewed both in HIV-positive and negative patients. We conclude by suggesting that the combined use of drugs with the least toxicity potential and the promotion of healthy behaviours (including appropriate nutrition and exercise) might be the best practice for ageing HIV-positive subjects.

The immunomodulatory properties of tucaresol (compound 589C80) were tested on in vitro antigen- and mitogen-stimulated proliferation and cytokine production by peripheral blood mononuclear cells (PBMC) of HIV-infected individuals and healthy controls (HC). Results showed that tucaresol: (1) increases influenza A virus-, gp 160 peptide-, and HLA alloantigen-stimulated proliferation as well as interleukin (IL)-2 and interferon gamma (IFN gamma) production by PBMC of HIV-infected individuals with higher CD4 counts (500/microl) but had only a marginal immunomodulatory effect on PBMC of patients with lower CD4 counts (500/microl); (2) did not modify IL-10 production; (3) augmented CD25 expression on mitogen-stimulated T cells of HC but not of HIV-infected individuals; and (4) marginally increased CTL activity. The immunomodulatory properties of tucaresol were confirmed by PCR analyses; additional data showed that tucaresol costimulated CD3-dependent triggering of T cells and that this stimulation was independent of CD28 costimulation. The immunomodulatory effects of tucaresol on T cell functions are characterized by a bell-shaped dose response curve; the action of the compound is optimal in the 100 to 300 microM range. Analyses of mitogen-stimulated apoptosis demonstrated that the lack of effect of tucaresol at higher doses is not the result of increased cell death, suggesting a role of functional impairment. These data confirm that tucaresol can stimulate T helper cell function and enhance the production of type 1 cytokines, thus eliciting cell-mediated immunity, and warrant its potential utility in the therapy of HIV infection.

Background: HIV infection in Africa is associated with immune activation and a cytokine profile that stimulates CCR5 expression. We investigated whether this immune activation is environmentally driven; if a dominant expression of CCR5 could indeed be detected in African individuals; and if R5 HIV strains would be prevalent in this population. Methods: Freshly drawn peripheral blood mononuclear cells from HIV-uninfected African and Italian individuals living in rural Africa, from HIV-uninfected Africans and Italians living in Italy, and from HIV-infected African and Italian patients were analysed. Determinations of HIV coreceptor-specific mRNAs and immunophenotype analyses were performed in all samples. Virological analyses included virus isolation and characterization of plasma neutralizing activity. Findings: Results showed that: immune activation is detected both in Italian and African HIV-uninfected individuals living in Africa but not in African subjects living in Italy; CCR5-specific mRNA is augmented and the surface expression of CCR5 is increased in African compared with Italian residents (CXCR4-specific mRNA is comparable); R5-HIV strains are isolated prevalently from lymphocytes of African HIVinfected patients; and plasma neutralizing activity in HIV-infected African patients is mostly specific for R5 strains. Conclusions: Immune activation in African residents is environmentally driven and not genetically predetermined. This immune activation results in a skewing of the CCR5 : CXCR4 ratio which is associated with a prevalent isolation of R5 viruses. These data suggest that the selection of the predominant virus strain within the population could be influenced by an immunologically driven pattern of HIV co receptor expression.

Infectious diseases are the major cause of death worldwide; in developing countries such diseases are responsible for nearly half the burden of premature death and disability. Therefore, the need for the development of new vaccine strategies aimed at preventing or limiting disease is extremely urgent. Important successes have been achieved against some infectious diseases that were once endemic or, even, epidemic (e.g., polio, smallpox, diptheria). Advances in our knowledge of the pathogenesis and immune correlates of protections are needed to develop novel vaccinal approaches to diseases such as hepatitis C, AIDS and malaria. In this review we will analyse the biological problems associated with the prevention of development and/or improvement of vaccine strategies for infectious diseases, focusing on the difficulties facing the creation of new effective vaccines for HIV infection and malaria.

The progression of HIV infection is accompanied by complex alterations in the production of adrenal steroids. Cortisol levels are increased in HIV infection whereas those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. The progression of HIV infection to AIDS is also characterised by a shift from a type 1-to-type 2 cytokine production. Thus, defective production of interferon gamma (IFNγ), interleukin (IL)-2, and IL-12 as well as increased production of IL-4, IL-5, IL-6, and IL-10 are observed in HIV-seropositive individuals and are proposed to be in vitro immunologic marker of progression. Cortisol and pharmacological doses of glucocorticoids (GC) suppress IL-2 and IFNγ production and favour the production of IL-4. Furthermore, GC and IL-4 stimulate the differentiation of B lymphocytes into IgE producing plasma cells, the concentration of which augments in HIV infection. Finally, GC induce programmed cell death (PCD) in a variety of different cells, including mature T lymphocytes, and type 2 cytokines were recently proposed to augment the susceptibility of T lymphocytes to PCD. It was suggested that the progressive shift from type 1 to type 2 cytokine production characteristic of HIV infection could be at least partially provoked by the increase in the production of cortisol and the reduction of DHEA. This hypothesis is discussed within the scenario of an endrocrinologic imbalance being responsible for HIV progression at least partially via increased susceptibility of HIV + CD4 lymphocyte to PCD.

The concentration of type 1 and type 2 cytokines and fibroblast-associated apoptosis-1 soluble receptor (sAPO-1/Fas) was analysed in the sera of Ugandan and Italian HIV-1-seropositive and seronegative individuals. The data were compared to determine whether the immunological status of these groups was different.Sixty-seven Ugandan and 30 Italian HIV-positive patients were analysed and stratified according to CD4 counts (group 1,500 x 10(6)/l; group 2, 200-500 x 10(6)/l; group 3,200 x 10(6)/l). Sera from 15 Ugandan and 11 Italian HIV-negative blood donors were also analysed. Serum concentration of type 1 cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-gamma] and type 2 cytokines (IL-4 and IL-10), and sAPO-1/Fas were measured by enzyme-linked immunosorbent assay.Serum levels of IL-2, IFN-gamma and IL-10 but not of IL-4 and IL-12, were elevated in HIV-positive group 1 and 2 Africans compared with HIV-positive Italian individuals. IL-4 was mildly augmented in HIV-positive group 3 African patients. Serum concentration of sAPO-1/Fas was reduced in HIV-positive Africans compared with HIV-positive Italian individuals. Finally, serum levels of IL-2 and IL-10 were increased and sAPO-1/Fas reduced when sera of HIV-negative African healthy controls were compared with their Italian counterparts. The ratio of type 1/type 2 cytokines was roughly 1.0 in HIV-negative African controls, and much greater than 1.0 in HIV-negative Italian controls.These preliminary findings indicate that immune activation is present in African HIV infection. Furthermore, these data raise the possibility that abnormal immune activation and increased susceptibility to antigen-induced cell death is present even in HIV-negative African controls.

Objectives: HIV-infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population. The primary objective of thisstudywastocomparetherelative rolesofinflammation,endothelialalterations,and metabolic factors in the induction and maintenance of atherosclerosis in antiretroviral therapy (ART)-treated or ART-naive patients. Design: Cross-sectional study; 79 HIV-infected patients (55 ART-treated and 24 naive individuals) were consecutively enrolled. In both groups, nearly 50% of the individuals had a high cardiovascular risk (Framingham value >20%). Methods: Echo-Doppler [intima‐media thickness (IMT)], inflammatory, thrombophilic, endothelial, metabolic indexes, and cholesterol efflux molecules were evaluated. Multivariate analysis adjusted for age, CD4 nadir, BMI, and Framingham’s score were used to analyze the results. Results: A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART-naive individuals, metabolic factors [low-density lipoprotein (LDL), apolipoprotein B (ApoB), lipoprotein A] seem to play a more prevalent role in ART-treated patients. Notably, ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART-treated individuals. Conclusion: Atherosclerosis in HIV infection results from the interaction of multiple factors: an inflammatory and HIV-driven disease could prevail in the absence of therapy; metabolic, non-inflammatory causes may be more important in patients undergoing therapy. Approaches to atherosclerotic disease in HIV infection should consider these differences. 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:381‐389

We studied the prevalence of anti-HTLV-I/II antibodies in 22 patients with AIDS-related non-Hodgkin lymphoma (NHL), 453 HIV-1-infected patients without lymphoma (194 of whom were diagnosed as having AIDS), and 6 HIV-1-positive and 75 HIV-1-negative patients with Hodgkin lymphoma. The frequency of serological reactivity against HTLV antigens was significantly higher in the AIDS patients with lymphoma than in those without (8 of 22, 36.4% vs. 20 of 194, 10.3%-p = 0.0027). One of the HIV-1-positive and none of the HIV-1-negative patients with Hodgkin lymphoma showed anti-HTLV-I/II reactivity. Four of the eight seropositive NHL patients showed antibodies directed against HTLV-II recombinant antigens when tested for serological discrimination in a Western blot assay. A PCR study of PBMCs from the only patient with NHL still alive at the time of the study showed HTLV-II-specific sequences in the genomic DNA. These data suggest that HTLV-II or a closely homologous retrovirus infects a high proportion of patients with AIDS-associated NHL.

To evaluate cytokine stimulation with 3 strains of Lactobacillus salivarius in vitro and to assess changes in intestinal microflora and clinical improvements in adults with atopic dermatitis (AD) induced by the strain showing the best immunomodulatory features.AD is a common skin disease in children and adults. It is characterized by chronic inflammation, eczema, and increasing intestinal permeability. Various studies have shown that patients with AD presented some modifications in the intestinal microbiota composition; as a result, intestinal microflora is thought to have a pivotal role in this disease.Thirty-eight patients aged from 18 to 46 years with moderate/severe AD were recruited. Subjects were randomized in a double-blind placebo-controlled study to receive active treatment with L. salivarius LS01: probiotic (n=19) or placebo (n=19). Cytokine production was determined by means of specific quantitative enzyme-linked immunosorbent assays. Intestinal bacterial groups were quantified using conventional culture techniques, whereas L. salivarius LS01 was identified using polymerase chain reaction and pulse field gel electrophoresis.L. salivarius LS01 showed the best immunomodulatory features and it was chosen for the second phase of the study. AD subjects showed a reduction in their SCORAD score after probiotic treatment and a significant decrease in the staphylococci load compared with the placebo group. Moreover, L. salivarius LS01 showed the ability to reduce the production of Th2 cytokines, maintaining the production of Th1 cytokines stable.Treatment with the L. salivarius LS01 strain seems to positively modify clinical and immunologic status and dermatology life quality in a group of adults affected by moderate/severe AD, leading to a rebalancing of altered intestinal microbiota.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by xerosis, pruritus and eczema. The role of probiotics in the prevention and the treatment of AD have been extensively studied in children with controversial results while there are few studies on an adult population. The aim of this randomized, double-blind, placebo-controlled study is to evaluate the clinical efficacy of the intake of a probiotic strain ( Lactobacillus salivarius LS01) in the treatment of adult patients with AD. A group of 38 patients was treated with probiotics or placebo (maltodextrin) for 16 weeks. The study was performed from January (T0) to May, 2009 (T16). The assessment of efficacy was based on change in SCORAD (SCORing Atopic Dermatitis) index, dermatology life quality index (DLQI) improvement, cytokine production by PBMCs and ability to modify faecal microbial flora. No significant adverse events were recorded during the study. Patients treated with probiotics showed a statistically improvement of both clinical parameters (SCORAD p< 0.0001 and DLQI p= 0.021) at the end of treatment (T16) compared with the placebo group. Furthermore, after four months of treatment there was a significant reduction of Th1 cytokines (IL-12+IFNγ) (p= 0.03) and Th1/Th2 ratio (IL-12+IFNγ/IL-4+IL-5) (p= 0.019) only in placebo-treated patients. A statistically relevant decrease of staphylococci in faeces of the probiotic-treated group was also observed at the end of treatment. In our study, the administration of L. salivarius LS01 was well tolerated and was associated with a significant improvement of clinical manifestation and QoL. This probiotic strain could have an important role in modulating Th1/Th2 cytokine profiles and could be considered as an important adjunctive therapy in the treatment of adult AD.

Several cohort studies reported a relation of cardiovascular events and periodontal disease. In particular, Porphyromonas gingivalis is associated with the development of atherosclerotic plaques. We verified in a longitudinal study whether inflammation biomarkers, endothelial adhesion molecules, leukocyte activation markers, and intima-media thickness could be beneficially modified by periodontal treatment alone. Thirty-five otherwise healthy individuals affected by mild to moderate parodontopathy were enrolled in the study. Echo-Doppler cardiography of the carotid artery, fluorescence-activated cell sorting analyses on lymphocytes and monocytes, and plasma inflammatory indices were evaluated at baseline and at multiple time points after the periodontal treatment. Results showed that inflammation biomarkers were abnormally increased at baseline. Periodontal treatment resulted in a significant reduction of the total oral bacterial load that was associated with a significant amelioration of inflammation biomarkers and of adhesion and activation proteins. Notably, intima-media thickness was significantly diminished after treatment. Inflammatory alterations associated with the genesis of atherosclerotic plaques are detected in otherwise healthy individuals affected by parodontopathy and are positively influenced by periodontal treatment. Reduction of oral bacterial load results in a modification of an anatomical parameter directly responsible for atherosclerosis. These results shed light on the pathogenesis of atherosclerosis and could have practical implications for public health.

Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.

BACKGROUND HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms. METHODS Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals. RESULTS The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells. CONCLUSIONS A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.