Herpesvirus linfotropici e infezione da HIV: modificazioni del sistema immunitario in corso di terapia antiretrovirale

Gli Herpesvirus umani linfotropici (CMV, EBV, HHV6, HHV7, HHV8) sono virus ubiquitari che dopo l’infezione primaria persistono nell’ospite in forma latente, causando generalmente manifestazioni cliniche benigne; nei soggetti immunocompromessi, invece, questi virus possono causare gravi forme morbose. Alcuni herpesvirus hanno la capacità di integrarsi nel genoma dell’ospite (es. EBV, HHV6), altri hanno proprietà trasformanti (es. EBV, HHV8) e pressocchè in tutti sono state individuate proteine con effetti immunomodulanti. È ormai noto, grazie ad alcuni studi riportati in letteratura, che l’infezione acuta e cronica da parte di alcuni virus erpetici, come CMV ed EBV, causa una condizione di immunoattivazione che nel caso di CMV ben si correla con la senescenza del sistema immunitario (entrambi fenomeni osservati anche in corso di infezione da HIV). Sappiamo inoltre che, nonostante la maggior parte dei pazienti HIV-positivi risponda alla terapia antiretrovirale con negativizzazione duratura della carica virale, esiste una particolare categoria di pazienti che presenta elevati livelli di immunoattivazione e uno scarso recupero immunologico (cosiddetti pazienti “discordanti”). Le cause di questo fenomeno sono ancora in via di definizione. L’immunoattivazione persistente sembra giocare un ruolo fondamentale nella patogenesi sia della sindrome AIDS sia dei disordini non AIDS-correlati, quali, ad esempio, l’osteoporosi, l’aumento del rischio cardiovascolare, il decadimento cognitivo, che sempre più vengono osservati in corso di infezione cronica da HIV, in una popolazione che grazie alla HAART ha visto enormemente prolungata la propria aspettativa di vita. I fattori causali dell’immunoattivazione sono molteplici e solo alcuni di essi sono stati ben caratterizzati, come ad esempio la traslocazione batterica dal compartimento gastrointestinale dovuta alla deplezione mucosale delle cellule T CD4+ (evento che avviene precocemente durante l’infezione da HIV), la persistente risposta immunitaria specifica anti-HIV che non riesce a debellare l’infezione, la produzione da parte di HIV di specifiche proteine con funzione immuno-attivatrice. Gli Herpesvirus umani linfotropici hanno un tropismo cellulare simile a quello di HIV e le riattivazioni di questi virus sono una delle possibili cause di immunoattivazione persistente nei pazienti discordanti. Pochi studi sono stati condotti sul grado di immunoattivazione causata da virus erpetici diversi da CMV ed EBV (come ad esempio HHV6, HHV7 ed HHV8) soprattutto nei pazienti HIV-positivi asintomatici per patologie herpes-correlate. Diversi studi suggeriscono inoltre che a livello del cavo orale HIV può interagire direttamente o indirettamente con i suddetti virus erpetici e che tali interazioni possono avere un’azione sinergica per la replicazione di entrambi e probabilmente per la trasmissione, considerato che lo shedding salivare è un’importante fonte di infezione per la maggior parte degli herpesvirus linfotropici. Gli scopi del nostro studio sono di: valutare la prevalenza di positività per la ricerca del DNA degli Herpesvirus umani linfotropici nel plasma e nella saliva di pazienti HIV-positivi in terapia antiretrovirale con soppressione della replicazione virale di HIV ed in un gruppo di controllo formato da donatori sani. Valutare il grado di immunoattivazione, la senescenza e la distribuzione nelle varie forme maturative (naïve, central memory, effector memory, effettori) delle cellule del compartimento dei linfociti T, confrontando i risultati ottenuti nel gruppo dei soggetti con infezione da HIV con quelli del gruppo di controlli sani. Correlare le alterazioni immunologiche con la presenza di virus erpetici linfotropici nei campioni di plasma e di saliva

Severe bloodstream infection due to KPC-producer e coli in a renal transplant recipient treated with the double-carbapenem regimen and analysis of in vitro synergy testing a case report

Transplant recipients are at high risk of infections caused by multidrug resistant microorganisms. Due to the limited thera- peutic options, innovative antimicrobial combinations against carbape- nem-resistant Enterobacteriaceae causing severe infections are necessary. A 61-year-old woman with a history of congenital solitary kidney underwent renal transplantation. The postoperative course was compli- cated by nosocomial pneumonia due to Stenotrophomonas maltophilia and pan-sensitive Escherichia coli, successfully treated with antimicrobial therapy. On postoperative day 22, diagnosis of surgical site infection and nosocomial pneumonia with concomitant bacteremia due to a Kle- bisella pneumoniae carbapenemase-producer E coli was made. The patient was treated with the double-carbapenem regimen (high dose of merope- nem plus ertapenem) and a potent synergistic and bactericidal activity of this un-conventional therapeutic strategy was observed in vitro. Despite a microbiological response with prompt negativity of blood cultures, the patient faced a worse outcome because of severe hemorrhagic shock. The double-carbapenem regimen might be considered as a rescue therapy in those subjects, including transplant recipients, in whom previous antimicrobial combinations failed or when colistin use might be discouraged. Performing in vitro synergy testing should be strongly encouraged in cases of infections caused by pan-drug resistant strains, especially in high-risk patients

HIV-2 infection in a migrant from Gambia: the history of the disease combined with phylogenetic analysis revealed the real source of infection

Human immunodeficiency virus type 2 (HIV-2) infection prevalence is increasing in some European countries. The increasing migratory flow from countries where HIV-2 is endemic has facilitated the spread of the virus into Europe and other regions. We describe a case of HIV-2 infection in a migrant individual in the Asylum Seeker Centre (ASC) in Italy. The patient's virus was sequenced, and found to be a typical HIV-2 genotype A virus. Bayesian evolutionary analysis revealed that the HIV-2 sequence from migrant dated back to 1986 in a subcluster including sequences from Guinea Bissau. This was coherent with the migrant history who lived in Guinea Bissau from his birth until 1998 when he was 13 years old. Monitoring for HIV-2 infection in migrants from western Africa is necessary using adequate molecular tools to improve the diagnosis and understand the real origin of infection

Persistent high plasma levels of sCD163 and sCD14 in adult patients with measles virus infection

Background and aims: Measles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated. Methods: sCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls. Results: At the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages. Conclusions. These results indicate that, despite the resolution of symptoms, an important macrophage/ monocyte activation persists in measles patients, even after two months from infection

Reactivation of hepatitis B virus with immune-escape mutations after ocrelizumab treatment for multiple sclerosis

Ocrelizumab is an anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS) that is closely related to rituximab. We describe a case of hepatitis B virus (HBV) reactivation in an MS patient with resolved HBV infection receiving ocrelizumab. HBV reactivation was monitored with HBV-DNA and HBV surface antigen periodic assessment. Anti-HBV treatment with entecavir was started after HBV-DNA detection. Ocrelizumab can reactivate viral replication in patients with resolved HBV infection. HBV reactivation monitoring seems an effective and safe option for the management of these patients. More studies are needed to assess the optimal management of HBV reactivation in MS patients on ocrelizumab treatment

Dynamic changes of mmp-9 plasma levels correlate with jvc reactivation and immune activation in natalizumab-treated multiple sclerosis patients

The aim of the study was to investigate the changes of matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels during natalizumab treatment and their correlation with JC virus (JCV) reactivation and T-lymphocyte phenotypic modifications in peripheral blood samples from 34 relapsing-remitting multiple sclerosis (RRMS) patients. MMP-9 levels were assessed by zymography in plasma samples. JCV-DNA was detected through quantitative real time PCR in plasma samples. T-lymphocyte phenotype was assessed with flow cytometry. MMP-9 plasma levels resulted increased from 12 to 24 natalizumab infusions. Stratifying plasma samples according to JCV-DNA detection, MMP-9 plasma levels were significantly increased in JCV-DNA positive than JCV-DNA negative samples. MMP-9 plasma levels resulted positively correlated with JCV viral load. CD4 immune senescence, CD8 immune activation and CD8 effector percentages were positively correlated to MMP-9 plasma levels, whereas a negative correlation between CD8 naïve percentages and MMP-9 plasma levels was found. Our data indicate an increase of MMP-9 plasma levels between 12 and 24 natalizumab infusions and a correlation with JCV-DNA detection in plasma, T-lymphocyte immune activation and senescence. These findings could contribute to understand PML pathogenesis under natalizumab treatment, suggesting a potential role of MMP-9 as a predictive marker of PML in RRMS patients

Higher levels of osteoprotegerin and immune activation/immunosenescence markers are correlated with concomitant bone and endovascular damage in HIV-suppressed patients

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases

Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon

Background and aims Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN). Methods sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls. Results At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with highsCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize. Conclusions These results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection

JC virus-DNA detection is associated with CD8 fffector accumulation in peripheral blood of patients with multiple sclerosis under natalizumab treatment, independently from JC virus serostatus

Although natalizumab (anti-α4 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 (N0), 1-12 (N12), 13-24 (N24), 25-36 (N36), and over 36 (N > 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 N0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV-) (p < 0.01 and p < 0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve p = 0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for N12 and N24 groups (p < 0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation

Low Vitamin D Status at Admission as a Risk Factor for Poor Survival in Hospitalized Patients With COVID-19: An Italian Retrospective Study

Preliminary findings suggest a relationship between lower serum 25-hydroxyvitamin D [25(OH)D] levels and incidence and severity of COVID-19. The aim of this study was to evaluate the relationship between vitamin D status at admission and different markers of inflammation, coagulation, and sepsis in hospitalized patients with COVID-19