Interleukin-12p70 expression by dendritic cells of HIV-1-infected patients fails to stimulate gag-specific immune responses.

A variety of immune-based therapies has been developed in order to boost or induce protective CD8(+) T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2 gag mRNA enhances their capacity to induce HIV gag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2 gag-expressing DCs to expand functional HIV-specific CD8(+) T cells. However, although most of the patients had detectable gag-specific CD8(+) T cell responses, no significant differences in the level of expansion of functional CD8(+) T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

The Use of Interferon-γ Release Assays for Tuberculosis Screening in International Travelers.

Tuberculosis (TB) infection is relatively frequent among travellers to high incidence-countries, especially in long-term travellers and those involved in health work. It is important to diagnose recent infection, both for the affected individual and to prevent further transmission. Based on published literature, we assess the value of interferon-γ release assays (IGRAs) as a complement to or replacement of the tuberculin skin test (TST) for the diagnosis of latent TB infection in the setting of a travel clinic. A comparison of available IGRAs with the TST in terms of operating characteristics and practical considerations is presented. We conclude that IGRAs offer some practical advantages that may benefit certain well-defined patient groups of a travel clinic, but that current evidence is incomplete. We identify research questions to better define the role of IGRAs in these populations.

Intravascular lymphoma presenting with hypoxaemia, platypnoea and lactic acidosis.

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive and rare type of diffuse extranodal B-cell lymphoma. Diagnosis and treatment are challenging and clinical presentation is variable. Physicians should be aware of this rare but life-threatening lymphoma without adenopathy and treatment should be promptly started. We describe the case of a 70-year-old woman who presented with general malaise, acute dyspnoea, platypnoea and lactic acidosis. Echocardiography revealed an extracardiac shunt, the cause of her orthodeoxia. The patient developed rapid liver failure and underwent liver biopsy. Anatomopathological findings suggested IVLBCL, non-germinal center type. She achieved complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, methylprednisolone chemotherapy but relapsed 1 year after initial presentation with multiple organ involvement. The patient's relapsed disease was treated with rituximab, iphosphamide, carboplatin, etoposide and she is still in complete remission 2 years later.

Immunogenicity of mRNA-1273 COVID vaccine after 6 months surveillance in health care workers; a third dose is necessary.

OBJECTIVES: Scarce data are currently available on the kinetics of antibodies after vaccination with mRNA vaccines as a whole and, with mRNA-1273, in particular. We report here an ad-interim analysis of data obtained after a 6-month follow-up in a cohort of healthcare workers (HCWs) who received the mRNA-1273 vaccine. These new data provide more insight into whether and in whom a 3rd dose could be necessary. METHODS: Our study compared the anti-S antibody kinetics at 2 weeks (T1), 3 months (T3) and 6 months (T4) after the first injection, and 2 weeks after the second injection (T2). The 201 participating HCWs were stratified according to their initial serological status. The vaccine effectiveness was also assessed through a medical questionnaire. RESULTS: We report here a marked and statistically significant antibody decrease (P < 0.05) between T3 and T4, especially in naïve vaccinees. The analysis of potential confounding factors or known risk factors for severe COVID-19 disease did not reveal any influence on the drop observed. Six-month after vaccination, only one, symptomatic, infection was reported in our cohort. CONCLUSIONS: In a supply-limited environment, our results plead for reserving the 3rd dose scheme, in the upcoming months, to seronegative individuals prior to vaccination, especially when the serological status is easily accessible.

Prevalence and epidemiology of HIV type 1 drug resistance among newly diagnosed therapy-naive patients in Belgium from 2003 to 2006.

This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium.

Zygomycosis in the immunocompromised patient: a case report.

Zygomycosis is a highly aggressive infection observed in immunocompromised patients, such as those with haematological malignancies. The sites most frequently involved are the sinuses and the lungs. New diagnostic tools and new antifungal treatments are essential in order to diagnose early and treat efficiently infections due to moulds. We report a case of sinusitis due to Absidia corymbifera occurring during chemotherapy-induced bone marrow aplasia in a patient with acute leukaemia. The sinusitis was successfully treated with AmBisome, and surgical debridement.

Intravesical instillation of cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient.

Hemorrhagic cystitis that occurs late after bone marrow transplantation (BMT) in BMT recipients is often associated with adenovirus or polyomavirus BK infections. Intravesical instillation of cidofovir in a BMT recipient with intractable hemorrhagic cystitis resulted in clinical improvement. Local cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of cidofovir.

A 68-year old male presenting with rhabdomyolysis-associated acute kidney injury following concomitant use of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate and pravastatin/fenofibrate: a case report.

INTRODUCTION: We present what we believe to be the first case in the literature of rhabdomyolysis-induced renal failure caused by a probable drug interaction between elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) and pravastatin/fenofibrate. CASE PRESENTATION: A 68-year old Caucasian man presented with progressive pain in both legs two weeks after commencing treatment with EVG/COBI/FTC/TDF. He was found to have biochemical evidence of rhabdomyolysis and acute renal failure. CONCLUSION: We emphasize the need for post marketing surveillance of adverse effects of new products. Pharmacokinetic studies are necessary to investigate the levels of pravastatin in patients taking COBI and fenofibrate with and without other comorbidities. Meanwhile, we suggest that creatine kinase levels should be monitored and patients advised to report myalgias when using concomitant EVG/COBI/FTC/TDF and pravastatin/fenofibrate. This case serves as an important reminder to use estimated glomerular filtration rates rather than serum creatinine levels when choosing new medications. If potentially nephrotoxic combinations are started in patients with borderline estimated glomerular filtration rates, it may be prudent to check these filtration rates more frequently than usual. In patients with reduced estimated glomerular filtration rates, potentially nephrotoxic combinations should be avoided wherever possible.

Toxocariasis diagnosed in international travelers at the Institute of Tropical Medicine, Antwerp, Belgium, from 2000 to 2013.

Although infection with Toxocara canis or T. catis (commonly referred as toxocariasis) appears to be highly prevalent in (sub)tropical countries, information on its frequency and presentation in returning travelers and migrants is scarce. In this study, we reviewed all cases of asymptomatic and symptomatic toxocariasis diagnosed during post-travel consultations at the reference travel clinic of the Institute of Tropical Medicine, Antwerp, Belgium. Toxocariasis was considered as highly probable if serum Toxocara-antibodies were detected in combination with symptoms of visceral larva migrans if present, elevated eosinophil count in blood or other relevant fluid and reasonable exclusion of alternative diagnosis, or definitive in case of documented seroconversion. From 2000 to 2013, 190 travelers showed Toxocara-antibodies, of a total of 3436 for whom the test was requested (5.5%). Toxocariasis was diagnosed in 28 cases (23 symptomatic and 5 asymptomatic) including 21 highly probable and 7 definitive. All but one patients were adults. Africa and Asia were the place of acquisition for 10 and 9 cases, respectively. Twelve patients (43%) were short-term travelers (< 1 month). Symptoms, when present, developed during travel or within 8 weeks maximum after return, and included abdominal complaints (11/23 symptomatic patients, 48%), respiratory symptoms and skin abnormalities (10 each, 43%) and fever (9, 39%), often in combination. Two patients were diagnosed with transverse myelitis. At presentation, the median blood eosinophil count was 1720/µL [range: 510-14160] in the 21 symptomatic cases without neurological complication and 2080/µL [range: 1100-2970] in the 5 asymptomatic individuals. All patients recovered either spontaneously or with an anti-helminthic treatment (mostly a 5-day course of albendazole), except both neurological cases who kept sequelae despite repeated treatments and prolonged corticotherapy. Toxocariasis has to be considered in travelers returning from a (sub)tropical stay with varying clinical manifestations or eosinophilia. Prognosis appears favorable with adequate treatment except in case of neurological involvement.

Lipoplexes carrying mRNA encoding Gag protein modulate dendritic cells to stimulate HIV-specific immune responses.

AIM: Cationic lipids (Lipofectamine™ [Invitrogen, Merelbeke, Belgium] and 1,2-dioleoyl-3-trimethylammonium-propane/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and polymers (jetPEI™ and in vivo-jetPEI™ [Polyplus-transfection, Illkirch, France]) were evaluated for their potential to deliver mRNA to monocyte-derived dendritic cells. MATERIALS & METHODS: Lipoplexes and polyplexes, containing mRNA encoding GFP or Gag protein, were incubated with human monocyte-derived dendritic cells and transfection efficiencies were assessed by flow cytometry. RESULTS: Lipofectamine was by far the most efficient in mRNA delivery, therefore it was used in further experiments. Incubation of monocyte-derived dendritic cells isolated from HIV-1-positive donors with mRNA encoding Gag protein complexed to Lipofectamine resulted in 50% transfection. Importantly, coculture of these Gag-transfected dendritic cells with autologous T cells induced an over tenfold expansion of IFN-γ- and IL-2-secreting CD4(+) and CD8(+) T cells. CONCLUSION: Cationic lipid-mediated mRNA delivery may be a useful tool for therapeutic vaccination against HIV-1. This approach can be applied to develop vaccination strategies for other infectious diseases and cancer.

The role of raltegravir in the treatment of HIV-2 infections: evidence from a case series.

We describe five patients with HIV-2 infection (four antiretroviral-experienced and one antiretroviral-naive) treated with a regimen containing raltegravir. All responded to treatment as demonstrated by viral load and CD4(+) T-cell count monitoring. Our series confirms the clinical effectiveness of raltegravir in HIV-2-infected patients when given with other antiretrovirals to which the virus is susceptible.

mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients.

BACKGROUND: In an effort to raise protective antiviral immunity, dendritic cell immunotherapy was evaluated in six adults infected with human immunodeficiency virus (HIV)-1 and stable under highly active antiretroviral therapy (HAART). DESIGN AND METHODS: Autologous monocyte-derived dendritic cells electroporated with mRNA encoding Gag and a chimeric Tat-Rev-Nef protein were administered, whereas patients remained on HAART. Feasibility, safety, immunogenicity and antiviral responses were investigated. RESULTS: Dendritic cell vaccine preparation and administration were successful in all patients and only mild adverse events were seen. There was a significant increase post-dendritic cell as compared to pre-dendritic cell vaccination in magnitude and breadth of HIV-1-specific interferon (IFN)-γ response, in particular to Gag, and in T-cell proliferation. Breadth of IFN-γ response and T-cell proliferation were both correlated with CD4(+) and CD8(+) polyfunctional T-cell responses. Importantly, dendritic cell vaccination induced or increased the capacity of autologous CD8(+) T cells to inhibit superinfection of CD4(+) T cells with the vaccine-related IIIB virus and some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-γ response. CONCLUSIONS: Therapeutic immunization with dendritic cells was safe and successful in raising antiviral cellular immune responses, including effector CD8(+) T cells with virus inhibitory activity. The stimulation of those potent immunological and antiviral effects, which have been associated with control of HIV-1, underscores the potential of dendritic cell vaccination in the treatment of HIV-1. The incomplete nature of the response in some patients helped to identify potential targets for future improvement, that is increasing antigenic spectrum and enhancing T-cell response.

Monocytes contribute to differential immune pressure on R5 versus X4 HIV through the adipocytokine visfatin/NAMPT.

BACKGROUND: The immune system exerts a diversifying selection pressure on HIV through cellular, humoral and innate mechanisms. This pressure drives viral evolution throughout infection. A better understanding of the natural immune pressure on the virus during infection is warranted, given the clinical interest in eliciting and sustaining an immune response to HIV which can help to control the infection. We undertook to evaluate the potential of the novel HIV-induced, monocyte-derived factor visfatin to modulate viral infection, as part of the innate immune pressure on viral populations. RESULTS: We show that visfatin is capable of selectively inhibiting infection by R5 HIV strains in macrophages and resting PBMC in vitro, while at the same time remaining indifferent to or even favouring infection by X4 strains. Furthermore, visfatin exerts a direct effect on the relative fitness of R5 versus X4 infections in a viral competition setup. Direct interaction of visfatin with the CCR5 receptor is proposed as a putative mechanism for this differential effect. Possible in vivo relevance of visfatin induction is illustrated by its association with the dominance of CXCR4-using HIV in the plasma. CONCLUSIONS: As an innate factor produced by monocytes, visfatin is capable of inhibiting infections by R5 but not X4 strains, reflecting a potential selective pressure against R5 viruses.

Therapy of vector-borne protozoan infections in nonendemic settings.

Vector-borne protozoan infections are responsible for a wide variety of illnesses (mainly malaria, trypanosomiasis and leishmaniasis) affecting tropical and subtropical areas, but increasingly diagnosed in nonendemic settings. This article summarizes the therapeutic developments for these conditions during the past decade and focuses specifically on treatment recommendations for returning travelers and migrants. The treatment of malaria has known the most spectacular improvements. Progress in the management of leishmaniasis and trypanosomiasis has also been substantial and includes introduction of new drugs into clinical practice, combinations of existing drugs, or new laboratory tools for treatment monitoring as well as extension of treatment indications to new groups of patients. Serious gaps still exist in terms of effectiveness and tolerance. Since the research pipeline is very limited for the coming 5-10 years, optimized combinations of existing drugs need to be urgently explored.

Genotypic impact of prolonged detectable HIV type 1 RNA viral load after HAART failure in a CRF01_AE-infected cohort.

HIV subtype-specific data on mutation type, rate, and accumulation following HAART treatment failure are limited. We studied patterns and accrual of drug resistance mutations in a Cambodian CRF01_AE-infected cohort continuing a virologically failing first-line, nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based, HAART. Between 2005 and 2007, 837 adult HIV-infected patients had regular plasma HIV-1 RNA viral load measurements at Sihanouk Hospital Centre of Hope (SHCH), Cambodia. Drug resistance testing was performed in all patients with HIV-1 RNA >1000 copies/ml after at least 6 months of HAART. Seventy-one patients with a mean age of 34 years, of whom 68% were male, were retrospectively assessed at virological failure. The median duration of antiretroviral therapy was 12.3 (IQR 7.1-18.23) months, the median CD4 cell count was 173 (IQR 118-256) cells/mm(3), and the mean plasma HIV-1 RNA viral load was 3.9 log (SD 0.72) at failure. NNRTI mutations, M184I/V mutation, thymidine analogue mutations, and K65R were observed in 78.9%, 69%, 20%, and 12.7% of patients, respectively. For 33 patients, genotypic testing was carried out on at least two occasions before the switch to second-line HAART after a median duration of 5.8 (IQR 4.3-6.1) months of virological failure: 54.5% of patients accumulated new mutations with a rate of 1.6 mutations per person-year. Accumulation was seen both for nucleoside and nonnucleoside reverse transcriptase inhibitors, and also in patients with low-level viremia. Subtype-specific data on mutation type, rate, and accumulation after HAART failure are urgently needed to optimize treatment strategies in resource-limited settings.

Fever after a stay in the tropics: clinical spectrum and outcome in HIV-infected travelers and migrants.

OBJECTIVE: To investigate the epidemiology and clinical spectrum of fever in HIV-infected returning travelers and migrants. METHODS: From April 2000 to December 2006, we explored prospectively, at our referral travel/HIV clinics, the etiology and outcome of febrile illnesses developing within 3 months after a stay in the tropics. For this study, we compared the morbidity profile between HIV-infected individuals and all other cases tested HIV negative. RESULTS: Of the 1850 adults (15 years and older) evaluated for 1921 fever episodes, 93 (5%) had HIV infection, including 5 presenting with primary infection. HIV prevalence was 2% in western travelers or expatriates, 11% in travelers "visiting friends and relatives," and 24% in foreign visitors/migrants. Fever episodes (n = 104) occurring in the HIV-infected individuals were mainly due to opportunistic infections (23%, including tuberculosis), respiratory tract infections (20%), sexually transmitted infections (9%), and noninfectious diseases (7%). All these conditions were more frequently diagnosed than in HIV-negative travelers (1035 fever episodes), although tropical infections (mostly malaria) were proportionally less prevalent. Morbidity (rate and duration of hospitalization) was more considerable in HIV-infected patients than in HIV-negative individuals. CONCLUSIONS: HIV infection was frequent in returning travelers and migrants presenting with fever at our setting and affected strongly the diagnostic spectrum and overall morbidity.