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Two diazabicyclo analogues of maraviroc, in which the azabicyclooctane moiety is replaced by diazabicyclooctane or diazabicyclononane, were synthesized and tested, through a viral neutralization assay, on a panel of six pseudoviruses., Two diazabicyclo analogues of maraviroc, in which the azabicyclooctane moiety is replaced by diazabicyclooctane or diazabicyclononane, were synthesized and tested, through a viral neutralization assay, on a panel of six pseudoviruses. The diazabicyclooctane derivative maintained a significant infectivity reduction power, whereas the diazabicyclononane was less effective. Biological data were rationalized through a computational study that allowed the conformational preferences of the compounds to be determined and a correlation between the inhibitory activity, the bridge length of the bicycle, and the rotational barrier around dihedral angle τ7 to be hypothesized. A high-field NMR analysis supported the modeling results.

Microbicides are considered a promising strategy for preventing human immunodeficiency virus (HIV-1) transmission and disease. In this report, we first analyzed the antiviral activity of the miniCD4 M48U1 peptide formulated in hydroxyethylcellulose (HEC) hydrogel in activated peripheral blood mononuclear cells (PBMCs) infected with R5- and X4-tropic HIV-1 strains. The results demonstrate that M48U1 prevented infection by several HIV-1 strains including laboratory strains, and HIV-1 subtype B and C strains isolated from the activated PBMCs of patients. M48U1 also inhibited infection by two HIV-1 transmitted/founder infectious molecular clones (pREJO.c/2864 and pTHRO.c/2626). In addition, M48U1 was administered in association with tenofovir, and these two antiretroviral drugs synergistically inhibited HIV-1 infection. In the next series of experiments, we tested M48U1 alone or in combination with tenofovir in HEC hydrogel with an organ-like structure mimicking human cervicovaginal tissue. We demonstrated a strong antiviral effect in absence of significant tissue toxicity. Together, these results indicate that co-treatment with M48U1 plus tenofovir is an effective antiviral strategy that may be used as a new topical microbicide to prevent HIV-1 transmission.

A multicentric Italian investigation on legionnaires' disease is in course to clarify host factors as well as pathogen associated characteristics involved in the infection/disease. The main goal of the research plan is to account for some critical aspects concerning identification and prevention of legionellosis. To improve knowledge on factors associated with Legionella spp colonisation in hot waters, to detect cases and to characterize risk factors in subjects which develop pneumonia are specific objectives of the research programme. Preliminary results show that hot waters of houses and hotels are frequently contaminated (22.6% and 54.6%, respectively), mainly by L. pneumophila. Microbial concentrations were low in domestic waters (1.000 ufc/l), but higher in samples from the hotels (geom. mean 1.85 x 10(3) ufc/l). Warming system, age of the plant, type of building were risk factors significantly associated with Legionella spp positivity. The active surveillance on patients affected by pneumonia with search for Legionella urinary antigen allowed the identification of 34 cases, 3 of which of nosocomial origin, corresponding to 4.2% of the screened pneumonia. After informed consent, 26 subjects were recruited for a case-control-study to clarify risk factors for the disease.

Obiettivi: é stato condotto uno studio di prevalenza per stabilire la presenza di anticorpi anti- Legionella in persone che svolgono diverse attività lavorative, tenendo conto dei fattori personali e ambientali che possono associarsi ad un maggior rischio espositivo.Metodi: sono state esaminate 160 persone di entrambi i sessi, suddivisi in base alla professione in operatori sanitari (n.52), operai (n.55) e impiegati (n.53). Dopo l’adesione tramite consenso informato, per ciascun soggetto veniva compilato un apposito questionario per indagare sui fattori di rischio per l’esposizione a Legionella spp e prelevato un campione di sangue per la ricerca sul siero di anticorpi IgG anti-Legionella (metodo IFA)Risultati: il 43,8% dei medici e il 33,3% degli infermieri sono risultati positivi (titolo›1:128), contro il 16,4% degli operai e il 13,2 degli impiegati (10,55, p‹0,05). I gruppi più frequenti erano L. pneumophila sierogruppo 7-14 (77,1% dei positivi) e L. non pneumophila, L’esame dei fattori di rischio non ha evidenziato associazioni significative con sesso, fumo, bevande alcoliche, anzianità lavorativa ed altre caratteristiche personali. I sintomi simil-influenzali nell’ultimo anno e gli episodi bronco-polmonari riferibili agli ultimi 10 anni non si associavano ad un maggior numero e/o grado di positività.Conclusioni: la sieropositività per Legionella è risultata associata con lo svolgimento delle mansioni di medico e/o infermiere ad indicare una maggior esposizione a Legionella spp negli ambienti sanitari, ma nella maggior parte dei casi si trattava di anticorpi verso i sierogruppi a bassa espressività clinica, come dimostrato dalla assenza anamnestica di legionellosi nel gruppo allo studio.

We describe a method to postlabel, in vivo, biotinylated monoclonal antibodies pretargeted onto tumor deposits when most of the non-tumor-bound antibodies have already been cleared as avidin-bound complexes. The application of this principle to tumor detection by immunoscintigraphy was tested in 20 patients with histologically documented cancer and increased circulating carcinoembryonic antigen levels. One mg of biotinylated anti-carcinoembryonic antigen monoclonal antibody (FO23C5) was administered i.v. (first step). After 3 days, 4-6 mg of cold avidin were injected i.v. (second step), followed 48 h later by 0.2-0.3 mg of a biotin derivative labeled with 111In (2-3 mCi) (third step). No evidence of toxicity was observed. Whole body radioactivity distribution was measured in five patients at various intervals postinjection by the conjugate counting technique. Tumors and metastases were detected in 18 of 19 patients (the remaining patient was a true negative) within 3 h after administration of 111In-biotin by planar or single photon emission tomography imaging. At the time of imaging, tumor/blood pool ratio was 5.5 +/- 3.2, and tumor/liver ratio was 6.7 +/- 3.9. Blood clearance of 111In-biotin was multiexponential, with the fast component having a t1/2 of 5 +/- 3 min. Urinary excretion of radioactivity over 3 h was 63.5 +/- 4.9% of the injected dose. Radioactivity at 3 h was 6.5 +/- 1.8% in blood, 1.6 +/- 0.3% in the kidney, and 2.4 +/- 0.6% in the liver. This approach represents an improvement in immunoscintigraphic techniques for tumor localization. The potential use for radioimmunotherapy is discussed.

Serum samples from 88 human immunodeficiency virus (HIV)-positive drug addicts have been investigated for the presence of antibodies to both beta 2-microglobulin (beta 2m)-free and beta 2m-associated HLA class I molecules. Using HIV-negative drug addicts as background control, we found that none of the Centers for Disease Control (CDC) stage II, 9.1% of CDC III, 36.4% of CDC IV A, and 45.5% of CDC IV C1 patients had significant levels of autoantibodies competing with the binding of the monoclonal antibody specific for beta 2m-free HLA I (L31 mAb). Using the mAb 01.65, recognizing the beta 2m-associated form of HLA class I molecules, a similar percentage of positive samples was found in the CDC II, CDC III, and CDC IV A patient groups; conversely, the percentage of positive serum samples was lower in the CDC IV C1 group. A lower number of systemic lupus erythematosus serum samples and none of the specimens from healthy adult subjects or patients suffering from recurrent Epstein-Barr virus infections were positive in both assays. Our data demonstrate the existence of an ongoing HLA class I-specific autoimmune response during AIDS disease development, which probably reflects a molecular mimicry between autologous histocompatibility antigens and HIV components. The relationship between the prevalence of autoantibodies against beta 2m-free HLA class I and disease progression suggests a possible pathogenetic role of these antibodies in the induction of the HIV-associated immune deficiency.