Search

Defects in cell surface expression of major histocompatibility complex class I antigen molecules are common in tumour cells. We have previously described the generation of adaptive immunity to tumour cells deficient in the transporter associated with antigen processing molecule. In this study, we demonstrate enhanced in vivo protection against growth of β2-microglobulin-deficient tumour cells in syngeneic C57Bl/6 mice, following vaccination with β2-microglobulin-deficient dendritic cells. In vitro analysis suggested that vaccinated mice produced CD3+ cells, which could induce apoptosis in syngeneic β2-microglobulin-deficient tumour and non-malignant cells. Further investigation of target cell recognition suggested that also tumour cells lacking expression of classical major histocompatibility complex class I heavy chains and functional transporter associated with antigen processing molecules were recognized by CD3+ effector cells from vaccinated mice. Histopathological examination of organs from vaccinated mice showed no significant vaccination-induced pathology. The present findings point to a new possible strategy to counteract the growth of major histocompatibility complex class I-deficient tumour cells. [ABSTRACT FROM AUTHOR]

To define the amino acids involved in IgG subclass reactivity to two overlapping HIV-1 gp41 (E34/32; amino acid positions 582-613) peptides, sera from 18 HIV-infected individuals were studied. Peptides mimicking E34 but with single amino acid deletions or glycine substitutions were used to define the amino add residues necessary for antibody binding. Two dominating immunogenic epitopes, containing highly hydrophilic amino acids, were found on the original peptide. Further analysis was undertaken with two corresponding omission sets of dodecapeptides representing halves of the complete E34 plus a terminal cystein peptide. The subclass reactivities usually differed between the patients with regard to the epitopes with which the different IgG subclasses reacted and also to the importance of different amino acids in antibody binding. The 600 glycine and the 601 lysine were involved in the binding of all IgG1,2 and 4 and most IgG3. The development of E34/32-reactive IgM and IgG subclasses showed different patterns in four patients with primary HIV infections, contradicting the existence of a general pattern for the development of IgG subclasses to this peptide. The findings suggest that different progenitor clones are selected for synthesis of the different subclasses. [ABSTRACT FROM AUTHOR]

Low concentrations of serum obtained from a patient with acquired immunodeficiency syndrome (AIDS) enhanced the replication of human immunodeficiency virus type I (HIV-1) in a particular subclone of the CD4-positive monocytoid cell line U937 clone 2. Cells of this subclone have a high expression of Fc receptors and a considerable degree of Fc-mediated phagocytic activity. IgG purified from the serum was also able to enhance the replication. These results indicate that low concentrations of human anti-HIV antibody may enhance HIV replication on human monocyte- macrophages. Furthermore, two mouse IgG1 monoclonal antibodies against gp120, the envelope g1ycoprotein of HIV-1, also induced enhancement at low concentrations. The binding of radiolabelled gp120 to the cells was increased at the same low concentrations. Antibodies against envelope glycoproteins may cause enhancement of HIV infection. Both normal and enhanced replication of H IV were completely inhibited by the masking of the binding site of CD4 molecules with F(ab′)2 fragments of anti-CD4 antibody. Moreover, CD4-positive, FcγRI-negative K562 cells and mouse macrophages failed to show any infection in the presence of antibody. These results suggest that CD4 molecules on the cell surface are necessary to cause enhancement of infection of HIV on monocyte-macrophages. [ABSTRACT FROM AUTHOR]

Background: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation.Methods: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue.Discussion: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa.Trial Registration: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019. [ABSTRACT FROM AUTHOR]

We have realized laser-doped all-silicon superconducting (S)/normal metal (N) bilayers of tunable thickness and dopant concentration. We observed a strong reduction of the bilayers' critical temperature when increasing the normal metal thickness, a signature of the highly transparent S/N interface associated to the epitaxial sharp laser doping profile. We extracted the interface resistance by fitting with the linearized Usadel equations, demonstrating a reduction of 1 order of magnitude from previous superconductor/doped Si interfaces. In this well-controlled crystalline system we exploited the low-resistance S/N interfaces to elaborate all-silicon lateral SNS junctions with long-range proximity effect. Their dc transport properties, such as the critical and retrapping currents, could be well understood in the diffusive regime. Furthermore, this work led to the estimation of important parameters in ultradoped superconducting Si, such as the Fermi velocity, the coherence length, or the electron-phonon coupling constant, fundamental to conceive all-silicon superconducting electronics. [ABSTRACT FROM AUTHOR]