Human Immunodeficiency Virus-1 Uses the Mannose-6-Phosphate Receptor to Cross the Blood-Brain Barrier

HIV-1 circulates both as free virus and within immune cells, with the level of free virus being predictive of clinical course. Both forms of HIV-1 cross the blood-brain barrier (BBB) and much progress has been made in understanding the mechanisms by which infected immune cells cross the blood-brain barrier BBB. How HIV-1 as free virus crosses the BBB is less clear as brain endothelial cells are CD4 and galactosylceramide negative. Here, we found that HIV-1 can use the mannose-6 phosphate receptor (M6PR) to cross the BBB. Brain perfusion studies showed that HIV-1 crossed the BBB of all brain regions consistent with the uniform distribution of M6PR. Ultrastructural studies showed HIV-1 crossed by a transcytotic pathway consistent with transport by M6PR. An in vitro model of the BBB was used to show that transport of HIV-1 was inhibited by mannose, mannan, and mannose-6 phosphate and that enzymatic removal of high mannose oligosaccharide residues from HIV-1 reduced transport. Wheatgerm agglutinin and protamine sulfate, substances known to greatly increase transcytosis of HIV-1 across the BBB in vivo, were shown to be active in the in vitro model and to act through a mannose-dependent mechanism. Transport was also cAMP and calcium-dependent, the latter suggesting that the cation-dependent member of the M6PR family mediates HIV-1 transport across the BBB. We conclude that M6PR is an important receptor used by HIV-1 to cross the BBB

Immune Responses Accelerate Ageing: Proof-of-Principle in an Insect Model

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies. Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology. Along with presenting a proof-of-principle study, we discuss a mechanism for the apparently counter-adaptive persistence of immunopathology in natural populations. If immunopathology from early immune response only becomes costly later in life, natural selection on reducing self-harm would be relaxed, which could explain the presence of immune self-harm in nature

Patterns of dye coupling in the imaginal wing disk of Drosophila melanogaster

Responses of developing tissues to experimental disruption demonstrate that cell interaction is important both in generating positional information and in controlling growth. However, the mechanism by which cells interact and the range over which the interactions are effective are not known. In the imaginai disks of Drosophila melanogaster, experiments on pattern regulation following surgical ablation suggest that the cell interactions are very local in nature; in fact, most of the data can be explained by assuming that cells interact only with their immediate neighbours. In contrast, studies of cell division patterns in the same tissue indicate that the ‘local’ proliferative response to an ablation extends over a distance of up to about eight cell diameters. Still longer-range interactions have been proposed on the basis of theoretical considerations. It is possible that the interactions are mediated by the transfer of small molecules through gap junctions, as gap junctions are abundant in imaginai disks at the appropriate developmental stages. We have explored the range, timing and directionality of dye coupling between the cells of the wing disk as a test of the possible role of gap junctions in imaginai disk patterning. Our results indicate that interactions over different ranges are possible depending on the nature of the molecule being transferred