SummaryHuman immunodeficiency virus type 1 (HIV-1), in contrast to animal retroviruses such as murine leukemia virus, is not lysed by human complement. Nevertheless, HIV-1 activates complement via the classical pathway independent of antibody, and C3b deposition facilitates infection of complement receptor-bearing cells. Using gel exclusion chromatography on Sephacryl S-1000, purified virions were found to bind 12sI-1abeled Clq, but not 12SI-labeled dimeric proenzyme Cls. Virions activated the C1 complex, reconstituted from Clq, proenzyme Clr, and 12SI-labeled proenzyme Cls, to an extent comparable with that obtained with immunoglobulin G-ovalbumin immune complexes. To determine the activating viral component, recombinant viral proteins were used: in the solid phase, soluble gp41 (sgp41) (the outer membrane part of gp41, residues 539-684 of gp160) bound Clq, but not dimeric proenzyme Cls, while gp120 was ineffective. In the fluid phase, sgp41 activated the C1 complex in a dose-and time-dependent manner, more efficiently than aggregated Ig, but less efficiently than immune complexes. To localize the C1 activating site(s) in gp41, synthetic peptides (15-residue oligomers spanning amino acids 531-695 of gp160) were used. Peptides covering positions 591-605 and 601-620 and, to a lesser extent, positions 561-575, had both the ability to bind Clq and to induce C3 deposition. These data provide the first experimental evidence of a direct interaction between the C1 complex and HIV-1, and indicate that C1 binding and activation are mediated by specific sites in gp41.

Conduit arteries react with a flow-mediated dilation in response to whole-body exercise. The impairment of this vasodilation observed in smokers was strongly related to a decrease of endothelium-dependent dilation induced by forearm ischemia, indicating that endothelial dysfunction represents the underlying mechanism.

Impaired endothelial function and increased IMT are associated with iron overload, with subsequent induction of oxidative stress, and are not linked to a genetic disability in HH patients. Consequent iron-depletion therapy normalizes endothelial function and may thus reduce the increased risk of cardiovascular events. Female patients may be at a reduced risk, presumably due to continuous iron loss by menstruation.

LRP1b and the closely related LRP1 are large members of the low-density lipoprotein receptor family. At the protein level LRP1b is 55% identical to LRP1, a multifunctional and developmentally essential receptor with roles in cargo transport and cellular signaling. Somatic LRP1b mutations frequently occur in non-small cell lung cancer and urothelial cancers, suggesting a role in the modulation of cellular growth. In contrast to LRP1, LRP1b-deficient mice develop normally, most likely due to its restricted expression pattern and functional compensation by LRP1 or other receptors. LRP1b is expressed predominantly in the brain, and a differentially spliced form is present in the adrenal gland and in the testis. Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species. Using a yeast two-hybrid approach, we have identified two intracellular proteins, the postsynaptic density protein 95 and the aryl hydrocarbon receptor-interacting protein, that bind to the intracellular domain of LRP1b. In addition, we have found several potential ligands that bind to the extracellular domain. Analysis of LRP1b knockout mice may provide further insights into the role of LRP1b as a tumor suppressor and into the mechanisms of cancer development.The low-density lipoprotein (LDL) receptor family comprises seven closely related receptors in mammals. These receptors share a typical arrangement of ligand-binding domains, epidermal growth factor homology domains, and YWTD propeller domains in their extracellular part and contain a cytoplasmic tail with at least one NPXY motif. Two LDL receptor family members, i.e., the LDL receptor and the LDL receptorrelated protein 1 (LRP1) are widely expressed in nearly all cells, while the pattern of the other members (very low density lipoprotein [VLDL] receptor, apoER2, and megalin) is more restricted. The biological functions of the receptors are highly diverse and include the uptake of lipoproteins and other ligands, the regulation of cell surface proteinase activity, the regulation of Ca 2ϩ homeostasis, and important functions in brain development and neurotransmission. Besides their classical role in receptor-mediated endocytosis, evidence is now accumulating that many of the family members play important roles in signal transduction through adaptor molecules that bind to their cytoplasmic tails (8).Two very large receptors of the LDL receptor family have been well characterized. LRP1 contains 31 ligand-binding repeats and binds a variety of ligands, including apoE-carrying lipoproteins, ␣2-macroglobulin, and proteinases and their inhibitors. A unique feature of LRP1 is the fact that this receptor is cleaved by furin in a late secretory compartment, which results in a carboxyl-terminal 85-kDa fragment and a noncovalently linked 515-kDa subunit. LRP1 can bind numerous ligands and has been implicated in a variety of biological functions, including lipoprotein metabolism, the regulation of the ...