Publications

Retroviruses must gain access to the host cell nucleus for subsequent replication and viral propagation. Human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses are distinguished from the gammaretroviruses by their ability to infect nondividing cells such as macrophages, an important viral reservoir in vivo. Rather than requiring nuclear membrane breakdown during cell division, the HIV-1 preintegration complex (PIC) enters the nucleus by traversing the central aqueous channel of the limiting nuclear pore complex. The HIV-1 PIC contains three nucleophilic proteins, matrix, integrase, and Vpr, all of which have been implicated in nuclear targeting. The mechanism by which Vpr can display such nucleophilic properties and yet also be available for incorporation into virions assembling at the plasma membrane is unresolved. We recently characterized Vpr as a nucleocytoplasmic shuttling protein that contains two novel nuclear import signals and an exportin-1-dependent nuclear export signal (NES). We now demonstrate that mutation of this NES impairs the incorporation of Vpr into newly formed virions. Furthermore, we find that the Vpr NES is required for efficient HIV replication in tissue macrophages present in human spleens and tonsils. These findings underscore how the nucleocytoplasmic shuttling of Vpr not only contributes to nuclear import of the HIV-1 PIC but also enables Vpr to be present in the cytoplasm for incorporation into virions, leading to enhancement of viral spread within nondividing tissue macrophages.

PURPOSE OF REVIEW

The models currently proposed for the genetic architecture of obesity are critically reviewed in the light of recent developments in the search for genetic causes of this condition.

RECENT FINDINGS

As for many other 'complex' diseases, most of the genetic variants predisposing to human obesity have not yet been identified. To date, investigation of the genetic contribution to obesity has been conducted according to two main hypotheses. The common disease/common variant hypothesis proposes that the genetic architecture of complex diseases (including obesity) is likely to consist of a limited number of alleles, each conferring a small increase in risk to the individual. Alternatively, it has also been proposed that complex diseases such as obesity may instead result from the effects of a large number of rare variants, with substantial allelic heterogeneity at disease-causing loci. These two hypotheses have shaped strategies for the identification of disease genes, including the use of linkage analysis, association studies and the systematic sequencing of candidate genes. Linkage studies have recently been very successful in identifying new genes in which mutations cause rare monogenic syndromes of obesity. In common obesity, numerous linkage and association studies have suggested that an increasing number of genetic loci could be involved. Overall, however, these studies have failed to identify the causal genetic variants. In contrast, the direct sequencing of well-chosen candidate genes has led to the identification of numerous rare alleles causing both syndromic and common obesity, which are less severe forms of the condition in humans.

SUMMARY

The genetic architecture of obesity is still a matter of debate. The previously accepted hypothesis of a small number of common variants has been undermined by the low reproducibility of association studies and inconsistencies among genome scans for obesity. While high-throughput association mapping of candidate regions holds some promise for the identification of common susceptibility alleles, it must also be considered that the genetic predisposition to obesity may instead result from multiple rare variants in a large number of genes.

Signals from integrins are now known to play critical roles in virtually every aspect of the behavior of epithelial cells, including survival, proliferation, maintenance of polarity, secretory differentiation, and malignant transformation. The cells that line the conducting airways and alveoli of the lung, like most surface epithelia, simultaneously express multiple members of the integrin family, including several with broadly overlapping ligand binding specificities. Although multiple integrins on airway epithelial cells may support adhesion to the same ligands, the functional roles of each integrin that has been examined in detail are quite distinct. Findings from mice expressing null mutations of some of these integrins have identified roles for epithelial cells and epithelial integrins in lung development and in the regulation of lung inflammation, macrophage protease expression, pulmonary fibrosis, and the pulmonary edema that follows acute lung injury. Epithelial integrins are thus attractive targets for intervention in a number of common lung disorders.