Setting the stage: host invasion by HIV

For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention.     

TGF-beta: a master of all T cell trades

A functional adaptive immune system depends on a diverse and self-tolerant population of T lymphocytes that are generated in the thymus and maintained in the peripheral lymphoid organs. Recent studies have defined the cytokine transforming growth factor-beta (TGF-beta) as a critical regulator of thymic T cell development as well as a crucial player in peripheral T cell homeostasis, tolerance to self antigens, and T cell differentiation during the immune response. The unique mechanism of TGF-beta activation and the plasticity of TGF-beta signaling create a stage for TGF-beta to integrate signals from multiple cell types and environmental cues to regulate T cells.     

Jack of one trade,master of none: host choice by Drosophila magnaquinaria

Summary Host selection by phytophagous insects is generally thought to be based on chemical or nutritional characteristics of the host. This is especially true for monophagous insects. However, many other factors may influence host choice. The present study examines host selection by Drosophila magnaquinaria, whose sole host is the yellow skunk cabbage, Lysichitum americanum. Utilization of skunk cabbage was tested relative to a set of alternative hosts. In the pre-alighting stage of host selection, skunk cabbage was found to be less attractive than tomato, cucumber, and commercial mushrooms. In pairwise oviposition tests, there were no differences among hosts. There were no differences in larval survivorship among skunk cabbage, tomato, cucumber, or Ramaria, and larvae developed into pupae earlier on tomato than on skunk cabbage. These results indicate that this monophagy is not based on characteristics of the host. We suggest that habitat selection is the more important factor in determining the association between D. magnaquinaria and skunk cabbage.     

New insights into the functionality of a virion-anchored host cell membrane protein: CD28 versus HIV type 1

It is now well established that the HIV type 1 (HIV-1) incorporates a vast array of host-encoded molecules in its envelope during the budding process. Interestingly, it was demonstrated that the attachment process is accentuated by supplementary interactions between virion-anchored host molecules and their cognate ligands. Such an enhancement of the viral attachment process was found to result in an increase of infectivity for both T and macrophage-tropic strains of HIV-1. Given that previous work indicates that HIV-1 is budding at the site of cell-to-cell contact, a location rich in the costimulatory CD28 glycoprotein, we investigated whether CD28 could be efficiently acquired by HIV-1. We have been able to generate progeny viruses bearing or not bearing on their surfaces host-derived CD28 using our previously described transient transfection and expression system. The physical presence of CD28 was found to markedly increase virus infectivity in a CD28/B7-dependent manner following infection of two human lymphoid cell lines expressing high levels of surface B7-1/B7-2, two natural ligands of CD28. The physiological significance of CD28 incorporation was provided by the observation that an anti-CD28 Ab decreased replication in primary human mononuclear cells of clinical isolates of HIV-1 propagated in such cells. A virus precipitation assay revealed that M-, T-, and dual-tropic clinical strains of HIV-1 produced in primary human mononuclear cells do indeed incorporate CD28. These results show for the first time that HIV-1 can incorporate CD28 and the acquisition of this specific host surface glycoprotein modulates the virus life cycle.     

Hijacking the host cell proteasome

Uropathogenic Escherichia coli subvert host cell signaling mechanisms to induce cellular responses that facilitate bacterial invasion and colonization. A recent publication in the November 15 issue of Cell shows that the bacterium may accomplish such a feat by hijacking the proteasome machinery.     

Mammalian target of rapamycin: master regulator of cell growth in the nervous system

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.     

Mycobacterial manipulation of the host cell

Phagosome biogenesis, the process by which macrophages neutralize ingested pathogens and initiate antigen presentation, has entered the field of cellular mycobacteriology research largely owing to the discovery 30 years ago that phagosomes harboring mycobacteria are refractory to fusion with lysosomes. In the past decade, the use of molecular genetics and biology in different model systems to study phagosome biogenesis have made significant advances in understanding subtle mechanisms by which mycobacteria inhibit the maturation of its phagosome. Thus, we are beginning to appreciate the extent to which these pathogens are able to interfere with innate immune responses and manipulate defense mechanisms to enhance their survival within the human host cell. Here, we summarize current knowledge about phagosome maturation arrest in infected macrophages and the subsequent attenuation of the macrophage-initiated adaptive anti-mycobacterial immune defenses.     

Pathogenic trickery: deception of host cell processes

Microbial pathogens cause a spectrum of diseases in humans. Although the disease mechanisms vary considerably, most pathogens have developed virulence factors that interact with host molecules, often usurping normal cellular processes, including cytoskeletal dynamics and vesicle targeting. These virulence factors often mimic host molecules, and mediate events as diverse as bacterial invasion, antiphagocytosis, and intracellular parastism.     

Rop GTPase: a master switch of cell polarity development in plants

Cell polarity is fundamentally important to plant growth and development, yet the mechanism governing its development is understood poorly. Several studies have revealed a role for Rop GTPases in pollen polar tip growth. Rop is also localized to the future site of root hair development and the tip of root hairs, and expression of constitutively active Rop mutants impacts on the morphogenesis of tip-growing root hairs as well as on non-tip-growing cells. These findings highlight the importance of Rop as a common switch in cell polarity control in plants.     

Cutting edge: class I presentation of host peptides following HIV infection

Class I MHC molecules bind intracellular peptides for presentation to cytotoxic T lymphocytes. Identification of peptides presented by class I molecules during infection is therefore a priority for detecting and targeting intracellular pathogens. To understand which host-encoded peptides distinguish HIV-infected cells, we have developed a mass spectrometric approach to characterize HLA-B*0702 peptides unique to or up-regulated on infected T cells. In this study, we identify 15 host proteins that are differentially presented on infected human T cells. Peptides with increased expression on HIV-infected cells were derived from multiple categories of cellular proteins including RNA binding proteins and cell cycle regulatory proteins. Therefore, comprehensive analysis of the B*0702 peptide repertoire demonstrates that marked differences in host protein presentation occur after HIV infection.     

A molecular signature for the "master" heart cell

The vertebrate heart comprises a variety of cell types, the majority of which are cardiomyocytes, smooth muscle and endothelial cells. Their origin is still an intriguing research topic and the question is whether these cells derive from a common or from multiple distinct progenitor cell(s). Three recent publications not only suggest the existence of a single progenitor cell that can give rise to cardiovascular lineages but additionally uncovered, at least in part, the molecular identity of such a multipotent precursor cell. These findings constitute major progress in the quest for stem-cell therapies for cardiac diseases.     

PP2A as a master regulator of the cell cycle

Protein phosphatase 2A (PP2A) plays a critical multi-faceted role in the regulation of the cell cycle. It is known to dephosphorylate over 300 substrates involved in the cell cycle, regulating almost all major pathways and cell cycle checkpoints. PP2A is involved in such diverse processes by the formation of structurally distinct families of holoenzymes, which are regulated spatially and temporally by specific regulators. Here, we review the involvement of PP2A in the regulation of three cell signaling pathways: wnt, mTOR and MAP kinase, as well as the G1→S transition, DNA synthesis and mitotic initiation. These processes are all crucial for proper cell survival and proliferation and are often deregulated in cancer and other diseases.     

Cryptosporidia: epicellular parasites embraced by the host cell membrane

The ultrastructure of two gastric cryptosporidia, Cryptosporidium muris from experimentally infected rodents (Mastomys natalensis) and Cryptosporidium sp. 'toad' from naturally infected toads (Duttaphrynus melanostictus), was studied using electron microscopy. Observations presented herein allowed us to map ultrastructural aspects of the cryptosporidian invasion process and the origin of a parasitophorous sac. Invading parasites attach to the host cell, followed by gradual envelopment, with the host's cell membrane folds, eventually forming the parasitophorous sac. Cryptosporidian developmental stages remain epicellular during the entire life cycle. The parasite development is illustrated in detail using high resolution field emission scanning electron microscopy. This provides a new insight into the ultrastructural detail of host-parasite interactions and species-specific differences manifested in frequency of detachment of the parasitophorous sac, radial folds of the parasitophorous sac and stem-formation of the parasitised host cell.     

Malaria: Targeting parasite and host cell kinomes

Malaria still remains one of the deadliest infectious diseases, and has a tremendous morbidity and mortality impact in the developing world. The propensity of the parasites to develop drug resistance, and the relative reluctance of the pharmaceutical industry to invest massively in the developments of drugs that would offer only limited marketing prospects, are major issues in antimalarial drug discovery. Protein kinases (PKs) have become a major family of targets for drug discovery research in a number of disease contexts, which has generated considerable resources such as kinase-directed libraries and high throughput kinase inhibition assays. The phylogenetic distance between malaria parasites and their human host translates into important divergences in their respective kinomes, and most Plasmodium kinases display atypical properties (as compared to mammalian PKs) that can be exploited towards selective inhibition. Here, we discuss the taxon-specific kinases possessed by malaria parasites, and give an overview of target PKs that have been validated by reverse genetics, either in the human malaria parasite Plasmodium falciparum or in the rodent model Plasmodium berghei. We also briefly allude to the possibility of attacking Plasmodium through the inhibition of human PKs that are required for survival of this obligatory intracellular parasite, and which are targets for other human diseases.     

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

Cytoskeletal components play a major role in the human immunodeficiency virus-1 (HIV-1) infection. A wide variety of molecules belonging to the microfilament system, including actin filaments and actin binding proteins, as well as microtubules have a key role in regulating both cell life and death. Cell shape maintenance, cell polarity and cell movements as well as cytoplasmic trafficking of molecules determining cell fate, including apoptosis, are in fact instructed by the cytoskeleton components. HIV infection and viral particle production seem to be controlled by cytoskeleton as well. Furthermore, HIV-associated apoptosis failure can also be regulated by the actin network function. In fact, HIV protein gp120 is able to induce cytoskeleton-driven polarization, thus sensitizing T cells to CD95/Fas-mediated apoptosis. The microfilament system seems thus to be a sort of cytoplasmic supervisor of the viral particle, the host cell and the bystander cell's very fate.     

Positive selection of HIV host factors and the evolution of lentivirus genes

Background  

Positive selection of host proteins that interact with pathogens can indicate factors relevant for infection and potentially be a measure of pathogen driven evolution.