HIV-1 Tat-based vaccines: from basic science to clinical trials

Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.     

Prostate cancer vaccines: the long road to clinical application

Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome tumor-related immune suppression. Immunotherapy, as a treatment modality for prostate cancer, has received significant attention in the past few years. The most intriguing characteristics that make prostate cancer a preferred target for immune-based treatments are (1) its relative indolence which allows sufficient time for the immune system to develop meaningful antitumor responses; (2) prostate tumor-associated antigens are mainly tissue-lineage antigens, and thus, antitumor responses will preferentially target prostate cancer cells. But, also in the event of eradication of normal prostate epithelium as a result of immune attack, this will have no clinical consequences because the prostate gland is not a vital organ; (3) the use of prostate-specific antigen for early detection of recurrent disease allows for the initiation of vaccine immunotherapy while tumor burden is still minimal. Finally, for improving clinical outcome further to increasing vaccine potency, it is imperative to recognize prognostic and predictive biomarkers of clinical benefit that may guide to select the therapeutic strategies for patients most likely to gain benefit.     

Schistosomes: unanswered questions on the basic biology of the host-parasite relationship

As is the case in many parasite infections, research into schistosomiasis has not yet yielded a vaccine and, although chemotherapy with praziquantel is very effective, the mechanism of action of this drug is unknown. John Kusel and colleagues here suggest that an understanding of basic biological phenomena, such as the role of Ca(2+) in skin penetration and the function of the adult excretory system, might lead to important breakthroughs. Other crucial questions are also addressed, with the hope of stimulating debate. They invite suggestions and correspondence from others working in related fields.     

International clinical trials of vaccines

Modern principles of organization and planning of international clinical trials of vaccines and stages of development of domestic vaccines are presented. Factors that determine the success of large-scale clinical trials are thoroughly described. Differences between domestic registration trials and international multicenter randomized clinical trials are discussed. It has been recommended how national regulatory acts that legitimate conducting of clinical trials of both national and foreign vaccines should be harmonized.     

Venom proteins from polydnavirus-producing endoparasitoids: their role in host-parasite interactions

Endoparasitoid wasps have evolved various mechanisms to ensure successful development of their progeny, including co-injection of a cocktail of maternal secretions into the host hemocoel, including venom, calyx fluid, and polydnaviruses. The components of each type of secretion may influence host physiology and development independently or in a synergistic fashion. For example, venom fluid consists of several peptides and proteins that promote expression of polydnavirus genes in addition to other activities, such as inhibition of prophenoloxidase activation, inhibition of hemocytes spreading and aggregation, and inhibition of development. This review provides a brief overview of advances and prospects in the study of venom proteins from polydnavirus-producing endoparasitoid wasps with a special emphasis on the role of C. rubecula venom proteins in host-parasitoid interactions.     

Heads or tails: host-parasite interactions in the Drosophila-Wolbachia system

Wolbachia strains are endosymbiotic bacteria typically found in the reproductive tracts of arthropods. These bacteria manipulate host reproduction to ensure maternal transmission. They are usually transmitted vertically, so it has been predicted that they have evolved a mechanism to target the host's germ cells during development. Through cytological analysis we found that Wolbachia strains display various affinities for the germ line of Drosophila. Different Wolbachia strains show posterior, anterior, or cortical localization in Drosophila embryos, and this localization is congruent with the classification of the organisms based on the wsp (Wolbachia surface protein) gene sequence. This embryonic distribution pattern is established during early oogenesis and does not change until late stages of embryogenesis. The posterior and anterior localization of Wolbachia resembles that of oskar and bicoid mRNAs, respectively, which define the anterior-posterior axis in the Drosophila oocyte. By comparing the properties of a single Wolbachia strain in different host backgrounds and the properties of different Wolbachia strains in the same host background, we concluded that bacterial factors determine distribution, while bacterial density seems to be limited by the host. Possible implications concerning cytoplasmic incompatibility and evolution of strains are discussed.     

Chemokines in host-parasite interactions in leishmaniasis

Crucial to the defense against leishmaniasis is the ability of the host to mount a cell-mediated immune response capable of controlling and/or eliminating the parasite. Cell recruitment to the site of infection is essential to the development of the host cellular immune response. The process is controlled by chemokines, which are chemotactic cytokines produced by leukocytes and tissue cells.     

Coevolution: Mathematical analysis of host-parasite interactions

An SIS epidemic transmitted by two similar strains of parasite acting on a host population of three genotypes which differ in their reaction to the disease is modelled and analyzed. Singular perturbation techniques are used to reduce the original system of nine differential equations to a coupled system of two equations describing the slowtime coevolution of gene frequency and parasite strain frequency.Karen Christine Beck died June 25, 1983 at home.Born February 8, 1952 in Madison, Wisconsin, She received a B.A. degree in 1974 from Luther College, Decorah, Iowa and a Ph.D. in mathematics in 1980 from the University of Iowa. Since that time she has been an instructor in the Mathematics Department at the University of Utah. She was to become an Assistant Professor at the University of Texas, Arlington, beginning Autumn, 1983. Dr. Beck's areas of specialization in mathematics were Mathematical Analysis and Mathematical Biology. She published numerous research articles that resolved various problems in these areas.     

Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions

Experimenta naturae, like the glucose-6-phosphate dehydrogenase deficiency, indicate that malaria parasites are highly susceptible to alterations in the redox equilibrium. This offers a great potential for the development of urgently required novel chemotherapeutic strategies. However, the relationship between the redox status of malarial parasites and that of their host is complex. In this review article we summarise the presently available knowledge on sources and detoxification pathways of reactive oxygen species in malaria parasite-infected red cells, on clinical aspects of redox metabolism and redox-related mechanisms of drug action as well as future prospects for drug development. As delineated below, alterations in redox status contribute to disease manifestation including sequestration, cerebral pathology, anaemia, respiratory distress, and placental malaria. Studying haemoglobinopathies, like thalassemias and sickle cell disease, and other red cell defects that provide protection against malaria allows insights into this fine balance of redox interactions. The host immune response to malaria involves phagocytosis as well as the production of nitric oxide and oxygen radicals that form part of the host defence system and also contribute to the pathology of the disease. Haemoglobin degradation by the malarial parasite produces the redox active by-products, free haem and H(2)O(2), conferring oxidative insult on the host cell. However, the parasite also supplies antioxidant moieties to the host and possesses an efficient enzymatic antioxidant defence system including glutathione- and thioredoxin-dependent proteins. Mechanistic and structural work on these enzymes might provide a basis for targeting the parasite. Indeed, a number of currently used drugs, especially the endoperoxide antimalarials, appear to act by increasing oxidant stress, and novel drugs such as peroxidic compounds and anthroquinones are being developed.     

Phenotypic plasticity of host-parasite interactions in response to the route of infection

The microsporidium Octosporea bayeri can infect its host, the planktonic crustacean Daphnia magna, vertically and horizontally. The two routes differ greatly in the way the parasite leaves the harbouring host (transmission) and in the way it enters a new, susceptible host (infection). Infections resulting from each route may thus vary in the way they affect host and parasite life-histories and, subsequently, host and parasite fitness. We conducted a life-table experiment to compare D. magna infected with O. bayeri either horizontally or vertically, using three different parasite isolates. Both the infection route and the parasite isolate had significant effects on host life-history. Hosts matured at different ages depending on the parasite isolate, and at a size that varied with infection route. The frequency of host sterility and the host's life-time reproductive success were affected by both the infection route and the parasite isolate. The infection route also affected parasite life-history. The production of parasite spores was much higher in vertically than in horizontally infected hosts. We found a trade-off between the production of spores (the parasite's horizontal fitness component) and the production of infected host offspring (the parasite's vertical fitness component). This study shows that hosts and parasites can react plastically to different routes of infection, suggesting that ecological factors that may influence the relative importance of horizontal and vertical transmission can shape the evolution of host and parasite life histories, and, consequently, the evolution of virulence.     

Heterogeneous interspecific interactions in a host-parasite system

Macroparasites of vertebrates usually occur in multi-species communities, producing infections whose outcome in individual hosts or host populations may depend on the dynamics of interactions amongst the different component species. Within a single co-infection, competition can occur between conspecific and heterospecific parasite individuals, either directly or via the host's physiological and immune responses. We studied a natural single-host, multi-parasite model infection system (polystomes in the anuran Xenopus laevis victorianus) in which the parasite species show total interspecific competitive exclusion as adults in host individuals. Multi-species infection experiments indicated that competitive outcomes were dependent on infection species composition and strongly influenced by the intraspecific genetic identity of the interacting organisms. Our results also demonstrate the special importance of temporal heterogeneity (the sequence of infection by different species) in competition and co-existence between parasite species and predict that developmental plasticity in inferior competitors, and the induction of species-specific host resistance, will partition the within-host-individual habitat over time. We emphasise that such local (within-host) context-dependent processes are likely to be a fundamental determinant of population dynamics in multi-species parasite assemblages.     

结核灭活疫苗的临床研究进展

分枝杆菌灭活疫苗(inactivated mycobacterium vaccines)是一种最原始、简单制备方法的产物,但在结核疫苗史上始终拥有一席之地。从早期的旧结核菌素和死卡介苗以及中期唯一的分枝杆菌疫苗,到如今逐个出现的新疫苗,分枝杆菌灭活疫苗仍受到研究者的重视,其用途也从结核病患者的免疫治疗,扩大到潜伏感染人群的预防和卡介苗(Bacillus Calmette-Guérin, BCG)初免后的加强免疫。现就分枝杆菌灭活疫苗的临床研究历史和现状作一综述,为新疫苗的研制提供参考。     

New technologies to study helminth development and host-parasite interactions

How parasites develop and survive, and how they stimulate or modulate host immune responses are important in understanding disease pathology and for the design of new control strategies. Microarray analysis and bulk RNA sequencing have provided a wealth of data on gene expression as parasites develop through different life-cycle stages and on host cell responses to infection. These techniques have enabled gene expression in the whole organism or host tissue to be detailed, but do not take account of the heterogeneity between cells of different types or developmental stages, nor the spatial organisation of these cells. Single-cell RNA-seq (scRNA-seq) adds a new dimension to studying parasite biology and host immunity by enabling gene profiling at the individual cell level. Here we review the application of scRNA-seq to establish gene expression cell atlases for multicellular helminths and to explore the expansion and molecular profile of individual host cell types involved in parasite immunity and tissue repair. Studying host-parasite interactions in vivo is challenging and we conclude this review by briefly discussing the applications of organoids (stem-cell derived mini-tissues) to examine host-parasite interactions at the local level, and as a potential system to study parasite development in vitro. Organoid technology and its applications have developed rapidly, and the elegant studies performed to date support the use of organoids as an alternative in vitro system for research on helminth parasites.