What they are, how they work and why they do what they do? The story of SV40-derived gene therapy vectors and what they have to offer

The natural function of viruses is to deliver their genetic material to cells. Among the most effective of viruses in doing that is Simian Virus-40 (SV40). The properties that make SV40 a successful virus make it an attractive candidate for use as a gene delivery vehicle: high titer replication, infectivity for almost all nucleated cell types whether the cells are dividing or resting, potential for integration into cellular DNA, a peculiar pathway for entering cells that bypasses the cells' antigen processing apparatus, very high stability, and the apparent ability to activate expression of its own capsid genes in trans. Exploiting these and other characteristics of wild type (wt) SV40, increasing numbers of laboratories are studying recombinant (r) SV40-derived vectors. Among the uses to which these vectors have been applied are: delivering therapy to inhibit HIV, hepatitis C virus (HCV) and other viruses; correction of inherited hepatic and other protein deficiencies; immunizing against lentiviral and other antigens; treatment of inherited and acquired diseases of the central nervous system; protecting the lung and other organs from free radical-induced injury; and many others. The effectiveness of these vectors is a reflection of the adaptive evolution that produced their parent virus, wt SV40. This article explores how and why these vectors work, their strengths and their limitations, and provides a functional model for their exploitation for experimental and clinical applications.     

Social support interventions: do they work?

Presence of support has repeatedly been linked to good long-term health outcomes based on demonstrations of better immune function, lower blood pressures, and reduced mortality (among others). Despite a massive literature on the benefits of support, there is surprisingly little hard evidence about how, and how well, social support interventions work. Using a computerized search strategy, 100 studies that evaluated the efficacy of such interventions were located. The presenting problems ranged from cancer, loneliness, weight loss, and substance abuse to lack in parenting skills, surgery, and birth preparation. For the purpose of review and evaluation, studies were subdivided into (1) group vs. individual interventions, (2) professionally led vs. peer-provided treatment, and (3) interventions where an increase of network size or perceived support was the primary target vs. those where building social skills (to facilitate support creation) was the focus. On the whole, this review provided some support for the overall usefulness of social support interventions. However, because of the large variety of existing different treatment protocols and areas of application, there is still not enough evidence to conclude which interventions work best for what problems. Specific methodological and conceptual difficulties that plague this area of research and directions for future research are discussed.     

Psychotherapists who abstain from personal therapy: do they practice what they preach?

The authors examined the attitudes and reasons of 119 American psychologists, counselors, and clinical social workers who had never sought personal therapy. Nontherapy seekers, compared to therapy seekers, expressed less-positive attitudes toward its value as a prerequisite for clinical work and for ongoing professional development. Women, men, and members of all three professions were equally likely to have sought therapy, but cognitive-behavioral therapists and academics were significantly less likely to do so. Top reasons for not undergoing personal therapy entailed dealing with stress in other ways, receiving sufficient support from friends and family, believing coping strategies were effective, and resolving the problem before therapy was needed. The likelihood of seeking personal treatment in the future as well as reasons for doing so are discussed.     

The cysteinyl leukotrienes: where do they come from? What are they? Where are they going?

Cysteinyl leukotrienes are established mediators of bronchial asthma and have agonist roles analogous to those of histamine in allergic rhinitis. We now know that the substance originally termed slow-reacting substance of anaphylaxis was composed of three cysteinyl leukotrienes that act in the inflammatory response via receptors on smooth muscle and on bone marrow-derived inflammatory cells. K. Frank Austen describes the work culminating in the identification, biosynthesis and functional characterization of these moieties.     

Leukemic stem cells: Where do they come from?

Leukemias can now be viewed as aberrant hematopoietic processes initiated by rare cancer stem cells, or leukemic stem cells (LSCs) that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSCs and the mechanisms responsible for their emergence in the course of the disease. Mouse models of human leukemias have provided a unique system to study the mechanisms influencing LSC generation and function, and were recently used to demonstrate that LSCs can arise from both self-renewing hematopoietic stem cells (HSCs) and committed progenitor populations. This striking finding indicates that LSC identity is largely dictated by the nature of the oncogenic events and by how these events perturb essential processes such as self-renewal, proliferation, differentiation, and survival. Such approaches in the mouse are essential for the basic understanding of leukemogenesis and for the conceptual design of novel therapeutic strategies that could lead to improved treatments for human leukemias.     

Manic symptoms in psychiatrically hospitalized children--what do they mean?

OBJECTIVE: To examine the clinical implications of manic symptoms in psychiatrically hospitalized children aged 5-12. METHODS: DSMIIIR manic symptoms, along with symptoms of other psychiatric disorders, were rated by parents and teachers on the Child Symptom Inventory IIIR prior to hospitalization. The Child Behavior Checklist (CBCL; was also completed. During hospitalization children were evaluated by structured interview (K-SADS-E), and numerous rating scales weekly. Children with symptoms of mania (mania criteria with/without episodes) were compared to those without mania. Severity of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), depression, CBCL factors, and comparable factors from teacher and parent inpatient rating scales were examined. Finally, a subgroup of both groups of children treated with stimulants were compared at baseline and at least two weeks of treatment. RESULTS: Children with manic symptoms had more severe ADHD, ODD and depression symptoms. CBCL scores on aggression, social and thought problems were higher. Teachers and nursing staff made similar observations. Time in hospital was greater for children with manic symptoms. Both groups improved significantly on stimulant medication though reduction in overall psychopathology was often modest. CONCLUSIONS: Manic symptoms, regardless of whether or not they represent bipolar disorder, are a marker of serious psychopathology and treatment resistance.     

HIV controllers: how do they tame the virus?

HIV controllers are rare, chronically HIV-1-infected patients in whom viral replication is undetectable in the absence of antiretroviral treatment. Most such patients are nonetheless infected by replication-competent viruses. An effective, multifunctional HIV-specific CD8(+) T-cell response is thought to be central to viral control in these individuals. The mechanisms underlying this spontaneous control of HIV infection and the particular characteristics of the CD8(+) T-cell response in HIV controllers are the focus of intensive investigations, because they should help to unravel the pathogenesis of AIDS and to provide new clues for the design of effective vaccine strategies. In this review, we examine recent findings from these studies.     

Workplace irritant exposures: do they produce true occupational asthma?

The recognition that irritant exposures can cause asthma is not new. Many investigators turn towards the gassings of soldiers in World War I as the first examples of this, while Brooks, in 1985, reported this in detail in workers and called it 'Reactive Airways Dysfunction Syndrome (RADS)'. There is considerable overlap with RADS and occupational asthma as both share respiratory symptoms which can be described as 'asthmatic', yet RADS is the result of an acute excessive exposure, while occupational asthma occurs due to a series of sensitizing exposures. Yet, a clear understanding of RADS has been limited by the lack of epidemiologic studies; rather the disease has been described by case series. This report contrasts RADS and occupational asthma and finds that although there may be some difference in lung pathology, reports for the past years since Brooks' initial reports have shown that the line separating occupational asthma and RADS has become increasingly blurred, rather than increasingly distinct, with considerable overlap in the clinical symptoms with the perspective that these described entities are a part of a continuum. Perhaps the development of animal models for RADS may hasten further understanding.     

Staphylococcal superantigens: do they play a role in sepsis?

In Staphylococcus aureus, 19 different superantigens (SAgs) have been described. Their genes are all located on mobile genetic elements, such as pathogenicity islands, plasmids, and phages. SAgs bypass conventional antigen recognition by directly cross-linking major histocompatibility complex class II (MHCII) molecules on antigen-presenting cells with T cell receptors. This leads to massive T cell proliferation and cytokine release, which may end in toxic shock syndrome. The role of SAgs in other forms of sepsis is less well defined. In animal models, SAgs and lipopolysaccharide (LPS) very efficiently synergize in the induction of lethal shock, and on the basis of these observations a two-hit model of sepsis has been proposed: LPS or another monocyte stimulus hits first, then SAg or another T cell stimulus hits. In clinical studies, however, evidence for an involvement of SAgs in sepsis has been difficult to obtain. This may have a number of reasons: differences between humans and rodents in their response to LPS and SAg, heterogeneity of SAg combinations in S.aureus clinical isolates, lack of tools to analyze SAg effects in patients, blocking anti-SAg serum antibodies, and MHCII polymorphisms.     

Surrogate endpoints: do they really contribute in therapeutic decision making?

Surrogate endpoints are substitutes for the true endpoints and measured in any clinical research to relate in some way to the outcome of primary interest. Inappropriate selection of surrogate markers may lead to controversies during clinical trials or therapeutic interventions. Use of surrogate markers depends upon thorough understanding of the pathophysiology of the disease and pharmacology of drugs. Results obtained with surrogates should be regarded as preliminary and necessitates definitive studies.     

Avian and simian malaria: do they have a cancer connection?

It has been claimed that infectious agents transmitted by mosquitoes (Diptera: Culicidae) may have a greater connection to cancer then hitherto supposed and that the immune system struggles to recognize and fight some of these infectious agents. One of the claims made is that there is a connection between human malaria and brain cancers in the USA. However, the USA declared itself free of human malaria in the last century, yet cancer incidences remain high, suggesting any overall cancer connection is slight. Two fundamental questions arise from the possible mosquito-cancer connection. Firstly, if mosquitoes are able to vector some pathogens and parasites linked with cancer pathogenesis, why has the fact not been discovered decades ago? Secondly, if there is a connection (other than in relation to Burkett’s lymphoma), what is its extent? The answers may well lie with the various types of malarias known to exist. The discovery in humans of the simian malaria, caused by Plasmodium knowlesi, suggests that other forms of simian or even avian malaria may be capable of survival in humans, albeit at low levels of parasitemia, and humans may be a dead-end host. Other carcinogenic infectious agents transmitted by mosquitoes may also go undetected because either no one is looking for them, or they are looking in wrong anatomical locations and/or with inadequate tools. Research on false negative test results with respect to many infectious agents is sadly lacking, so its extent is unknown. However, electronic and other media provide numerous instances of patients failing to be diagnosed for both human malaria and Lyme’s disease, to take just two examples. This review suggests that to shed light on a potential mosquito-cancer connection, more research is required to establish whether other simian and avian forms of malaria play a part. If so, then they potentially provide unique markers for early cancer detection.