Volume 15 Issue 8, August 2009

James Ironside, professor of clinical neuropathology at the University of Edinburgh, was recently appointed as the director of the new UK Brain Banks Network. Jon Evans recently caught up with Ironside to discuss his new leadership position and how the brain network will benefit neuroscience research.

The bacterium that causes stomach ulcers and deadly gastric cancer, Helicobacter pylori, is disappearing in many developed countries. Many physicians see this as cause for celebration. But at least one researcher thinks the bacterium is more than just a pathogen. Cassandra Willyard investigates whether H. pylori may be preventing diseases as well as causing them.

Two studies suggest that low levels of antibodies, when present continuously, effectively limit or prevent HIV infection (pages 951–954 and 901–906). The findings provide hope for the development of a vaccine.

Mammary epithelial cell development is thought to progress from undifferentiated stem cells into at least two differentiated cell types. A new study has now characterized some of these distinct developmental stages and links them to tumor subtypes previously defined by gene expression profiling (pages 907–913).

Inflammation in neural tissue has long been suspected to have a role in stroke. A new study in mouse models of focal cerebral ischemia suggest that a stereotyped sequence of T cell infiltration and activation may underlie the progression of brain injury that can last up to days after stroke onset (pages 946–950).

Obesity generates a proinflammatory environment in adipose tissue, but the factors that initiate this inflammatory cascade have been unclear. Three studies now show that alterations in the composition of adipose tissue T cells occur early in obesity and shape the relationship between immunity and metabolism (pages 914–920, 921–929 and 930–939).

Genetic approaches in animal models have recently led to new ways of thinking about inherited neuropsychiatric disorders. Many such disorders were thought to originate during early development, but newer findings have suggested that processes in the adult nervous system also contribute. Dan Ehninger and Alcino J. Silva outline how such events in the adult may be amenable to therapy, including some approaches in clinical trials. In Bedside to Bench, Petrus de Vries questions the utility of genome-wide association studies for autism spectrum disorders and other neuropsychiatric conditions.

What are the most important questions that the HIV field needs to answer to make progress? Nature Medicine asked this question to a group of HIV researchers to identify some of the key roadblocks in HIV research.

There are three established HIV-1 lineages, M, N and O, which arose after cross-species transmission of simian immunodeficiency virus circulating in chimpanzees. An unusual variant of HIV-1 has now been identified that seems to be the prototype of a new lineage derived from gorillas.

The phase 2b trial of Merck's recombinant adenovirus type 5–based HIV-1 vaccine was halted as the vaccine seemed to have increased HIV-1 acquisition in vaccine recipients who had preexisting immunity to the adenovirus vector. One theory to explain these results is that the preexisting antibody response to the vector may have been a surrogate for increased vector-specific CD4⁺ T cells, which would have been amplified after vaccination and may have served as increased target cells during subsequent HIV-1 exposure. Daniel Barouch and his colleagues and Michael Betts and his colleagues now challenge this view.

The phase 2b trial of Merck's recombinant adenovirus type 5-based HIV-1 vaccine was halted as the vaccine seemed to have increased HIV-1 acquisition in vaccine recipients who had preexisting immunity to the adenovirus vector. One theory to explain these results is that the preexisting antibody response to the vector may have been a surrogate for increased vector-specific CD4⁺ T cells, which would have been amplified after vaccination and may have served as increased target cells during subsequent HIV-1 exposure. Daniel Barouch and his colleagues and Michael Betts and his colleagues now challenge this view.

Natural hosts of simian immunodeficiency virus (SIV)—such as African green monkeys—have evolved to tolerate SIV infection without developing immune deficiency. Jason Brenchley and his colleagues provide a mechanism. They show that CD4⁺ T cells from these animals downregulate the CD4 receptor upon entering the memory pool. Immune functions normally attributed to CD4⁺ T cells are preserved, but the cells become resistant to SIV infection.

Infection with HSV-2 increases the likelihood of HIV acquisition, but suppression of HSV-2 reactivation with antiviral drugs does not seem to reduce the acquisition of HIV. Laurence Corey and colleagues provide a potential mechanism underlying this observation, showing that even after acyclovir treatment for the HSV-2 infection, many inflammatory and immune cells possessing the receptors required for HIV infection persist in the mucosa, making the initial 'spark' of infection more likely.

Highly active antiretroviral therapy is unable to eliminate HIV infection, because the virus persists in latently infected CD4⁺ T cells—a so-called virus reservoir. Rafick-Pierre Sekaly and his colleagues have shown that central memory CD4⁺ T cells and transitional memory CD4⁺ T cells are the main cellular reservoirs for HIV, and they suggest a mechanism that ensures the stability of this reservoir of virus.

Antibodies capable of neutralizing a wide array of HIV isolates are rarely elicited by the adaptive immune response during HIV infection, and it is not known how to elicit such protective antibodies by vaccination. Philip Johnson and his colleagues have circumvented this hurdle through gene transfer technology. They show that it is possible to protect monkeys from SIV infection by administering intramuscular injections of adeno-associated virus vectors that express broadly neutralizing antibodies that can access the circulation (841–842 pages 951–954).

Contrary to the belief that basal-like breast cancers develop from mammary stem cells in BRCA1 mutation carriers, an aberrant luminal progenitor population might be the target for transformation in basal tumors in these individuals (pages 842–844).

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes (pages 846–847, 921–929 and 930–939).

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes (pages 846–847, 914–920 and 930–939).

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes (pages 846–847, 914–920 and 921–929).

Mast cells, which are involved in inflammation and wound healing, have now been shown to have a role in obesity and diabetes in a new report by Guo-Ping Shi and his colleagues. They go on to show that pharmacological inhibition of mast cell function is sufficient to reduce these metabolic disturbances in mice, suggesting a new therapeutic avenue in the clinic for these disorders.

Inflammatory cells invade the brain after stroke, but their role in disease has been unclear. Now, Akihiko Yoshimura and colleagues report that a particular population of T cells that express the inflammatory cytokine IL-17 plays a key role in stroke progression: depletion of these cells—even as late as 1 day after stroke—can alleviate brain injury in mice pages 844–846).

Studies in macaques have shown that neutralizing antibodies can offer robust protection from infection with a simian counterpart of HIV, yet these studies have also suggested that high concentrations of antibodies are required for efficient protection. Unfortunately, it's not generally thought to be feasible to elicit such high neutralizing antibody titers by vaccination. Dennis Burton and his colleagues now show that lower concentrations of antibodies can offer protection to macaques if a repeated low-dose challenge model is used—a model that may better recapitulate the acquisition of infection in humans.

Women seem to progress to AIDS more rapidly than men after HIV-1 infection. Marcus Altfeld and his colleagues show that, after adjusting for viral load, HIV-1–infected women have higher levels of immune activation, and the authors provide a potential mechanism to account for this difference between the sexes.

Although the TGF-β signaling pathway has been implicated in breast cancer metastasis, studies are hampered by a lack of animal models for in vivo analysis of metastasis signaling pathways. Here a noninvasive xenograft model is described that uses a dual bioluminescence reporter system to study TGF-β signaling in bone metastasis. Disruption of TGF-β signaling in early—not late—stage metastasis is shown to markedly reduce bone metastasis burden.

Caspases are intracellular proteases and key initiators and effectors of apoptosis. Here the authors describe fluorescently labeled activity-based probes that allow the noninvasive in vivo monitoring of the kinetics of caspase activity. Approaches to optimize the probes to enhance their specificity and increase uptake into apoptotic cells are outlined, and their use in tracking the early stages of apoptosis in two mouse models (dexamethasone and the monoclonal antibody Apomab) is demonstrated.