Hot off the presses! Aug 01 Nat Med

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Latest Articles Include:

• Back to basics
  - Nat Med 15(8):821 (2009)
  Basic HIV research has, over the past two decades, brought about enormous advances that have transformed a fatal disease into a manageable illness. HIV vaccine research has suffered more setbacks than successes, but a renewed focus on fundamental questions about HIV pathogenesis will provide new glimmers of hope.
• Trauma trials kick off, putting patient consent rules in focus
  - Nat Med 15(8):823 (2009)
  In early July, paramedics in some US metropolitan areas began packing a new piece of equipment: an EpiPen-like injector that will deliver an experimental dose of anticonvulsant medication.The injected medication, if shown to be effective, could dramatically improve immediate care for people suffering from sustained, life-threatening seizures.
• Dismissal of bioethics council leads to speculation about its future
  - Nat Med 15(8):824 (2009)
  US President Barack Obama abruptly dissolved the President's Council on Bioethics in late June, with one day's written notice to members stating that their services were no longer needed. With its two-year term having been scheduled to end in September, the Council was set to meet one more time.
• Sequencing push brings new UK genome analysis center
  - Nat Med 15(8):824 (2009)
  Last month, DNA sequencing in the UK got a boost with the launch of the Genome Analysis Centre (TGAC) in the eastern city of Norwich. The £13.
• Cancer meeting in Germany highlights need for national registry
  - Nat Med 15(8):825 (2009)
  Germany has high hopes for improving care for cancer patients across the country. But at a recent medical meeting, it became clear that the country needs to radically improve its cancer registries to track and promote progress in this area.
• Gaps in genetic antidiscrimination law spur state action
  - Nat Med 15(8):826 (2009)
  Just over a year ago, advocates celebrated the signing of a landmark piece of legislation barring health insurers and employers from discriminating against people on the basis of their genetic information.The Genetic Information Nondiscrimination Act (GINA), signed into law by US President George W.
• Production of radioactive isotopes proves problematic
  - Nat Med 15(8):826 (2009)
  Australia's Open Pool Australian Lightwater (OPAL) research reactor has the potential to "make a real difference" in the effort to deal with the global shortage of radioactive isotopes used for medical research and testing, according to Michael Graham, president of the international Society of Nuclear Medicine.Sustained global supply of medical isotopes is in long-term jeopardy as a result of problems with two reactors that have typically provided more than half the world's medical isotopes: Canada's Chalk River reactor and the Netherlands' Petten rector.
• Patients see proposed FDA opioid rules as painfully restrictive
  - Nat Med 15(8):827 (2009)
  When treating patients suffering from severe pain, doctors are often reluctant to recommend opioids, the most potent analgesics, because of federal scrutiny of prescribing practices and fear of addiction. Now, a new trifecta of initiatives by the US Food and Drug Administration (FDA) could make patients' access to oral opiates, such as morphine, fentanyl and oxycodone, and effective pain relief even more difficult.
• NIH stem cell rules expand funding
  - Nat Med 15(8):827 (2009)
  Four months after an executive order from US President Barack Obama, stem cell funding guidelines issued by the US National Institutes of Health (NIH) trulyended the 2001 restriction limiting federal funding to research involving just 21 usable human embryonic stem cell lines.The rules, which went into effect on 7 July, call for a registry of fundable lines.
• From cells, secrets of the secretome leak out
  - Nat Med 15(8):828 (2009)
  Cells talk to each other, and understanding their language could spawn new therapies. "Scientists have known for years that there are intertissue communications, but now we can pick up more of the factors released, such as the hundreds of factors secreted from skeletal muscle," says Matthew Watt, associate professor of physiology at Monash University in Victoria, Australia.
• Experts applaud policy overhaul of US AIDS relief program
  - Nat Med 15(8):829 (2009)
  Since its inception in 2003, the United States President's Emergency Plan for AIDS Relief—PEPFAR—has spent $18.8 billion curbing the HIV epidemic in developing countries.
• Rectal microbicides in development
  - Nat Med 15(8):829 (2009)
  Despite some disappointing results from recent trials, microbicides have been touted as a potential tool to stop HIV infection through vaginal sex. Last month, however, the International AIDS Society conference in Cape Town, South Africa dedicated an entire session to rectal microbicides for the first time.
• AIDS advocates and doctors brace for impact of lost funding
  - Nat Med 15(8):830 (2009)
  "Now is not the time to falter," UN Secretary-General Ban Ki-moon announced at a UN General Assembly meeting on 16 June. He was referring to global commitments in the fight against HIV, which he worries might be suffering as a result of the current economic situation.
• HIV gender clues emerge
  - Nat Med 15(8):830 (2009)
  Women with untreated HIV tend to develop AIDS faster than HIV-infected men. Now, a new study provides insights as to why: women infected with the virus produce more immune-stimulating protein than infected men do.
• Expanded HIV testing planned, but some remain less than positive
  - Nat Med 15(8):831 (2009)
  With the AIDS pandemic going strong and the prospects of a successful HIV vaccine uncertain, public health experts and advocacy groups are considering a new strategy that some claim could end the pandemic within 50 years.The plan, which calls for universal annual testing followed immediately with antiretroviral therapy in infected individuals, could cut new HIV cases by an estimated 95% within a decade, according to a mathematical model used by the World Health Organization (WHO) (Lancet 373, 48–57; 2009).
• US moves on controversial travel ban
  - Nat Med 15(8):831 (2009)
  For the first time in decades, HIV-positive individuals from other countries may soon be able to set foot on US soil. The nation's Department of Health and Human Services (HHS) is weighing comments on a proposal it released in early July to reverse the law that has prevented people with HIV from entering the US since 1987—a law that patient advocates have for years argued is counterproductive.
• News in brief
  - Nat Med 15(8):832-833 (2009)
  Jun 12A survey of more than 700 people revealed public ignorance of anatomy: when shown pictures of the human body, only 45% of respondents correctly identified the location of the heart, and nearly 70% misidentified the position of the lungs (BMC Fam. Pract. 10, 43; 2009
• Straight talk with...James Ironside
  - Nat Med 15(8):834-835 (2009)
  Would you entrust your brain to a bank? Well, many people do after they die, and such brain banks—often funded by government agencies or disease charities—are essential for neuroscience research. They collect and store the healthy and diseased brain specimens that neuroscientists need to explore neurological disorders such as Alzheimer's disease, schizophrenia and autism. Each brain bank typically has a limited supply of samples and tends to operate fairly independently. This means that researchers often have to trawl through numerous brain banks to find their desired specimens. Furthermore, there is a general shortage of brain samples. To help resolve these issues in the UK, James Ironside, professor of clinical neuropathology at the University of Edinburgh, was appointed in June as the director of the new UK Brain Banks Network. An expert in human prion diseases, particularly Creutzfeldt-Jakob disease (CJD), Ironside knows all about brain banks. He established the Brain and Tissue Bank at the UK's National CJD Surveillance Unit and is involved in the Sudden Death Brain and Tissue Bank at the University of Edinburgh. Jon Evans recently caught up with Ironside to discuss his new leadership position and how the brain network will benefit neuroscience research.
• A tough controversy to stomach
  - Nat Med 15(8):836-839 (2009)
  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.
• The case for medical marijuana
  - Nat Med 15(8):840 (2009)
  In 1996, a group of chronically and terminally ill patients in Santa Cruz, California, gave up on prescription medications and started using marijuana as a way to control the seizures, pain and depression caused by their conditions. They had varying personal experiences with the drug—some were old hippies, whereas others had never smoked pot before—but what brought them together was the conviction that marijuana, unlike other drugs, made their lives more livable.
• Blocking and tackling HIV
  - Nat Med 15(8):841-842 (2009)
  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 development meets cancer genomics
  - Nat Med 15(8):842-844 (2009)
  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).
• T time in the brain
  - Nat Med 15(8):844-846 (2009)
  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).
• T-ing up inflammation in fat
  - Nat Med 15(8):846-847 (2009)
  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).
• An earlier start for HIV therapy
  - Nat Med 15(8):848 (2009)
  Three recent studies1, 2, 3 bolster the argument for initiating antiretroviral therapy for HIV infection earlier than previously thought. Such arguments have been brewing for a while now, say three experts.
• Genetics and neuropsychiatric disorders: Treatment during adulthood
  - Nat Med 15(8):849-850 (2009)
  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.
• Genetics and neuropsychiatric disorders: Genome-wide, yet narrow
  - Nat Med 15(8):850-851 (2009)
  A genetics consortium recently reported the first positive genome-wide association study (GWAS) of autism. The findings suggest that there may be a common genetic variant associated with autism on chromosome 5p14.
• Research Highlights
  - Nat Med 15(8):852-853 (2009)
  
• Roadblocks in HIV research: five questions
  - Nat Med 15(8):855-859 (2009)
  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.
• Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts
  - Nat Med 15(8):861-865 (2009)
  The design of an effective AIDS vaccine has eluded the efforts of the scientific community to the point that alternative approaches to classic vaccine formulations have to be considered. We propose here that HIV vaccine research could greatly benefit from the study of natural simian immunodeficiency virus (SIV) infections of African nonhuman primates. Natural SIV hosts (for example, sooty mangabeys, African green monkeys and mandrills) share many features of HIV infection of humans; however, they usually do not develop immunodeficiency. These natural, nonprogressive SIV infections represent an evolutionary adaptation that allows a peaceful coexistence of primate lentiviruses and the host immune system. This adaptation does not result in reduced viral replication but, rather, involves phenotypic changes to CD4+ T cell subsets, limited immune activation and preserved mucosal immunity, all of which contribute to the avoidance of disease progression and, possibly, to the r! eduction of vertical SIV transmission. Here we summarize the current understanding of SIV infection of African nonhuman primates and discuss how unraveling these evolutionary adaptations may provide clues for new vaccine designs that might induce effective immune responses without the harmful consequences of excessive immune activation.
• A new human immunodeficiency virus derived from gorillas
  Plantier JC Leoz M Dickerson JE De Oliveira F Cordonnier F Lemée V Damond F Robertson DL Simon F - Nat Med 15(8):871-872 (2009)
  We have identified a new human immunodeficiency virus in a Cameroonian woman. It is closely related to gorilla simian immunodeficiency virus (SIVgor) and shows no evidence of recombination with other HIV-1 lineages. This new virus seems to be the prototype of a new HIV-1 lineage that is distinct from HIV-1 groups M, N and O. We propose to designate it HIV-1 group P.
• Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans
  - Nat Med 15(8):873-875 (2009)
  The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study.
• Baseline Ad5 serostatus does not predict Ad5 HIV vaccine–induced expansion of adenovirus-specific CD4+ T cells
  - Nat Med 15(8):876-878 (2009)
  The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5–HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4+ T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4+ T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4+ T cells in increasing HIV-1 susceptibility in the STEP trial.
• CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection
  - Nat Med 15(8):879-885 (2009)
  African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4+ T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4- memory T cells maintain functions that are normally attributed to CD4+ T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4- T cells can mainta! in major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4+ T cell function while being resistant to SIV infection in vivo.
• Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition
  - Nat Med 15(8):886-892 (2009)
  To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4+ and CD8+ T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4+ T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor–positive inflammat! ory cells in the genitalia help explain the inability of anti–HSV-2 therapy to reduce HIV acquisition.
• HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation
  - Nat Med 15(8):893-900 (2009)
  HIV persists in a reservoir of latently infected CD4+ T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (TCM) and transitional memory (TTM) CD4+ T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in TCM cells in subjects showing reconstitution of the CD4+ compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in TTM cells from aviremic individuals with low CD4+ counts and higher amounts of interleukin-7–mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that i! nterfere with the self renewal and persistence of proliferating memory T cells.
• Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys
  - Nat Med 15(8):901-906 (2009)
  The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV va! ccine.
• Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers
  - Nat Med 15(8):907-913 (2009)
  Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell–enriched population. The c-KIT tyrosine kinase recept! or (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
• CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity
  Nishimura S Manabe I Nagasaki M Eto K Yamashita H Ohsugi M Otsu M Hara K Ueki K Sugiura S Yoshimura K Kadowaki T Nagai R - Nat Med 15(8):914-920 (2009)
  Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8+ effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4+ helper and regulatory T cells were diminished. The infiltration by CD8+ T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8+ T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8+ T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions b! etween CD8+ T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8+ T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation.
• Normalization of obesity-associated insulin resistance through immunotherapy
  Winer S Chan Y Paltser G Truong D Tsui H Bahrami J Dorfman R Wang Y Zielenski J Mastronardi F Maezawa Y Drucker DJ Engleman E Winer D Dosch HM - Nat Med 15(8):921-929 (2009)
  Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4+ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon- (IFN-)-secreting T helper type 1 (TH1) cells, overwhelming static numbers of TH2 (CD4+GATA-binding protein-3 (GATA-3)+) and regulatory forkhead box P3 (Foxp3)+ T cells. CD4+ (but not CD8+) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through TH2 cells. In o! bese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')2 fragment, reduces the predominance of TH1 cells over Foxp3+ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4+ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.
• Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters
  Feuerer M Herrero L Cipolletta D Naaz A Wong J Nayer A Lee J Goldfine AB Benoist C Shoelson S Mathis D - Nat Med 15(8):930-939 (2009)
  Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4+ Foxp3+ T regulatory (Treg) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these Treg cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties o! f Treg cells to inhibit elements of the metabolic syndrome may have therapeutic potential.
• Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice
  Liu J Divoux A Sun J Zhang J Clément K Glickman JN Sukhova GK Wolters PJ Du J Gorgun CZ Doria A Libby P Blumberg RS Kahn BB Hotamisligil GS Shi GP - Nat Med 15(8):940-945 (2009)
  Although mast cell functions have classically been related to allergic responses1, 2, 3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer4, 5, 6, 7, 8. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experim! ents of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon- (IFN-), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.
• Pivotal role of cerebral interleukin-17–producing T cells in the delayed phase of ischemic brain injury
  - Nat Med 15(8):946-950 (2009)
  Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delay! ed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that T lymphocytes, but not CD4+ helper T cells, were a major source of IL-17. Moreover, depletion of T lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including T lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.
• Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques
  - Nat Med 15(8):951-954 (2009)
  Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required1. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus2, 3, 4. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus–HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function–deficient variant of the neutralizing antibody ! was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody–treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.
• Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1
  - Nat Med 15(8):955-959 (2009)
  Manifestations of viral infections can differ between women and men1, and marked sex differences have been described in the course of HIV-1 disease. HIV-1–infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men2, 3, 4, 5, 6, 7. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon- (IFN-) in response to HIV-1–encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral lo! ad and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1–associated pathology.
• Imaging transforming growth factor- signaling dynamics and therapeutic response in breast cancer bone metastasis
  - Nat Med 15(8):960-966 (2009)
  Although the transforming growth factor- (TGF-) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-–SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF- signaling activity in vivo. Strong TGF- signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-–SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF- signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF- signaling provides a proof of principle for using similar strategies to analyze the in vivo dynami! cs of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.
• Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes
  - Nat Med 15(8):967-973 (2009)
  Imaging agents that enable direct visualization and quantification of apoptosis in vivo have great potential value for monitoring chemotherapeutic response as well as for early diagnosis and disease monitoring. We describe here the development of fluorescently labeled activity-based probes (ABPs) that covalently label active caspases in vivo. We used these probes to monitor apoptosis in the thymi of mice treated with dexamethasone as well as in tumor-bearing mice treated with the apoptosis-inducing monoclonal antibody Apomab (Genentech). Caspase ABPs provided direct readouts of the kinetics of apoptosis in live mice, whole organs and tissue extracts. The probes produced a maximum fluorescent signal that could be monitored noninvasively and that coincided with the peak in caspase activity, as measured by gel analysis. Overall, these studies demonstrate that caspase-specific ABPs have the potential to be used for noninvasive imaging of apoptosis in both preclinical and c! linical settings.