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Despite highly active antiretroviral therapy, active replication persists and drives immune activation in some individuals with HIV. This activation is higher if therapy is intensified by additional antiretroviral drugs (pages 373–374).
HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to antiretroviral therapy. This study shows that some hematopoietic stem cells are latently infected and may therefore constitute such a reservoir.
Programmed death-1 (PD-1) and interleukin-10 (IL-10) impair T cell function during chronic viral infections. Microbial products are now found to inhibit T cell function during HIV infection by upregulating PD-1 and IL-10 production by monocytes.
Kynurenine, a metabolite produced by the action of the enzyme indoleamine 2,3-dioxygenase on tryptophan, accumulates under inflammatory conditions and has immunomodulatory effects. This study by Yutang Wang et al. describes a new function for kynurenine as an endogenous vasodilator under conditions of systemic inflammation, such as malaria infection and endotoxemia in mice, and provides insight into the molecular mechanisms involved (pages 265–267).
Muscle spasticity is a major problem for individuals with SCI. Now, Laurent Vinay and his colleagues report that downregulation of the potassium-chloride cotransporter in spinal cord motor neurons after SCI has a key role in the development of spasticity (pages 270–271).
Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 (pages 268–270 and 324–328).
The concerted action of JNK and Pin1 on viral integrase regulate permissiveness of activated CD4+ T cells to HIV-1 infection, whereas lack of these modifications restricts viral infection in nonactivated lymphocytes.
Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 (pages 268–270 and pages 319–323).
Metastasis is a fatal complication of prostate cancer, but its mechanisms remain largely unknown. In this report, the authors identify a signaling pathway commonly deregulated in human prostate cancer and describe how it can foster both primary growth and metastatic tumor progression. Epigenetic silencing of the RasGAP DAB2IP by EZH2 overexpression results in aberrant activation of Ras signaling, but also of NF-κB. These two events are mediated by different DAB2IP domains and have distinct roles in localized growth and distant dissemination.
Defects in the ion transporter CFTR result in cystic fibrosis, which is marked by excessive mucous buildup in the lungs and colon and premature death. Christopher Glass and his colleagues now show that these aspects of the disease are associated with defects in PPAR-γ signaling in epithelial cells and that a synthetic agonist of this nuclear receptor is sufficient to partially normalize signaling and improve survival of a mouse model (pages 267–268).
The expression of blood group antigens causes deletion of cells that generate self-specific antibodies to those antigens, but this deletion could limit adaptive immunity toward pathogens bearing cognate antigens. Two innate immune lectins, galectin-4 and galectin-8, are now reported to recognize and kill human blood group antigen–expressing bacteria.
Osteoporosis results from misregulation of bone catabolism and bone anabolism, resulting in severe bone loss. Most current therapies act by decreasing bone catabolism, but targeting bone anabolism is more desired, because once bone is lost, it is difficult to replace. In a new report by Gerard Karsenty and his colleagues, they show that orally delivered pharmacological targeting of serotonin synthesis in the gut is sufficient to increase bone anabolism and thus restore lost bone in rat and mouse models of well-established osteoporosis (pages 264–265).
Lukas Flatz et al. have exploited the characteristics of the lymphocytic choriomeningitis virus (LCMV) to create a vaccine vector platform that elicits potent CD8+ T cell immunity. Using a recombinant, replication-defective LCMV, they show that these modified viral vectors target dendritic cells in vivo and trigger cytotoxic T lymphocyte responses that compare favorably with existing vectors. Other benefits include low global seroprevalence to LCMV and minimal interference of preexisting antibodies with vaccine efficacy.
Chikungunya virus (CHIKV) is an emerging infectious agent that can cause severe disease in humans and against which there is presently no vaccine. Akahata et al. now describe their development of a virus-like particle (VLP) vaccine that elicits neutralizing antibodies against CHIKV and can protect nonhuman primates from infection. Their VLP-based approach may facilitate development of a CHIKV vaccine for human use.
Two amplified genes from chromosome 8q22—YWHAZ and LAPTM4B—are associated with metastatic breast cancer recurrence by promoting resistance to anthracyclines. YWHAZ codes for an antiapoptotic protein and LAPTM4B encodes a previously undescribed lysosomal protein.
Transduced hematopoietic stem cells can benefit patients with X-linked chronic granulomatous disease (a genetic immunodeficiency), but it's not risk free. In two treated patients, insertional activation of MDS1–EVI1, PRDM16 and SETBP1 markedly increased the number of transduced cells in the blood, leading to oligoclonal hematopoiesis, monosomy 7 and a myelodysplastic syndrome (pages 163–165).
In β-thalassemia, decreased β-globin synthesis leads to red blood cell loss, iron overload and anemia. Using a mouse model of this disease, Huihui Li et al. now describe a new approach for treating β-thalassemia: injection of the iron transporter transferrin. This therapy had many beneficial effects, including reversing splenomegaly and raising red blood cell counts.
Angiotensin II contracts blood vessels and has been implicated as a causative factor in hypertension. Christophe Guilluy et al. now demonstrate that the guanine exchange factor Arghef1 is required for the hypertensive effects of angiotensin II in mice, and describe a new signaling pathway by which angiotensin II triggers Jak2-dependent activation of Arghef1 to cause smooth muscle cell contraction (pages 165–166).
Jeffrey Weiser and his colleagues provide a mechanism for a beneficial effect from commensal bacteria that colonize the gut. They show that peptidoglycan from gut microbiota traverses the gut mucosa and boosts the systemic innate immune response by priming neutrophils in the bone marrow. Such priming requires the recognition of peptidoglycan by the intracellular receptor Nod-1 (pages 160–161).
Smallpox was eradicated by vaccination with a related poxvirus, vaccinia virus, which was applied to superficially injured skin in a process called scarification. Recombinant poxvirus–based vaccines are attractive candidates for protecting against a number of different infections, but they are nowadays usually administered intramuscularly. Thomas Kupper and his colleagues now show that the traditional route of administration, scarification, enables poxvirus-based vaccines to mediate more potent immunity compared with the intramuscular route. In particular, scarification with the poxvirus vaccines induced the sort of immune responses that are required for protection of distant tissues, including the lung mucosa.