Nature Medicine

HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs.

Publication Date: 2010 Mar 7 PMID: 20208541
Authors: Carter, C. C. - Onafuwa-Nuga, A. - McNamara, L. A. - Riddell, J. 4th - Bixby, D. - Savona, M. R. - Collins, K. L.
Journal: Nat Med

HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

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Programmed death-1-induced interleukin-10 production by monocytes impairs CD4(+) T cell activation during HIV infection.

Publication Date: 2010 Mar 7 PMID: 20208540
Authors: Said, E. A. - Dupuy, F. P. - Trautmann, L. - Zhang, Y. - Shi, Y. - El-Far, M. - Hill, B. J. - Noto, A. - Ancuta, P. - Peretz, Y. - Fonseca, S. G. - Van Grevenynghe, J. - Boulassel, M. R. - Bruneau, J. - Shoukry, N. H. - Routy, J. P. - Douek, D. C. - Haddad, E. K. - Sekaly, R. P.
Journal: Nat Med

Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4(+) T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4(+) T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.

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Research highlights.

Publication Date: 2010 Mar PMID: 20208516
Authors:
Journal: Nat Med

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Asthma and allergy: The early beginnings.

Publication Date: 2010 Mar PMID: 20208515
Authors: Hawrylowicz, C. - Ryanna, K.
Journal: Nat Med

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Asthma and allergy: The emerging epithelium.

Publication Date: 2010 Mar PMID: 20208514
Authors: Lloyd, C. M. - Saglani, S.
Journal: Nat Med

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New drugs may improve, complicate treatment for multiple sclerosis.

Publication Date: 2010 Mar PMID: 20208513
Authors:
Journal: Nat Med

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Spasticity: a switch from inhibition to excitation.

Publication Date: 2010 Mar PMID: 20208512
Authors: Edgerton, V. R. - Roy, R. R.
Journal: Nat Med

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HIV vaccines: mosaic approach to virus diversity.

Publication Date: 2010 Mar PMID: 20208511
Authors: Corey, L. - McElrath, M. J.
Journal: Nat Med

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Lipids control mucus production in cystic fibrosis.

Publication Date: 2010 Mar PMID: 20208510
Authors: Gulbins, E.
Journal: Nat Med

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Ido brings down the pressure in systemic inflammation.

Publication Date: 2010 Mar PMID: 20208509
Authors: Hofmann, F.
Journal: Nat Med

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Rebuilding Humpty Dumpty with a serotonin inhibitor.

Publication Date: 2010 Mar PMID: 20208508
Authors: Seeman, E.
Journal: Nat Med

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A sweet target for innate immunity.

Publication Date: 2010 Mar PMID: 20208507
Authors: Liu, F. T. - Bevins, C. L.
Journal: Nat Med

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Globalizing pharmaceutical trials.

Publication Date: 2010 Mar PMID: 20208506
Authors: Annas, G. J.
Journal: Nat Med

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Straight talk with...Shlomo Yanai.

Publication Date: 2010 Mar PMID: 20208505
Authors: Watzman, H.
Journal: Nat Med

Shlomo Yanai has led the world's largest generic drug manufacturer, Teva Pharmaceutical Industries, as its chief executive officer since March 2007. Last year-barely his third in pharmaceuticals and his sixth in business-he was named the world's most influential pharma CEO by World Pharmaceutical Frontiers and Israel's top business executive by the Tel Aviv financial newspaper Calcalist. A twice-wounded veteran of the Yom Kippur War of 1973, Yanai served in the Israel Defense Forces for 32 years. This interview was conducted in Hebrew by Haim Watzman, who also translated the discussion into English.

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An apt approach.

Publication Date: 2010 Mar PMID: 20208504
Authors: Dove, A.
Journal: Nat Med

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The knockout rat pack.

Publication Date: 2010 Mar PMID: 20208503
Authors: Dolgin, E.
Journal: Nat Med

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News in brief.

Publication Date: 2010 Mar PMID: 20208502
Authors:
Journal: Nat Med

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Pharma sets its sights on secondary data use.

Publication Date: 2010 Mar PMID: 20208501
Authors: Torres, C.
Journal: Nat Med

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Small practices find little incentive to go electronic.

Publication Date: 2010 Mar PMID: 20208500
Authors: Torres, C.
Journal: Nat Med

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'HIPAA2' legislation means more delicate handling of data.

Publication Date: 2010 Mar PMID: 20208499
Authors: May, M.
Journal: Nat Med

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Grassley probes health care technology.

Publication Date: 2010 Mar PMID: 20208498
Authors: May, M.
Journal: Nat Med

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Electronic records pose dilemma in developing countries.

Publication Date: 2010 Mar PMID: 20208497
Authors: Willyard, C.
Journal: Nat Med

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Comparative push concerns minorities.

Publication Date: 2010 Mar PMID: 20208496
Authors: Torres, C.
Journal: Nat Med

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State of denial.

Publication Date: 2010 Mar PMID: 20208495
Authors: Scudellari, M.
Journal: Nat Med

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A timeline of the Wakefield retraction.

Publication Date: 2010 Mar PMID: 20208494
Authors:
Journal: Nat Med

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New commissioner spells new direction for EU research funding.

Publication Date: 2010 Mar PMID: 20208493
Authors: Laursen, L.
Journal: Nat Med

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Researchers unite to improve Parkinson's drug discovery.

Publication Date: 2010 Mar PMID: 20208492
Authors: Dolgin, E.
Journal: Nat Med

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Patents draw new lines in the battle to commercialize stem cells.

Publication Date: 2010 Mar PMID: 20208491
Authors: Dolgin, E.
Journal: Nat Med

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Patent disputes could trip up genome wide scans for disease.

Publication Date: 2010 Mar PMID: 20208490
Authors: Borrell, B.
Journal: Nat Med

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Industry's influence in biologics legislation examined.

Publication Date: 2010 Mar PMID: 20208489
Authors: Dolgin, E.
Journal: Nat Med

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FDA initiative may crack wall of secrecy.

Publication Date: 2010 Mar PMID: 20208488
Authors: Schubert, C.
Journal: Nat Med

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Vaccine funds will save lives.

Publication Date: 2010 Mar PMID: 20208487
Authors: Willyard, C.
Journal: Nat Med

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Pharma spends big to buy influence.

Publication Date: 2010 Mar PMID: 20208486
Authors:
Journal: Nat Med

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Obama's budget boosts biomedicine.

Publication Date: 2010 Mar PMID: 20208485
Authors:
Journal: Nat Med

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In Haiti, collapsed AIDS clinics fret over new challenges.

Publication Date: 2010 Mar PMID: 20208484
Authors: Dolgin, E.
Journal: Nat Med

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Rare opportunities appear on the horizon to treat rare diseases.

Publication Date: 2010 Mar PMID: 20208483
Authors: Torres, C.
Journal: Nat Med

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Peering into review.

Publication Date: 2010 Mar PMID: 20208482
Authors:
Journal: Nat Med

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Kynurenine is an endothelium-derived relaxing factor produced during inflammation.

Publication Date: 2010 Mar PMID: 20190767
Authors: Wang, Y. - Liu, H. - McKenzie, G. - Witting, P. K. - Stasch, J. P. - Hahn, M. - Changsirivathanathamrong, D. - Wu, B. J. - Ball, H. J. - Thomas, S. R. - Kapoor, V. - Celermajer, D. S. - Mellor, A. L. - Keaney, J. F. Jr - Hunt, N. H. - Stocker, R.
Journal: Nat Med

Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.

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Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury.

Publication Date: 2010 Mar PMID: 20190766
Authors: Boulenguez, P. - Liabeuf, S. - Bos, R. - Bras, H. - Jean-Xavier, C. - Brocard, C. - Stil, A. - Darbon, P. - Cattaert, D. - Delpire, E. - Marsala, M. - Vinay, L.
Journal: Nat Med

Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABA(A)) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl(-)) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl(-) equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.

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Mosaic vaccines elicit CD8(+) T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys.

Publication Date: 2010 Mar PMID: 20173754
Authors: Santra, S. - Liao, H. X. - Zhang, R. - Muldoon, M. - Watson, S. - Fischer, W. - Theiler, J. - Szinger, J. - Balachandran, H. - Buzby, A. - Quinn, D. - Parks, R. J. - Tsao, C. Y. - Carville, A. - Mansfield, K. G. - Pavlakis, G. N. - Felber, B. K. - Haynes, B. F. - Korber, B. T. - Letvin, N. L.
Journal: Nat Med

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8(+) T lymphocytes that control HIV replication and CD4(+) T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8(+) T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8(+) T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

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Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4(+) T lymphocytes.

Publication Date: 2010 Mar PMID: 20173753
Authors: Manganaro, L. - Lusic, M. - Gutierrez, M. I. - Cereseto, A. - Del Sal, G. - Giacca, M.
Journal: Nat Med

Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells, partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired. Here we show that cellular c-Jun N-terminal kinase (JNK), an enzyme that is not expressed in resting CD4(+) T cells, regulates permissiveness to HIV-1 infection, and we unravel a new, sequential post-translational pathway of protein modification that regulates viral DNA integration. We found that, in activated T lymphocytes, viral integrase, which mediates HIV-1 cDNA integration into the host cell genome, is phosphorylated by JNK on a highly conserved serine residue in its core domain. Phosphorylated integrase, in turn, becomes a substrate for the cellular peptidyl prolyl-isomerase enzyme Pin1, which catalyzes a conformational modification of integrase. These concerted activities increase integrase stability and are required for efficient HIV-1 integration and infection. Lack of these modifications restricts viral infection in nonactivated, primary CD4(+) T lymphocytes.

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Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys.

Publication Date: 2010 Mar PMID: 20173752
Authors: Barouch, D. H. - O'Brien, K. L. - Simmons, N. L. - King, S. L. - Abbink, P. - Maxfield, L. F. - Sun, Y. H. - La Porte, A. - Riggs, A. M. - Lynch, D. M. - Clark, S. L. - Backus, K. - Perry, J. R. - Seaman, M. S. - Carville, A. - Mansfield, K. G. - Szinger, J. J. - Fischer, W. - Muldoon, M. - Korber, B.
Journal: Nat Med

The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.

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An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.

Publication Date: 2010 Mar PMID: 20154697
Authors: Min, J. - Zaslavsky, A. - Fedele, G. - McLaughlin, S. K. - Reczek, E. E. - De Raedt, T. - Guney, I. - Strochlic, D. E. - Macconaill, L. E. - Beroukhim, R. - Bronson, R. T. - Ryeom, S. - Hahn, W. C. - Loda, M. - Cichowski, K.
Journal: Nat Med

Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

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Innate immune lectins kill bacteria expressing blood group antigen.

Publication Date: 2010 Mar PMID: 20154696
Authors: Stowell, S. R. - Arthur, C. M. - Dias-Baruffi, M. - Rodrigues, L. C. - Gourdine, J. P. - Heimburg-Molinaro, J. - Ju, T. - Molinaro, R. J. - Rivera-Marrero, C. - Xia, B. - Smith, D. F. - Cummings, R. D.
Journal: Nat Med

The expression of ABO(H) blood group antigens causes deletion of cells that generate self-specific antibodies to these antigens but this deletion limits adaptive immunity toward pathogens bearing cognate blood group antigens. To explore potential defense mechanisms against such pathogens, given these limitations in adaptive immunity, we screened for innate proteins that could recognize human blood group antigens. Here we report that two innate immune lectins, galectin-4 (Gal-4) and Gal-8, which are expressed in the intestinal tract, recognize and kill human blood group antigen-expressing Escherichia coli while failing to alter the viability of other E. coli strains or other Gram-negative or Gram-positive organisms both in vitro and in vivo. The killing activity of both Gal-4 and Gal-8 is mediated by their C-terminal domains, occurs rapidly and independently of complement and is accompanied by disruption of membrane integrity. These results demonstrate that innate defense lectins can provide immunity against pathogens that express blood group-like antigens on their surface (pages 263 -264).

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Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice.

Publication Date: 2010 Mar PMID: 20154695
Authors: Harmon, G. S. - Dumlao, D. S. - Ng, D. T. - Barrett, K. E. - Dennis, E. A. - Dong, H. - Glass, C. K.
Journal: Nat Med

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

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Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity.

Publication Date: 2010 Mar PMID: 20139992
Authors: Flatz, L. - Hegazy, A. N. - Bergthaler, A. - Verschoor, A. - Claus, C. - Fernandez, M. - Gattinoni, L. - Johnson, S. - Kreppel, F. - Kochanek, S. - Broek, M. - Radbruch, A. - Levy, F. - Lambert, P. H. - Siegrist, C. A. - Restifo, N. P. - Lohning, M. - Ochsenbein, A. F. - Nabel, G. J. - Pinschewer, D. D.
Journal: Nat Med

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4(+) T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

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Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.

Publication Date: 2010 Mar PMID: 20139991
Authors: Yadav, V. K. - Balaji, S. - Suresh, P. S. - Liu, X. S. - Lu, X. - Li, Z. - Guo, X. E. - Mann, J. J. - Balapure, A. K. - Gershon, M. D. - Medhamurthy, R. - Vidal, M. - Karsenty, G. - Ducy, P.
Journal: Nat Med

Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

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A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection.

Publication Date: 2010 Mar PMID: 20111039
Authors: Akahata, W. - Yang, Z. Y. - Andersen, H. - Sun, S. - Holdaway, H. A. - Kong, W. P. - Lewis, M. G. - Higgs, S. - Rossmann, M. G. - Rao, S. - Nabel, G. J.
Journal: Nat Med

Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.

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