Introduction of an aromatic group into the fatty acyl chain of α-GalCer modulates the activity and selectivity of IFN-γ/IL-4 secretion through CD1d-mediated activation of NKT cells. Compound 14-16 are more potent than α-Galcer and biased for IFN-γ than for IL-4. These new glycolipids may find use as adjuvants or as antimetastatic agents. Copyright © 2006 American Chemical Society.

Fujio Masakazu    Wu Douglass    Garcia-Navarro Raquel    何大一     Tsuji Moriya    翁启惠   

Journal of the American Chemical Society

2006

The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most affected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1. © 2006 Elsevier Ltd. All rights reserved.

Simon Viviana    何大一     Quarraisha Abdool Karim   

Lancet

2006

Background: Dating back to the first epidemic among injection drug users in 1989, the Yunnan province has had the highest number of human immunodeficiency virus type 1 (HIV-1) infections in China. However, the molecular epidemiology of HIV-1 in Yunnan has not been fully characterized. Methods and Findings: Using immunoassays, we identified 103,015 accumulated cases of HIV-1 infections in Yunnan between 1989 and 2004. We studied 321 patients representing Yunnan's 16 prefectures from four risk groups, 11 ethnic populations, and ten occupations. We identified three major circulating subtypes: C/CRF07_BC/CRF08_BC (53%), CRF01_AE (40.5%), and B (6.5%) by analyzing the sequence of p17, which is part of the gag gene. For patients with known risk factors, 90.9% of injection drug users had C/CRF07_BC/CRF08_BC viruses, whereas 85.4% of CRF01_AE infections were acquired through sexual transmission. No distinct segregation of CRF01_AE viruses was found among the Dai ethnic group. Geographically, C/CRF07_BC/CRF08_BC was found throughout the province, while CRF01_AE was largely confined to the prefectures bordering Myanmar. Furthermore, C/CRF07_BC/CRF08_BC viruses were found to consist of a group of viruses, including C, CRF08_BC, CRF07_BC, and new BC recombinants, based on the characterization of their reverse transcriptase genes. Conclusions: This is the first report of a province-wide HIV-1 molecular epidemiological study in Yunnan. While C/CRF07_BC/CRF08_BC and CRF01_AE are codominant, the discovery of many sexually transmitted CRF01_AE cases is new and suggests that this subtype may lead to a new epidemic in the general Chinese population. We discuss implications of our results for understanding the evolution of the HIV-1 pandemic and for vaccine development. © 2006 Zhang et al.

Zhang Yong    Lin Lu    Ba Lei    Li Liu    Li Yang    Manhong Jia    Haibo Wang    Fang Qing    Shi Yuhua    Yan Wenyun    Chang Guangcai    Linqi Zhang    何大一     Zhiwei Chen   

PLoS Medicine

2006

The goal of this study was to define, by surgical removal of the thymus in juvenile rhesus macaques, the role of the thymus in peripheral T cell homeostasis and to assess the significance of thymic output in SIV infection. By monitoring the changes in phenotypic T cell markers as well as in the numbers of TCR excisional circles - a recently described marker for recent thymic emigrants - following thymectomy, we present evidence that surgical thymectomy in juvenile macaques results in a faster decay of peripheral CD4 cells, but does not cause a substantial shift in CD45RA and CD45RA populations. We were able to measure a thymic output of 0.32% and 0.21% per day of CD4 and CD8 cells, respectively. No compensatory extra-thymic source was detected in lymphoid tissues, although there was a small compensatory increase in T cell proliferation in the peripheral T cell pool. After SIV infection, thymectomized animals did not have higher viral loads, greater T cell decay, or faster disease progression. We therefore conclude that peripheral destructive processes, rather than a loss of thymic output, appear to be the main causes of T cell depletion in SIV infection. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sarah tuttleton Arron    Ruy Ribeiro    Gettie Agegnehu    Bohm Rudolf P.    Blanchard James    Yu Jian    Alan Perelson    何大一     Zhang Linqi   

European Journal of Immunology

2005

The CD1 family of proteins binds self and foreign glycolipids for presentation to CD1-restricted T cells. To identify previously uncharacterized active CD1 ligands, especially those of microbial origin, numerous glycolipids were synthesized and tested for their ability to stimulate mouse and human natural killer T (NKT) cells. They included analogs of the well known NKT cell agonist α-galactosyl ceramide (α-GalCer), bacterial glycolipids, and variations of the self-glycolipid, sulfatide. Bacterial glycolipids, α-galacturonosyl-ceramides from Sphingomonas wittichii, although structurally similar to α-GalCer, have significant differences in the sugar head group as well as the ceramide portion. The Sphingomonas glycosphingolipids (GSLs) and sulfatide variants were shown to activate human NKT cells as measured by IL-4 and IFN-γ secretion. Moreover, CD1d-dimer staining revealed human NKT cell reactivity toward these GSLs and to the sulfatides in a fashion comparable with α-GalCer. Because α-GalCer is a marine-sponge-derived ligand, our study here shows that bacterium-derived antigens are also able to stimulate mouse and human NKT cells.

Wu Douglass    Xing Guo-Wen    Poles Michael    Horowitz Amir    Kinjo Yuki    Sullivan Barbara A.    Bodmer-Narkevitch Vera    Plettenburg Oliver    Kronenberg Mitchell    Tsuji Moriya    何大一     翁启惠   

Proceedings of the National Academy of Sciences of the United States of America

2005

Immunization with a killed or inactivated viral vaccine provides significant protection in animals against challenge with certain corresponding pathogenic coronaviruses (CoVs). However, the promise of this approach in humans is hampered by serious concerns over the risk of leaking live severe acute respiratory syndrome (SARS) viruses. In this study, we generated a SARS vaccine candidate by using the live-attenuated modified vaccinia virus Ankara (MVA) as a vector. The full-length SARS-CoV envelope Spike (S) glycoprotein gene was introduced into the deletion III region of the MVA genome. The newly generated recombinant MVA, ADS-MVA, is replication incompetent in mammalian cells and highly immunogenic in terms of inducing potent neutralizing antibodies in mice, rabbits, and monkeys. After two intramuscular vaccinations with ADS-MVA alone, the 50% inhibitory concentration in serum was achieved with reciprocal sera dilutions of more than 1,000- to 10,000-fold in these animals. Using fragmented S genes as immunogens, we also mapped a neutralizing epitope in the region of N-terminal 400 to 600 amino acids of the S glycoprotein (S400-600), which overlaps with the angiotensin-converting enzyme 2 (ACE2) receptor-binding region (RBR; S318-510). Moreover, using a recombinant soluble RBR-Fc protein, we were able to absorb and remove the majority of the neutralizing antibodies despite observing that the full S protein tends to induce a broader spectrum of neutralizing activities in comparison with fragmented S proteins. Our data suggest that a major mechanism for neutralizing SARS-CoV likely occurs through blocking the interaction between virus and the cellular receptor ACE2. In addition, ADS-MVA induced potent immune responses which very likely protected Chinese rhesus monkeys from pathogenic SARS-CoV challenge.

Zhiwei Chen    Zhang Linqi    秦川    Ba Lei    Yi Christopher E.    Zhang Fengwen    Wei Qiang    He T.    Wenjie Yu    Yu Jian    Gao Hong    Tu Xinming    Gettie Agegnehu    Michael Farzan    袁国勇    何大一    

Journal of Virology

2005

Two novel hybrid molecules 3-O-sulfo-α/β-galactosylceramide 3 and 4, which are derived from an immunostimulatory agent α-GalCer 1 and self-glycolipid ligand sulfatide 2, were designed and synthesized. Compound 3 was shown to efficiently stimulate human NKT cells to secret IL-4 and IFN-γ, with activities similar to 1, suggesting that modification of the 3″-OH position of the galactose moiety with sulfate has no significant effect on NKT cell stimulation. As a comparison, the β-isomer 4 has no affinity to NKT cells, which demonstrates that the α-glycosidic bond of galactosylceramide is crucial to the NKT cells activation. © 2005 Elsevier Ltd. All rights reserved.

Xing Guo-Wen    Wu Douglass    Poles Michael    Horowitz Amir    Tsuji Moriya    何大一     翁启惠   

Bioorganic and Medicinal Chemistry

2005

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) α-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.

Kinjo Yuki    Wu Douglass    Kim Gisen    Xing Guo-Wen    Poles Michael    何大一     Tsuji Moriya    Kawahara Kazuyoshi    翁启惠    Kronenberg Mitchell   

Nature

2005

HIV-1 infected patients after being treated with potent combinations of antiretroviral drugs for 2-6 months typically reach a state in which virus can no longer be detected within their blood. These patients with undetectable virus occasionally have viral load measurements that are above the limit of detection of current assays. Such measurements are called blips. Here we examine the possibility that such blips represent infrequent measurements taken during a period of time in which there is a transient elevation of virus in the patient's blood, i.e., a so-called transient episode of viremia. By analyzing time series of blips from a large number of patients, we conclude that transient episodes of viremia exist and that on average they extend for a period of about 3 weeks.

Di Mascio Michele    Percus Jerome K.    Percus Ora E.    Markowitz Martin    何大一     Alan Perelson   

Bulletin of Mathematical Biology

2005

何大一    

Nature

2005