Development of Epstein-Barr virus-associated gastric cancer: Infection,inflammation, and oncogenesis

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.     

CD5, an important regulator of lymphocyte selection and immune tolerance

The CD5 coreceptor is a cysteine-rich scavenger receptor family glycoprotein that is expressed constitutively on all T cells and a subset of B cells (B1a B cells). It is now generally accepted that the biologic role of CD5 is to regulate intracellular strength induced by antigen receptors in both T and B cells. However, at present it is unclear if this coreceptor's effect on antigen receptor signaling is primarily costimulatory or inhibitory since support for both exists. Our studies focus on understanding the physiologic role of CD5 in the context of regulation of antigen receptor activation, B and T cell selection, and generation/maintenance of immune tolerance. In this overview, I discuss studies using experimental models of lymphocyte selection and tolerance showing that CD5 plays a key role in B and T cell selection as well as generation and maintenance of tolerance. I and others, reviewed here, now provide clear evidence that CD5 is a key regulator of immune tolerance and that alterations of its activity can promote development of autoreactivity.     

The evolution of human immunodeficiency virus type-1 (HIV-1) envelope molecular properties and coreceptor use at all stages of infection in an HIV-1 donor-recipient pair

To trace the evolutionary patterns underlying evolution of coreceptor use within a host, we studied an HIV-1 transmission pair involving a donor who exclusively harbored CCR5-using (R5) variants throughout his entire disease course and a recipient who developed CXCR4-using variants. Over time, R5 variants in the donor optimized coreceptor use, which was associated with an increased number of potential N-linked glycosylation sites (PNGS) and elevated V3 charge in the viral envelope. Interestingly, R5 variants that were transmitted to the recipient preserved the viral characteristics of this late stage genotype and phenotype. Following a selective sweep, CXCR4-using variants subsequently emerged in the recipient coinciding with a further increase in the number of PNGS and V3 charge in the envelope of R5 viruses.Although described in a single transmission pair, the transmission and subsequent persistence of R5 variants with late stage characteristics demonstrate the potential for coreceptor use adaptation at the population level.     

四川彝族人群HIV-1辅助受体CCR5△32和CCR2-64I基因多态性分析

目的了解中国四川彝族人群艾滋病病毒-1(HIV-1)辅助受体CCR5△32和CCR2．64I基因多态性特点。方法提取119份彝族正常人和88份HIV-1感染人群外周血基因组DNA。用聚合酶链反应(PCR)方法检测CCR5△32突变,阳性产物经克隆、测序进一步证实;用PCR-限制性片段长度多态性技术检测CCR2．64I突变,并测序验证。结果119份正常人样本中,CCR5 wt／△32等位基因突变杂合子2例(1．68％),未检测到CCR5△32／△32突变纯合子,CCR5△32等位基因频率为0．0084;CCR2-64I突变杂合子26例(21．85％),突变纯合子2例(1．68％),等位基因频率为01261。88份HIV-1感染者样本中,未检测到CCR5△32突变;CCR2．64I突变杂合子12例(13．64％),突变纯合子7例(7．95％),等位基因频率为0．1327。统计分析表明,上述等位基因多态性在该群体中均呈Hardy-Weinberg平衡分布;两种等位基因的突变频率在正常人和感染人群中的差异均无统计学意义。结论研究获得了中国四川彝族人群CCR5△32、CCR2-64I等位基因多态性资料,结果有助于综合评估中国人群对HIV-1感染的遗传易感性,同时为深入研究HIV-1抗性基因在中国不同民族的HIV感染及发病机制中的作用奠定基础。     

γδ T cells develop, respond and survive - with a little help from CD27

Although the TNF receptor family member CD27 has been known for some time, its functional role as a coreceptor on T and B cells remains poorly understood. Recent reports have shown that CD27 and its ligand CD70 play a critical role in the development and function of γδ T cells in mice. In this issue of the European Journal of Immunology, a study now extends these findings to the Vγ9Vδ2(+) subset of human γδ T cells. This subset, whose responses are readily elicited by phosphoantigens, plays an important role in anti-tumor immune responses. This study shows that most Vγ9Vδ2(+) cells express CD27, and signaling via the CD27-CD70 axis is needed for their survival, proliferation and cytokine secretion. Moreover, CD27 functions as a coreceptor, which promotes, in conjunction with TCR-mediated signals, expansion of Th1-biased Vγ9Vδ2(+) cells. This new information underscores the significance of CD27 in γδ T-cell functional differentiation, and is likely to facilitate the development of γδ T-cell-based clinical immunotherapy.     

AIDS的流行趋势及防治措施研究进展

目的：综述获得性免疫缺陷综合征(Acquired Immunodeficiency Syndrome，AIDS)的流行趋势及防治措施研究进展。方法：参阅中外文献阐述AIDS是由人类免疫缺陷病毒(Human Immunodeficiency Virus，HIV)引起的一种严重的传染病。HIV通过病毒包膜糖蛋白gp^120／gp^41主要与人体免疫细胞膜上表达的CD4受体和辅助受体结合，进而侵入易感细胞，并且损伤宿主的免疫系统，最终导致AIDS的发生。HIV主要通过密切性接触、静脉吸毒经感染者的血液传播以及母婴传播。结果：自1981年由美国首次报道以来，到2004年底，全球已有190多个国家报道有HIV／AIDS感染者已达3940万人，其中310万人已死于AIDS。疫情蔓延迅速，死亡率极高，至今尚无有效防治措施。其传播方式已由高危人群转向普通人群。发病率、死亡率均有上升趋势。结论：因此，有效的预防及治疗措施的研究已经刻不容缓。本文就AIDS的流行趋势及防治措施研究进展作一简要综述。     

An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8⁺ T cells that ultimately lead to elimination of virus‐infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide‐MHCI complexes (pMHCI). Mouse CD8αβ can form two different complexes with pMHCI via either the CD8α‐ or CD8β‐dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8αβ (CD8α^m3β) capable of forming only the CD8β‐dominated CD8αβ/pMHCI complex. These mice show sub‐optimal thymic differentiation with reduced populations of CD8⁺ single‐positive thymocytes. Tg CD8⁺ T cells exhibit a compromised developmental capacity when competing with CD8⁺ T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8⁺ T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8β‐dominated CD8αβ/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8αα and/or CD8αβ with CD8α‐dominated CD8/pMHCI complexes.     

The role of the alternative coreceptor GPR15 in SIV tropism for human cells

Many SIV isolates can employ the orphan receptor GPR15 as coreceptor for efficient entry into transfected cell lines, but the role of endogenously expressed GPR15 in SIV cell tropism is largely unclear. Here, we show that several human B and T cell lines express GPR15 on the cell surface, including the T/B cell hybrid cell line CEMx174, and that GPR15 expression is essential for SIV infection of CEMx174 cells. In addition, GPR15 expression was detected on subsets of primary human CD4⁺, CD8⁺ and CD19⁺ peripheral blood mononuclear cells (PBMCs), respectively. However, GPR15⁺ PBMCs were not efficiently infected by HIV and SIV, including cells from individuals homozygous for the defective Δ32 ccr5 allele. These results suggest that GPR15 is coexpressed with CD4 on PBMCs but that infection of CD4⁺, GPR15⁺ cells is not responsible for the well documented ability of SIV to infect CCR5⁻ blood cells.     

Molecular identification of 13 new enterovirus types, EV79-88, EV97, and EV100-101, members of the species Human Enterovirus B

Paired PBMCs and plasma samples from 34 HIV-infected patients were studied to verify the relationship between coreceptor use based on genotyping of V3 region of HIV-1 envelope gp120 and biological phenotype with virus isolation and subsequent correlation to clinical characteristics. The “11/25” rule, geno2pheno and PSSM were compared. All SI patients were HIV-1 subtype B (p = 0.04) and had a lower CD4 count than NSI patients (p = 0.01), while no differences were observed in mean HIV-RNA _log (p = 0.6). SI phenotype was not associated with AIDS-defining events (p = 0.1) or with concurrent antiretroviral therapy (p = 0.4). With geno2pheno, which shows the highest sensibility (83%), an X4 or X4/R5 genotype in PBMC DNA was also associated to B-subtype and lower CD4 count (p = 0.01) compared to R5 isolates. Based on plasma RNA sequences, the predicted coreceptor usage agreed with PBMC DNA in 79% of cases with the “11/25” rule, 82% with geno2pheno, and 82% with PSSM. A X4 virus in plasma (but not in PBMCs) was significantly associated with HAART in all three methods (p = 0.01 for “11/25” rule, p = 0.01 for geno2pheno and p = 0.03 for PSSM). Due to viral mixtures and/or difficulties in genotype interpretation, current V3 sequence-based methods cannot accurately predict HIV-1 coreceptor use.     

Maturation of the viral core enhances the fusion of HIV-1 particles with primary human T cells and monocyte-derived macrophages

HIV-1 infection requires fusion of viral and cellular membranes in a reaction catalyzed by the viral envelope proteins gp120 and gp41. We recently reported that efficient HIV-1 particle fusion with target cells is linked to maturation of the viral core by an activity of the gp41 cytoplasmic domain. Here, we show that maturation enhances the fusion of a variety of recombinant viruses bearing primary and laboratory-adapted Env proteins with primary human CD4+ T cells. Overall, HIV-1 fusion was more dependent on maturation for viruses bearing X4-tropic envelope proteins than for R5-tropic viruses. Fusion of HIV-1 with monocyte-derived macrophages was also dependent on particle maturation. We conclude that the ability to couple fusion to particle maturation is a common feature of HIV-1 Env proteins and may play an important role during HIV-1 replication in vivo.