HIV感染者胃黏膜HIV感染状态及局部免疫功能改变的研究
|
摘要
目的：黏膜相关淋巴组织(mucosa associated lymphoid tissue，MALT)是人体CD4~+T细胞的主要储存部位，研究人类免疫缺陷病毒(human immunodeficiency virus，HIV)感染对粘膜中CD4~+T细胞和黏膜局部免疫功能的影响，将有助于深化对HIV感染和获得性免疫缺陷综合征(acquired immune deficiency syndrome，AIDS)发病机制的认识，并为HIV感染的治疗提供新的潜在的干预途径和方法。本研究拟通过对HIV感染者胃黏膜中CD4~+T细胞、CD8~+T细胞、NK细胞、B细胞等免疫细胞变化、免疫状态改变及胃黏膜HIV感染状况的研究，阐述胃肠黏膜免疫与HIV感染之间的关系，为进一步探讨HIV／AIDS的感染和发病机制提供依据。
方法：收集HIV感染者胃镜活检或尸检胃黏膜组织，常规中性甲醛固定，石蜡包埋。1．采用原位杂交(in situ hybridization，ISH)和免疫组织化学(immunohistochemistry，IHC)方法，检测HIV感染者尸检胃黏膜组织中HIV感染状况。2．采用IHC法检测HIV感染者活检胃黏膜组织中CD3~+T细胞、CD4~+T细胞、CD8~+T细胞、NK细胞、B细胞的数量及分布状况，探讨HIV感染对胃黏膜内免疫细胞的影响。3．采用银染和IHC法，检测HIV感染者活检胃黏膜组织中幽门螺旋杆菌(helicobacter pylori，Hp)的感染情况。4．采用IHC法观察活检胃黏膜组织中CD38、Ki-67的表达，评价HIV感染胃黏膜内免疫细胞增生与激活的改变。5．采用Masson三色染色法，观察HIV感染后胃黏膜组织中胶原纤维的沉积。
结果：1．HIV在胃黏膜中的感染状况：(1)HIV感染者胃黏膜内HIVgag区基因不仅见于CD4~+T细胞等免疫细胞中，少数胃黏膜上皮、腺上皮、小凹内上皮细胞和间质梭形细胞中亦有阳性杂交信号；(2)HIV感染者尸检胃黏膜内HIVp24蛋白于T细胞、浆细胞及少部分胃黏膜黏膜上皮、腺上皮及小凹上皮细胞中呈阳性表达。2．HIV感染无症状者和AIDS患者胃黏膜活检组织中CD3~+T细胞、CD4~+T细胞、CD8~+T细胞、NK细胞、B细胞的数量及分布：与非HIV感染对照组相比，(1)AIDS患者胃黏膜内CD4~+T细胞显著减少(P＜0.01)，而无症状者与对照组无显著差异(P＞0.05)；(2)胃黏膜内CD3~+T细胞、CD8~+T细胞、NK细胞(CD57~+)显著增加(P＜0.01)，并呈现较明显普遍性噬胃黏膜上皮和腺体现象；(3)各组胃黏膜内CD20~+B淋巴细胞的数量分布变化不明显。3．采用银染和IHC方法检测HIV感染者Hp感染情况：HIV感染者胃黏膜活检组织中，Hp感染率为33.3％(14／42)，其中无症状者Hp感染率高达50％(5／10)，明显高于非HIV感染对照组(3／10)(P＜0.01)。4．HIV感染无症状者和AIDS患者胃黏膜活检组织中CD38、Ki-67的表达：与非HIV感染对照组比较，Ki-67表达显著减少，而CD38表达呈明显上调改变。5．HIV感染无症状者和AIDS患者胃黏膜组织中固有淋巴滤泡部位可见不同程度胶原纤维沉积，固有层间质不同程度细胞外基质增生。
结论：1．研究发现，HIV-1不仅可以感染CD4~+T细胞，并可感染胃黏膜上皮、腺上皮及小凹上皮细胞，以及少数间质细胞，研究结果显示胃黏膜是HIV免疫系统外感染的靶部位之一，胃黏膜上皮及腺上皮细胞等是HIV感染的靶细胞之一。2．HIV感染胃黏膜呈不同程度的炎症反应，间质增生，黏膜上皮及腺上皮变性、凋亡，固有淋巴滤泡萎缩纤维化，提示HIV／AIDS疾病的进程与胃黏膜局部病理改变之间可能存在一定关联性。3．AIDS患者胃黏膜内CD4~+T细胞显著减少，CD8~+T细胞、NK细胞等免疫细胞呈相对增生性改变，HIV感染无症状者及AIDS患者胃黏膜内CD8~+T细胞、NK细胞噬黏膜上皮及噬腺体现象普遍且明显，而胃黏膜内CD20~+B细胞的数量及分布改变较轻。结果提示HIV感染可能导致胃黏膜局部免疫细胞数量、比例及功能异常，致黏膜局部免疫状态失调。CD8~+T细胞、NK细胞(CD57~+)噬胃黏膜上皮及腺体现象推测可能与HIV感染胃黏膜上皮、腺上皮细胞及黏膜局部细胞免疫和天然免疫功能异常有关。4．Hp感染率在HIV感染者中上升，而无症状者感染率更高，提示黏膜局部免疫细胞功能的缺陷或紊乱可能较免疫细胞数量的减少对黏膜局部包括抗感染能力在内的免疫功能影响更大。5．根据HIV感染无症状者和AIDS患者胃黏膜内Ki-67和CD38表达改变，以及胶原
纤维沉积情况，提示HIV的感染可导致胃黏膜中免疫细胞增殖能力失衡，表型激活异常，并推测可能为胃黏膜局部免疫细胞过度消耗致MALT渐进性破坏的机制之一。
Objective: Mucosa associated lymphoid tissue (MALT) is one of the main site in which CD4~+ T cells are located. Reserching on the changes of mucosal CD4~+ T cells and local immune function during HIV infection will help us better understand the mechanism of HIV infection and AIDS, and suggest novel potential therapeutic strategy in clinical settings. The present study was performed using gastro-mucosal tissues from HIV infection patients to explore the changes of CD4~+ T cells, CD8~+ T cells, NK cells, B cells and their immune activation, which could have important implications in terms of mechanisms of HIV infection and pathogenesis.
Methods: Gastro-mucosal tissues of HIV patients were prepared from autopsy and biopsy under gastroscope, in turns 10% buffer formalin fixing and paraffin imbedding. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect HIV in gastro-mucosal tissues of HIV infection patients. Meanwhile, the distribution and quantity of immunocytes, including CD3~+ T cells, CD4~+ T cells, CD8~+ T cells, NK cells and B cells, were performed with IHC method to discuss the influence of HIV infection on immunocytes and innate immunity of gastro-mucosal tissues. In addition, we observed the expression of CD38 and Ki-67 in gastro-mucosal tissues of HIV patients to expound alterations of immunoproliferating and activation by using IHC. Subsequently, the infection of helicobacter pylori (Hp) was checked in gastro-mucosal tissues of HIV patients with silver staining and IHC. At last, collagen deposition in gastro-mucosal tissues of HIV patients was estimated with Masson's trichromatic staining.
Result: 1. The situation of HIV infection in gastro-mucosal tissues: (1) Our study found HIV gag sequence in not only CD4~+ T cells but also mucosal
epithelial cells, gland epithelial cells in lamina propria and spindle stromal cells; (2) HIV p24 was expressed in T cells, plasmocyte, and a few mucosa epithelial cells, gland epithelial cellls and dell epithelial cellls. 2. Comparing with control group, CD4~+ T cells of AIDS patient were markedly depleted in gastro-mucosal tissues(P＜0.01), but in presymptomatic patients CD4~+ T cells were not significantly different. CD3~+ T cells, CD8~+ T cells and NK. cells were notably increased (P<0.01), and they severely infiltrated glands and epitheliums in gastro-mucosal tissues. And the quantity and distribution of CD20~+ B cells between patients and control group were not obviously different. 3. 14 of 42 patients infected Hp, and total infection ratio was 33.3% which was higher than control group (P＜0.01), the infection ratio in presymptomatic HIV infection group was 50% which was the highest among them. 4. Comparing with control group, the expression of Ki-67 was markedly down-regulated (P<0.01), while the expression of CD38 was markedly up-regulated (P＜0.01). 5. Collagen deposition was noted in stroma and folliculus lymphaticus of gastro-mucosa tissues.
Conclusions:
1. In gastro-mucosal tissues from HIV infection patients, HIV could infect not only CD4~+ T cells but also mucosal, gland epithelial cells and dell epithelial cells, as well as a few stroma cells, which suggested that gastro-mucosa is an infected site of HIV infection,and mucosal and gland epithelial cells are target cells of HIV infection.
2. There are different degree of inflammatory reaction, stroma proliferation, glandular and mucosal epithelial degeneration, apoptosis, and atrophy of folliculus lymphaticus in gastro-mucosa.
3. CD4~+ T cells in gastro-mucosa of AIDS patients were markedly decreased. The numbers of CD3~+ T cells, CD8~+ T cells, NK cells and so on were relatively increased, which cells severely infiltrated the glands and epitheliums in gastro-mucosa of HIV infection. However distinctions of CD20~+ B cells in number and distribution between HIV infection and control subjects was not noted. These changes imply that the alteration of CD4~+ T cells and local immune homeostasis induced by HIV infection could result in aggregation of CD8~+ T cells
and NK cells in local gastro-mucosa. CD8~+ T cells and NK cells infiltrating the glands and epitheliums in lamina propria could be associated with HIV infecting mucosal and gland cells. The state of CD8~+ T cells, NK cells and B cells in HIV infection gastro-mucosa shows that cell immunity and innate immunity are predominantly influenced rather not humoral immunity during HIV infection.
4. Hp infection ratio in HIV infection patients was increased, especially in presymptomatic HIV infection group, which suggested the changes of local mucosa immunocytes in function might be more obviously influence than in number in HIV infection.
5. According to the result of down-regulated expression of Ki-67 and up-regulated expression of CD38 and collagen deposition, we could infer that HIV infection could lead to unbalance of lymphocyte regeneration and immune phenotype activation, which might result in the depletion of immune system, and lead to breakdown of MALT structure.
方法：收集HIV感染者胃镜活检或尸检胃黏膜组织，常规中性甲醛固定，石蜡包埋。1．采用原位杂交(in situ hybridization，ISH)和免疫组织化学(immunohistochemistry，IHC)方法，检测HIV感染者尸检胃黏膜组织中HIV感染状况。2．采用IHC法检测HIV感染者活检胃黏膜组织中CD3~+T细胞、CD4~+T细胞、CD8~+T细胞、NK细胞、B细胞的数量及分布状况，探讨HIV感染对胃黏膜内免疫细胞的影响。3．采用银染和IHC法，检测HIV感染者活检胃黏膜组织中幽门螺旋杆菌(helicobacter pylori，Hp)的感染情况。4．采用IHC法观察活检胃黏膜组织中CD38、Ki-67的表达，评价HIV感染胃黏膜内免疫细胞增生与激活的改变。5．采用Masson三色染色法，观察HIV感染后胃黏膜组织中胶原纤维的沉积。
结果：1．HIV在胃黏膜中的感染状况：(1)HIV感染者胃黏膜内HIVgag区基因不仅见于CD4~+T细胞等免疫细胞中，少数胃黏膜上皮、腺上皮、小凹内上皮细胞和间质梭形细胞中亦有阳性杂交信号；(2)HIV感染者尸检胃黏膜内HIVp24蛋白于T细胞、浆细胞及少部分胃黏膜黏膜上皮、腺上皮及小凹上皮细胞中呈阳性表达。2．HIV感染无症状者和AIDS患者胃黏膜活检组织中CD3~+T细胞、CD4~+T细胞、CD8~+T细胞、NK细胞、B细胞的数量及分布：与非HIV感染对照组相比，(1)AIDS患者胃黏膜内CD4~+T细胞显著减少(P＜0.01)，而无症状者与对照组无显著差异(P＞0.05)；(2)胃黏膜内CD3~+T细胞、CD8~+T细胞、NK细胞(CD57~+)显著增加(P＜0.01)，并呈现较明显普遍性噬胃黏膜上皮和腺体现象；(3)各组胃黏膜内CD20~+B淋巴细胞的数量分布变化不明显。3．采用银染和IHC方法检测HIV感染者Hp感染情况：HIV感染者胃黏膜活检组织中，Hp感染率为33.3％(14／42)，其中无症状者Hp感染率高达50％(5／10)，明显高于非HIV感染对照组(3／10)(P＜0.01)。4．HIV感染无症状者和AIDS患者胃黏膜活检组织中CD38、Ki-67的表达：与非HIV感染对照组比较，Ki-67表达显著减少，而CD38表达呈明显上调改变。5．HIV感染无症状者和AIDS患者胃黏膜组织中固有淋巴滤泡部位可见不同程度胶原纤维沉积，固有层间质不同程度细胞外基质增生。
结论：1．研究发现，HIV-1不仅可以感染CD4~+T细胞，并可感染胃黏膜上皮、腺上皮及小凹上皮细胞，以及少数间质细胞，研究结果显示胃黏膜是HIV免疫系统外感染的靶部位之一，胃黏膜上皮及腺上皮细胞等是HIV感染的靶细胞之一。2．HIV感染胃黏膜呈不同程度的炎症反应，间质增生，黏膜上皮及腺上皮变性、凋亡，固有淋巴滤泡萎缩纤维化，提示HIV／AIDS疾病的进程与胃黏膜局部病理改变之间可能存在一定关联性。3．AIDS患者胃黏膜内CD4~+T细胞显著减少，CD8~+T细胞、NK细胞等免疫细胞呈相对增生性改变，HIV感染无症状者及AIDS患者胃黏膜内CD8~+T细胞、NK细胞噬黏膜上皮及噬腺体现象普遍且明显，而胃黏膜内CD20~+B细胞的数量及分布改变较轻。结果提示HIV感染可能导致胃黏膜局部免疫细胞数量、比例及功能异常，致黏膜局部免疫状态失调。CD8~+T细胞、NK细胞(CD57~+)噬胃黏膜上皮及腺体现象推测可能与HIV感染胃黏膜上皮、腺上皮细胞及黏膜局部细胞免疫和天然免疫功能异常有关。4．Hp感染率在HIV感染者中上升，而无症状者感染率更高，提示黏膜局部免疫细胞功能的缺陷或紊乱可能较免疫细胞数量的减少对黏膜局部包括抗感染能力在内的免疫功能影响更大。5．根据HIV感染无症状者和AIDS患者胃黏膜内Ki-67和CD38表达改变，以及胶原
纤维沉积情况，提示HIV的感染可导致胃黏膜中免疫细胞增殖能力失衡，表型激活异常，并推测可能为胃黏膜局部免疫细胞过度消耗致MALT渐进性破坏的机制之一。
Objective: Mucosa associated lymphoid tissue (MALT) is one of the main site in which CD4~+ T cells are located. Reserching on the changes of mucosal CD4~+ T cells and local immune function during HIV infection will help us better understand the mechanism of HIV infection and AIDS, and suggest novel potential therapeutic strategy in clinical settings. The present study was performed using gastro-mucosal tissues from HIV infection patients to explore the changes of CD4~+ T cells, CD8~+ T cells, NK cells, B cells and their immune activation, which could have important implications in terms of mechanisms of HIV infection and pathogenesis.
Methods: Gastro-mucosal tissues of HIV patients were prepared from autopsy and biopsy under gastroscope, in turns 10% buffer formalin fixing and paraffin imbedding. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect HIV in gastro-mucosal tissues of HIV infection patients. Meanwhile, the distribution and quantity of immunocytes, including CD3~+ T cells, CD4~+ T cells, CD8~+ T cells, NK cells and B cells, were performed with IHC method to discuss the influence of HIV infection on immunocytes and innate immunity of gastro-mucosal tissues. In addition, we observed the expression of CD38 and Ki-67 in gastro-mucosal tissues of HIV patients to expound alterations of immunoproliferating and activation by using IHC. Subsequently, the infection of helicobacter pylori (Hp) was checked in gastro-mucosal tissues of HIV patients with silver staining and IHC. At last, collagen deposition in gastro-mucosal tissues of HIV patients was estimated with Masson's trichromatic staining.
Result: 1. The situation of HIV infection in gastro-mucosal tissues: (1) Our study found HIV gag sequence in not only CD4~+ T cells but also mucosal
epithelial cells, gland epithelial cells in lamina propria and spindle stromal cells; (2) HIV p24 was expressed in T cells, plasmocyte, and a few mucosa epithelial cells, gland epithelial cellls and dell epithelial cellls. 2. Comparing with control group, CD4~+ T cells of AIDS patient were markedly depleted in gastro-mucosal tissues(P＜0.01), but in presymptomatic patients CD4~+ T cells were not significantly different. CD3~+ T cells, CD8~+ T cells and NK. cells were notably increased (P<0.01), and they severely infiltrated glands and epitheliums in gastro-mucosal tissues. And the quantity and distribution of CD20~+ B cells between patients and control group were not obviously different. 3. 14 of 42 patients infected Hp, and total infection ratio was 33.3% which was higher than control group (P＜0.01), the infection ratio in presymptomatic HIV infection group was 50% which was the highest among them. 4. Comparing with control group, the expression of Ki-67 was markedly down-regulated (P<0.01), while the expression of CD38 was markedly up-regulated (P＜0.01). 5. Collagen deposition was noted in stroma and folliculus lymphaticus of gastro-mucosa tissues.
Conclusions:
1. In gastro-mucosal tissues from HIV infection patients, HIV could infect not only CD4~+ T cells but also mucosal, gland epithelial cells and dell epithelial cells, as well as a few stroma cells, which suggested that gastro-mucosa is an infected site of HIV infection,and mucosal and gland epithelial cells are target cells of HIV infection.
2. There are different degree of inflammatory reaction, stroma proliferation, glandular and mucosal epithelial degeneration, apoptosis, and atrophy of folliculus lymphaticus in gastro-mucosa.
3. CD4~+ T cells in gastro-mucosa of AIDS patients were markedly decreased. The numbers of CD3~+ T cells, CD8~+ T cells, NK cells and so on were relatively increased, which cells severely infiltrated the glands and epitheliums in gastro-mucosa of HIV infection. However distinctions of CD20~+ B cells in number and distribution between HIV infection and control subjects was not noted. These changes imply that the alteration of CD4~+ T cells and local immune homeostasis induced by HIV infection could result in aggregation of CD8~+ T cells
and NK cells in local gastro-mucosa. CD8~+ T cells and NK cells infiltrating the glands and epitheliums in lamina propria could be associated with HIV infecting mucosal and gland cells. The state of CD8~+ T cells, NK cells and B cells in HIV infection gastro-mucosa shows that cell immunity and innate immunity are predominantly influenced rather not humoral immunity during HIV infection.
4. Hp infection ratio in HIV infection patients was increased, especially in presymptomatic HIV infection group, which suggested the changes of local mucosa immunocytes in function might be more obviously influence than in number in HIV infection.
5. According to the result of down-regulated expression of Ki-67 and up-regulated expression of CD38 and collagen deposition, we could infer that HIV infection could lead to unbalance of lymphocyte regeneration and immune phenotype activation, which might result in the depletion of immune system, and lead to breakdown of MALT structure.
引文
1 D'Agati V, Suh J, Carbone L, et al. Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study. Kidney Int, 1989, 35:1358-1370.
2 Ross MJ, Koltman PE. HIV-associated nephropathy. AIDS, 2004, 18:1089-1099.
3 Zhong J, Zuo Y, Ma J, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int, 2005, 68:1048-1060.
4 He JC, Husain M, Sunamoto M, et al. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1, 2 pathways. J Clin Invest, 2004, 114:643-651.
5 Kramer-Hammede S, Rothenaigner I, Wolff H, et al. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res, 2005, 111:194-213.
6 Bissel SJ, Willey CA. Human immunodeficiency virus infection of the brain: pitfalls in evaluating infected/affected cell populations. Brain Pathol, 2004, 14:97-108.
7 Liu Y, Liu H, Kim BO, et al. CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol, 2004, 78:4120-4133.
8 Thompson KA, Churchill MJ, Gony PR, et al. Astrocyte specific viral strains in HIV dementia. Ann Neurol, 2004, 56:873-877.
9 Veazey RS, Mansfield KG, Tham IC, et al. Dynamics of CCR5 expression by CD4~+ T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol, 2000, 74:11001-11007.
10 Guillot C, Menoret S, Guillonneau C, et al. Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig. Blood, 2003,101:3325-3333.
11 Granelli-Piperno A., Moser B, Pope M, et al. Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J Exp Med, 1996,184:2433-2438.
12 Rubbert A, Combadiere C, Ostromski M, et al. Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry. J Immunol, 1998,160:3933-3941.
13 Turville SG, Artho J, Donald KM, et al. HIV gp120 receptors on human dendritic cells. Blood, 2001, 98:2482-2488.
14 Ignatius R, Wei Y, Beaulieu S, et al. The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells. AIDS Res. Hum. Retroviruses, 2000, 16:1055-1059.
15 Geijtenbeek TB, Torensma R, van Vilet SJ, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell, 2000,100:575-585.
16 Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cellspecific HIV-1-binding protein that enhances transinfection of T cells. Cell, 2000,100:587-597.
17 Teleshova N, Frank I, Pope M. Immunodeficiency virus exploitation of dendritic cells in the early steps of infection. J Leukoc Biol, 2003, 74:683-690.
18 McDonald D, Wu L, Bohks SM, et al. Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science, 2003, 300:1295-1297.
19 Izmailova E, Bertley FM, Huang Q, et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat Med, 2003, 9:191-197.
20 Salahuddin SZ, Rose RM, Groopman JE, et al. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood, 1986, 68:281-284.
21 Sierra-Madero JG, Toossi Z, Hom DL, et al. Relationship between load of virus in alveolar macrophages from human immunodeficiency virus type 1-infected persons, production of cytokines, and clinical status. J Infect Dis, 1994, 169:18-27.
22 Meireles de Souza LR, Shattock RL. Therapeutic role of CD8~+ T cells in HIV-1 infection: targets and suppressors of viral replication. Expert opin Biol Ther, 2005, 5:321-323.
23 Rappocciolo G, Piazza P, Fuller CL, et al. DC-SIGN on B lymphocytes is required for transmission of HFV-1 to T lymphocytes. PloS pathog, 2006, 2:691-704.
24 Moir S, Malaspina A, Li Y, et al. B cells of HIV-1-infected patients bind virions through CD21 -complement interactions and transmit infectious virus to activated T cells. J Exp Med, 2000,192: 637-646.
25 Malaspina A, Moir S, Nickle DC, et al. Human immunodeficiency virus type 1 bound to B cells: relationship to virus replicating in CD4tT cells and circulating in plasma. J Virol, 2002, 76: 8855-8863.
26 Dopper S, Wilflingseder D, Prodinger WM, et al. Mechanism(s) promoting HIV-1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co-cultures. Eur J Immunol, 2003, 33:2098-2107.
27 Asin SN, Fanger MW, Wildt-Perinic D, et al. Transmission of HIV-1 by primary human uterine epithelial cells and stromal fibroblasts. J Infect Dis, 2004,190:236-245.
28 Meng G, Wei X, Wu X, et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med, 2002, 8:150-156.
29 Yahi N, Baghdiguian S, Moreau H, et al. Galactosyl ceramide (or a closely related molecule) is the receptor for human immunodeficiency virus type 1 on human colon epithelial HT29 cells. J Virol, 1992,66:4848-4854.
30 Liu X, Zha J, Chen H, et al. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes. J Virol, 2003, 77:3470-3476.
31 Koulinska IN, Villamor E, Chaplin B, et al. Transmission of cell-free and cell-associated HIV-1 through breast-feeding. J Acquir Immune Defic Syndr, 2006,41:93-99.
32 Ledergerber B, Flepp M, Boni J, et al. HIV-1 p24 concentration measured by boosted ELISA of heat-denatured plasma correlates with decline in CD4 cells, progression to AIDS, and survival: Comparison with vira RNA measurement. J Infect Dis, 2000,181: 1280-1288.
33 Sterling TR, Hoover DR, Astemborski J, et al. Heat-denatured HIV-1 protein p24 antigen: Prognostic value in adults with early stage disease. J Infect Dis, 2002,186:1181-1185.
34 Schupbach J, Boni J, Bisset LR, et al. HIV-1 p24 antigen is a signifi cant inverse correlate of CD4 T-cell change in patients with suppressed viremia under long-term antiretroviral therapy. J Acquir Immune Defic Syndr, 2003, 33: 292-299.
35 Schupbach J, Gunthard H, Joos B, et al. HIV-1 p24 may persist during long-term highly active antiretroviral therapy, increases little during short treatment breaks, and its rebound after treatment stop correlates with CD4+ T cell loss. J Acquir Immune Defi c Syndr, 2005,40: 250-256.
36 Jason MB, David AP, Timothy WS, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2006, 12:1351-1352.
1 Picker LJ, Haqen SI, Lum R, et al. Insufficient production and tissue delivery of CD4~+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004, 200: 1299-1314.
2 Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 1998, 280: 427-431.
3 Veazey RS, Marx PA, Lackner AA. Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis, 2003,187:769-776.
4 Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004,200:749-759.
5 Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004, 200:761-770.
6 Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol, 2003, 77:11708-11717.
7 Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4~+ T cells in multiple tissues during acute SIV infection. Nature, 2005, 434:1093-1097.
8 Li Q, Duan L, Estes JD, Ma ZM, et al. Peak SIV replication in resting memory CD4~+ T cells depletes gut lamina propria CD4~+ T cells. Nature, 2005, 434:1148-1152.
9 Kovacs JA, Lempecki RA, Sidorov IA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med, 2001,194:1731-1741.
10 Macallan DC, Asquith B, Irvine AJ, et al. Measurement and modeling of human T cell kinetics. Eur J Immunol, 2003,33:2316-2326.
11 McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature, 2001,410:974-979.
12 Hazenberg MD, Hamann D, Schuitemaker H, et al. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol, 2000,1:285-289.
13 Grossman Z, Meier Schellersheim M, Sousa AE, et al. CD4~+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med, 2002, 8:319-323.
14 Silvestri G, Feinberg MB. Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest, 2003, 112:821-824.
15 Guadalupe M, Reay E, Sankaran S, et al. Severe CD4~+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol, 2003, 77:11708-11717.
16 Douek DC, Betts MR, Hill BJ, et al. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J Immunol, 2001, 167:6663-6668.
17 Schacker TW, Nguyen PL, Beilman GJ, et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest, 2002, 110:1133-1139.
18 Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4~+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006, 13:556-560.
19 Estes JD, Wietgrefe S, Schacker T, et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor Beta 1-positive regulatory T cells and begins in early infection. J Infect Dis, 2007,195:551-556.
20 Dion ML, Poulin JF, Bordi R, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity, 2004,21,757-768.
21 Grossman Z, Min B, Meier Schellersheim M, et al. Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol, 2004,4, 387-395.
22 Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol, 2003,21:265-304.
23 Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006,439:682-687.
24 Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med, 2006,12:1198-1202.
25 Wherry EJ, Barber DL, Kaech SM, et al. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA, 2004,101:16004-16009.
26 Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat. Med, 2004, 10:806-810.
27 Malaspina A, Moir S, Ho J. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: Correlation with increased IL-7. Proc Natl Acad Sci USA, 2006,103:2262-2267.
28 Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation andimmunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med, 1983, 309:453-458.
29 Malaspina A, Moir S, Kottilil S, et al. Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol, 2003,170:5965-5972.
30 De Milito A., Nilsson A, Titanji K, et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood, 2004,103:2180-2186.
31 De Boer RJ, Mohri H, Ho DD, et al. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol. 2003,170:2479-2487.
32 Martinez Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol, 2002,14:528-532.
33 De Milito A, Morch C, Sonnerborg A, et al. Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS, 2001, 5:957-964.
34 Degli Esposti MA, Smyth MJ. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol, 2005, 5:112-124.
1 Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol, 2003, 21: 265-304.
2 Lawn SD, Butera ST, Folks TM. Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. Clin Microbiol Rev, 2001, 14: 753-777.
3 De Boer RJ, Mohri H, Ho DD, et al, Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol, 2003, 170: 2479-2487.
4 Lee C, Liu OH, Tomkowicz B, et al. Macrophage activation through CCR5-and CXCR4-mediated gp 120-elicitedsignaling pathways. J Leukoc Biol, 2003, 74: 676-682.
5 Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4~+ T cells. Nature, 2002, 417: 95-98.
6 Doisne JM, Urrutia A, lacabaratz Porret C, et al. CD8~+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection. J Immunol, 2004, 173: 2410-2418.
7 Brenchley JM, Hill BJ, Ambrozak DR, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol, 2004, 78, 1160-1168.
8 Grossman Z, Min B, Meier Schellersheim M, et al. Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol, 2004,4, 387-395.
9 Schindler M, Munch J, Kutsch O, et al. nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1. Cell, 2006,125:1034-1035.
10 Schacker TW, Nguyen PL, Beilman GJ, et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest, 2002, 110:1133-1139.
11 Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006, 13:556-560.
12 Estes JD, Wietgrefe S, Schacker T, et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor Beta 1-positive regulatory T cells and begins in early infection. J Infect Dis, 2007,195:551-556.
13 Silvestri G, Feinberg MB. Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest, 2003,112:821-824.
14 Hellerstein MK, Hoh RA, Hanley MB, et al. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest, 2003, 112:956-966.
15 Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4~+ T cells in multiple tissues during acute SIV infection. Nature, 2005, 434:1093-1097.
16 Picker LJ, Haqen SI, Lum R, et al. Insufficient production and tissue delivery of CD4~+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004, 200:1299-1314.
17 Kunkel EJ, Boisvert J, Murphy K, et al. Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. Am J Pathol, 2001,160: 347-355.
18 Qin S, Rottman JB, Myers P, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest, 1998, 101: 746-754.
19 Galati D, Paiardini M, Cervasi B, et al. Specific changes in the posttranslational regulation of nucleolin in lymphocytes from patients infected with human immunodeficiency virus. J Infect Dis, 2003, 188:1483-1491.
20 Yue FY, Kovacs CM, Dimayuga RC, et al. Preferential apoptosis of HIV-1-specific CD4~+ T cells. J Immunol, 2005,174:2196-2204.
21 Smed Sorensen A, lore K, Vasudevan J, et al. Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J Virol, 2005, 79:8861-8869
22 Swingler S, Brichacek B, Jacque JM, et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature, 2003,424:213-219.
23 Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol, 2005, 174:4407-4414.
24 Min B, Foucras G, Meier Schellersheim M, et al. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci USA, 2004,101:3874-3879.
25 Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol, 2004,4:478-485.
26 Acheson DW, Luccioli S. Microbial-gut interactions in health and disease. Mucosalimmune responses. Best Pract Res Clin Gastroenterol, 2004, 18: 387-404.
27 Dion ML, Poulin JF, Bordi R, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity, 2004,21:757-768.
28 Haynes BF, Hale LP, Weinhold KJ, et al. Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J Clin Invest, 1999, 103:921.
1 WHO. Coronavirus never before seen in humans is the cause of SARS. http://www.who.int/entity/esr/sasaschive/2004-04-16/en.
2 Magiorkinis G, Magiorkinis E, Paraskevis D, et al. Phylogenetic analysis of the full-length SARS-CoV sequences: evidence for phylogenetic discordance in three genomic regions. J-Med-Virol. 2004, 74: 369-372.
3 Zhao Z, Li H, Wu X, et al. Moderate mutation rate in the SARS coronavirus genome and its implications. BMC-Evol-Biol. 2004, 4: 21.
4 Song HC, Seo MY, Stadler K, et al. Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavims spike glycoprotein. J Virol, 2004, 78: 10328-10335.
5 Ying W, Hao Y, Zhang Y, et al. Proteomic analysis on structural proteins of Severe acute respiratory syndrome coronaviru. Proteomics, 2004, 4: 492-504.
6 Luo C, Luo H, Zheng S, et al. Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A. Biochem Biophys Res Commun, 2004, 321: 557-654.
7 Arbely E, Khattar Z, Brotons G, et al. A highly unusual palindromic transmembrane helical hairpin formed by SARS coronavirus E protein. J Mol Bio, 2004, 341:769-779.
8 He Y, Zhou Y, Wu H, et al. Identification of immunodominant sites on the spike protein of Severe acute respiratory syndrome (SARS) coronavirus: plications for developing SARS diagnostics and vaccines. J Immunol, 2004, 3: 4050-4057.
9 Pang H, Liu Y, Han X, et al. Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine. J Gen Virol, 2004, 85: 3109-3113.
10 Seto WH, Tsang D, Yung R, et al. Effectiveness of precautions agaist droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome(SARS). Lancet, 2003, 361: 1519-1520.
11 Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med, 2003, 348: 1967-1976.
12 Cinatl JJ, Hoever G, Morgenstern B, et al. Infection of cultured intestinal epithelial cells with severe acute respiratory syndrome coronavirus. Cell Mol Life Sc, 2004, 61: 2100-2112.
13 Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426,450-454.
14 Jeffers SA, Tusell SM, Laura GR, et al. CD209L (L-SIGN) is a receptorfor severe acute respiratory syndrome coronavirus. PNAS, 2004, 101, 15748-15753.
15 Glass WG, Subbarao K, Murphy B, et al. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol, 2004,173: 4030-4039.
16 Barnard DL, Hubbard VD, Burton J, et al. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivi Chem Chemother, 2004, 15: 15-22.
17 周先志，赵敏，王福生，等．北京地区首批SARS病人的发病特点和临床诊治．中华医学杂志，2003，83：1018-1021．
18 Liu JH, Ma SX, Ouyang X, et al. Determination and comparison of anti-SARS antibody in children and adults. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2004, 12: 217-219.
19 Zhao Z, Zhang F, Xu M, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol, 2003, 52: 715-720.
20 Zhou XZ, Yang YP, Zou ZS, et al. Diganosis and treatment severe SARS. Rev Int Set Sante Forces Ammess, 2004, 77: 63-66.
21 Lee N, Hui D, Wu A, et al. A Major Outbreak of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med, 2003, 348: 1986-1994.
22 Chau TN, Lee PO, Choi KW, et al. Value of initial chest radiographs for predicting clinical outcomes in patients with severe acute respiratory syndrome. Am J Med, 2004, 117: 249-254.
23 Chan CW, Chiu W-K, Chan CC, et al. Osteonecrosis in children with severe acute respiratory syndrome. Pediatr Infect Dis J, 2004, 23: 888-890.
1 Bomsel M. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell barrier. Nat Med, 1997, 3: 42-47.
2 Meng G, Wei X, Wu X, et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med, 2002, 8: 150-156.
3 Yahi N, Baghdiguian S, Moreau H, et al. Galactosyl ceramide (or a closely related molecule) is the receptor for human immunodeficiency virus type 1 on human colon epithelial HT29 cells. J Virol, 1992, 66: 4848-4854.
4 Bouhlal H, Chomont N, Haeffher-Cavaillon N, et al. Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells. J Immunol, 2002,169:3301-3306.
5 Van de Perre P. Mother-to-child transmission of HIV-1: the 'all mucosal' hypothesis as a predominant mechanism of transmission. AIDS, 1999, 13:1133-1138.
6 Koulinska IN, Villamor E, Chaplin B, et al. Transmission of cell-free and cell-associated HIV-1 through breast-feeding. J Acquir Immune Defic Syndr, 2006,41:93-99.
7 Liu X, Zha J, Chen H, et al. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes.J Virol, 2003, 77:3470-3476.
8 Amerongen HM, Weltzin R, Farnet CM, et al. Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS. J Acquir Immune Defic Syndr, 1991,4:760-765.
9 Owen R. M cells as portals of entry for HIV. Pathobiology, 1998, 66:141-144.
10 Fotopoulos G, Harari A, Michetti P, et al. Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc Natl Acad Sci USA, 2002, 99:9410-9414.
11 Smith PD, Meng G, Sellers MT, et al. Biological parameters of HIV-1 infection in primary intestinal lymphocytes and macrophages. J Leukoc Biol, 2000,68:360-365.
12 Meng G, Sellers MT, Mosteller-Barnum M, et al. Lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and are the likely target cell for human immunodeficiency virus type 1 in the intestinal mucosa. J Infect Dis, 2000,182:785-791.
13 Ndolo T, Rheinhardt J, Zaragoza M, et al. Alterations in RANTES gene expression and T-cell prevalence in intestinal mucosa during pathogenic or nonpathogenic simian immunodeficiency virus infection. Virology, 1999, 259:110-118.
14 Anton PA, Elliott J, Poles MA, et al. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS, 2000,14:1761-1765.
15 Poles MA, Elliott J, Taing P, et al. A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol, 2001, 75:8390-8399.
16 Geijtenbeek TBH, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell, 2000,100:587-597.
17 Engering A, Van Vliet SJ, Geijtenbeek TBH, et al. Subset of DC-SIGN(+)dendritic cells in human blood transmits HIV-1 to T lymphocytes.blood, 2002,100:1780-1786.
18 Geijtenbeek TBH, Engering A, van Kooyk Y. DC-SIGN,a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology. J Leukoc Biol, 2002, 71:921-931.
19 Karin L, Anna SS, Jayanand V, et al. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells.JEM, 2005,201:2023-2033.
20 Kwon DS, Gregorio G, Bitton N, et al. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity, 2002, 16:135-144.
21 Angela GP, Angelika G, Christine T, et al. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci USA, 2004,101:7669-7674.
22 Fantini J, Yahi N, Delezay O, et al. GalCer, CD26 and HIV infection of intestinal epithelial cells. AIDS, 1994, 8:1347-1351.
23 Kotler DP, Reka S, Borcich A, et al. Detection, localization,and quantitation of HIV-associated antigens in intestinal biopsies from patients with HIV. Am JPathol, 1991,139:823-830.
24 Neildez O, Le Grand R, Caufour P, et al. Selective quasispecies transmission after systemic or mucosal exposure of macaques to simian immunodeficiency virus. Virology, 1998,243:12-20.
25 Harouse JM, Gertie A, Tan RC, et al. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science, 1999, 284:816-819.
26 Poles MA, Elliott J, Vingerhoets J, et al. Despite high concordance, distinct mutational and phenotypic drug resistance profiles in human immunodeficiency virus type 1 mRNA are observed in gastrointestinal mucosal biopsy specimens and peripheral blood mononuclear cells compared with plasma. J Infect Dis, 2001, 183:143-148.
27 Schneider T, Jahn HU, Schmidt W, et al. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Gut, 1995, 37:524-529.
28 Clayton F, Snow G, Reka S, et al. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin Exp Immunol, 1997,107:288-292.
29 Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 1998,280:427-431.
30 Fackler OT, Schafer M, Schmidt W, et al. HIV-1 p24 but not proviral load is increased in the intestinal mucosa compared with the peripheral blood in HIV-infected patients. AIDS, 1998,12:139-146.
31 Schmidt W, Fackler OT, Schafer M, et al. Similar proviral load but increased HIV-1 p24 in the intestinal mucosa compared to the peripheral blood in HIV-infected patients. Ann NY Acad Sci, 1998, 859:276-279.
32 Finkel TH, Tudor Williams G, Banda NK, et al. Apoptosis occurs predominantly in bystander cells and not productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med, 1995,1:129-134.
33 Boirivant M, Viora M, Giordani L, et al. HIV-1 gp120 accelerates Fas-mediated activation-induced human lamina propria T cell apoptosis. J Clin Immunol, 1998,18:39-47.
34 Talal AH, Irwin CE, Dieterich DT, et al. Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr, 2001,26:208-217.
35 McGowan, Ian MD, Elliott, et al. Increased HIV-1 Mucosal Replication Is Associated With Generalized Mucosal Cytokine Activation. J Acquir Immune Defic Syndr, 2004, 37:1228-1236.
36 Olsson J, Poles M, Spetz AL, et al. Human immunodeficiency virus type 1 infection is associated with significant mucosal inflammation characterized by increased expression of CCR5, CXCR4, and beta-chemokines. J Infect Dis, 2000,182:1625-1635.
37 Clayton F, Cronin WJ, Reka S, et al. Rectal mucosal histopathology in HIV infection varies with disease stage and HIV protein content. Gastroenterology, 1992,103:919-933.
2 Ross MJ, Koltman PE. HIV-associated nephropathy. AIDS, 2004, 18:1089-1099.
3 Zhong J, Zuo Y, Ma J, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int, 2005, 68:1048-1060.
4 He JC, Husain M, Sunamoto M, et al. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1, 2 pathways. J Clin Invest, 2004, 114:643-651.
5 Kramer-Hammede S, Rothenaigner I, Wolff H, et al. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res, 2005, 111:194-213.
6 Bissel SJ, Willey CA. Human immunodeficiency virus infection of the brain: pitfalls in evaluating infected/affected cell populations. Brain Pathol, 2004, 14:97-108.
7 Liu Y, Liu H, Kim BO, et al. CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol, 2004, 78:4120-4133.
8 Thompson KA, Churchill MJ, Gony PR, et al. Astrocyte specific viral strains in HIV dementia. Ann Neurol, 2004, 56:873-877.
9 Veazey RS, Mansfield KG, Tham IC, et al. Dynamics of CCR5 expression by CD4~+ T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol, 2000, 74:11001-11007.
10 Guillot C, Menoret S, Guillonneau C, et al. Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig. Blood, 2003,101:3325-3333.
11 Granelli-Piperno A., Moser B, Pope M, et al. Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J Exp Med, 1996,184:2433-2438.
12 Rubbert A, Combadiere C, Ostromski M, et al. Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry. J Immunol, 1998,160:3933-3941.
13 Turville SG, Artho J, Donald KM, et al. HIV gp120 receptors on human dendritic cells. Blood, 2001, 98:2482-2488.
14 Ignatius R, Wei Y, Beaulieu S, et al. The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells. AIDS Res. Hum. Retroviruses, 2000, 16:1055-1059.
15 Geijtenbeek TB, Torensma R, van Vilet SJ, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell, 2000,100:575-585.
16 Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cellspecific HIV-1-binding protein that enhances transinfection of T cells. Cell, 2000,100:587-597.
17 Teleshova N, Frank I, Pope M. Immunodeficiency virus exploitation of dendritic cells in the early steps of infection. J Leukoc Biol, 2003, 74:683-690.
18 McDonald D, Wu L, Bohks SM, et al. Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science, 2003, 300:1295-1297.
19 Izmailova E, Bertley FM, Huang Q, et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat Med, 2003, 9:191-197.
20 Salahuddin SZ, Rose RM, Groopman JE, et al. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood, 1986, 68:281-284.
21 Sierra-Madero JG, Toossi Z, Hom DL, et al. Relationship between load of virus in alveolar macrophages from human immunodeficiency virus type 1-infected persons, production of cytokines, and clinical status. J Infect Dis, 1994, 169:18-27.
22 Meireles de Souza LR, Shattock RL. Therapeutic role of CD8~+ T cells in HIV-1 infection: targets and suppressors of viral replication. Expert opin Biol Ther, 2005, 5:321-323.
23 Rappocciolo G, Piazza P, Fuller CL, et al. DC-SIGN on B lymphocytes is required for transmission of HFV-1 to T lymphocytes. PloS pathog, 2006, 2:691-704.
24 Moir S, Malaspina A, Li Y, et al. B cells of HIV-1-infected patients bind virions through CD21 -complement interactions and transmit infectious virus to activated T cells. J Exp Med, 2000,192: 637-646.
25 Malaspina A, Moir S, Nickle DC, et al. Human immunodeficiency virus type 1 bound to B cells: relationship to virus replicating in CD4tT cells and circulating in plasma. J Virol, 2002, 76: 8855-8863.
26 Dopper S, Wilflingseder D, Prodinger WM, et al. Mechanism(s) promoting HIV-1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co-cultures. Eur J Immunol, 2003, 33:2098-2107.
27 Asin SN, Fanger MW, Wildt-Perinic D, et al. Transmission of HIV-1 by primary human uterine epithelial cells and stromal fibroblasts. J Infect Dis, 2004,190:236-245.
28 Meng G, Wei X, Wu X, et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med, 2002, 8:150-156.
29 Yahi N, Baghdiguian S, Moreau H, et al. Galactosyl ceramide (or a closely related molecule) is the receptor for human immunodeficiency virus type 1 on human colon epithelial HT29 cells. J Virol, 1992,66:4848-4854.
30 Liu X, Zha J, Chen H, et al. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes. J Virol, 2003, 77:3470-3476.
31 Koulinska IN, Villamor E, Chaplin B, et al. Transmission of cell-free and cell-associated HIV-1 through breast-feeding. J Acquir Immune Defic Syndr, 2006,41:93-99.
32 Ledergerber B, Flepp M, Boni J, et al. HIV-1 p24 concentration measured by boosted ELISA of heat-denatured plasma correlates with decline in CD4 cells, progression to AIDS, and survival: Comparison with vira RNA measurement. J Infect Dis, 2000,181: 1280-1288.
33 Sterling TR, Hoover DR, Astemborski J, et al. Heat-denatured HIV-1 protein p24 antigen: Prognostic value in adults with early stage disease. J Infect Dis, 2002,186:1181-1185.
34 Schupbach J, Boni J, Bisset LR, et al. HIV-1 p24 antigen is a signifi cant inverse correlate of CD4 T-cell change in patients with suppressed viremia under long-term antiretroviral therapy. J Acquir Immune Defic Syndr, 2003, 33: 292-299.
35 Schupbach J, Gunthard H, Joos B, et al. HIV-1 p24 may persist during long-term highly active antiretroviral therapy, increases little during short treatment breaks, and its rebound after treatment stop correlates with CD4+ T cell loss. J Acquir Immune Defi c Syndr, 2005,40: 250-256.
36 Jason MB, David AP, Timothy WS, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2006, 12:1351-1352.
1 Picker LJ, Haqen SI, Lum R, et al. Insufficient production and tissue delivery of CD4~+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004, 200: 1299-1314.
2 Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 1998, 280: 427-431.
3 Veazey RS, Marx PA, Lackner AA. Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis, 2003,187:769-776.
4 Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004,200:749-759.
5 Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004, 200:761-770.
6 Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol, 2003, 77:11708-11717.
7 Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4~+ T cells in multiple tissues during acute SIV infection. Nature, 2005, 434:1093-1097.
8 Li Q, Duan L, Estes JD, Ma ZM, et al. Peak SIV replication in resting memory CD4~+ T cells depletes gut lamina propria CD4~+ T cells. Nature, 2005, 434:1148-1152.
9 Kovacs JA, Lempecki RA, Sidorov IA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med, 2001,194:1731-1741.
10 Macallan DC, Asquith B, Irvine AJ, et al. Measurement and modeling of human T cell kinetics. Eur J Immunol, 2003,33:2316-2326.
11 McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature, 2001,410:974-979.
12 Hazenberg MD, Hamann D, Schuitemaker H, et al. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol, 2000,1:285-289.
13 Grossman Z, Meier Schellersheim M, Sousa AE, et al. CD4~+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med, 2002, 8:319-323.
14 Silvestri G, Feinberg MB. Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest, 2003, 112:821-824.
15 Guadalupe M, Reay E, Sankaran S, et al. Severe CD4~+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol, 2003, 77:11708-11717.
16 Douek DC, Betts MR, Hill BJ, et al. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J Immunol, 2001, 167:6663-6668.
17 Schacker TW, Nguyen PL, Beilman GJ, et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest, 2002, 110:1133-1139.
18 Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4~+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006, 13:556-560.
19 Estes JD, Wietgrefe S, Schacker T, et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor Beta 1-positive regulatory T cells and begins in early infection. J Infect Dis, 2007,195:551-556.
20 Dion ML, Poulin JF, Bordi R, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity, 2004,21,757-768.
21 Grossman Z, Min B, Meier Schellersheim M, et al. Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol, 2004,4, 387-395.
22 Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol, 2003,21:265-304.
23 Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006,439:682-687.
24 Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med, 2006,12:1198-1202.
25 Wherry EJ, Barber DL, Kaech SM, et al. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA, 2004,101:16004-16009.
26 Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat. Med, 2004, 10:806-810.
27 Malaspina A, Moir S, Ho J. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: Correlation with increased IL-7. Proc Natl Acad Sci USA, 2006,103:2262-2267.
28 Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation andimmunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med, 1983, 309:453-458.
29 Malaspina A, Moir S, Kottilil S, et al. Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol, 2003,170:5965-5972.
30 De Milito A., Nilsson A, Titanji K, et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood, 2004,103:2180-2186.
31 De Boer RJ, Mohri H, Ho DD, et al. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol. 2003,170:2479-2487.
32 Martinez Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol, 2002,14:528-532.
33 De Milito A, Morch C, Sonnerborg A, et al. Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS, 2001, 5:957-964.
34 Degli Esposti MA, Smyth MJ. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol, 2005, 5:112-124.
1 Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol, 2003, 21: 265-304.
2 Lawn SD, Butera ST, Folks TM. Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. Clin Microbiol Rev, 2001, 14: 753-777.
3 De Boer RJ, Mohri H, Ho DD, et al, Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol, 2003, 170: 2479-2487.
4 Lee C, Liu OH, Tomkowicz B, et al. Macrophage activation through CCR5-and CXCR4-mediated gp 120-elicitedsignaling pathways. J Leukoc Biol, 2003, 74: 676-682.
5 Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4~+ T cells. Nature, 2002, 417: 95-98.
6 Doisne JM, Urrutia A, lacabaratz Porret C, et al. CD8~+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection. J Immunol, 2004, 173: 2410-2418.
7 Brenchley JM, Hill BJ, Ambrozak DR, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol, 2004, 78, 1160-1168.
8 Grossman Z, Min B, Meier Schellersheim M, et al. Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol, 2004,4, 387-395.
9 Schindler M, Munch J, Kutsch O, et al. nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1. Cell, 2006,125:1034-1035.
10 Schacker TW, Nguyen PL, Beilman GJ, et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest, 2002, 110:1133-1139.
11 Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006, 13:556-560.
12 Estes JD, Wietgrefe S, Schacker T, et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor Beta 1-positive regulatory T cells and begins in early infection. J Infect Dis, 2007,195:551-556.
13 Silvestri G, Feinberg MB. Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest, 2003,112:821-824.
14 Hellerstein MK, Hoh RA, Hanley MB, et al. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest, 2003, 112:956-966.
15 Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4~+ T cells in multiple tissues during acute SIV infection. Nature, 2005, 434:1093-1097.
16 Picker LJ, Haqen SI, Lum R, et al. Insufficient production and tissue delivery of CD4~+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004, 200:1299-1314.
17 Kunkel EJ, Boisvert J, Murphy K, et al. Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. Am J Pathol, 2001,160: 347-355.
18 Qin S, Rottman JB, Myers P, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest, 1998, 101: 746-754.
19 Galati D, Paiardini M, Cervasi B, et al. Specific changes in the posttranslational regulation of nucleolin in lymphocytes from patients infected with human immunodeficiency virus. J Infect Dis, 2003, 188:1483-1491.
20 Yue FY, Kovacs CM, Dimayuga RC, et al. Preferential apoptosis of HIV-1-specific CD4~+ T cells. J Immunol, 2005,174:2196-2204.
21 Smed Sorensen A, lore K, Vasudevan J, et al. Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J Virol, 2005, 79:8861-8869
22 Swingler S, Brichacek B, Jacque JM, et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature, 2003,424:213-219.
23 Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol, 2005, 174:4407-4414.
24 Min B, Foucras G, Meier Schellersheim M, et al. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci USA, 2004,101:3874-3879.
25 Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol, 2004,4:478-485.
26 Acheson DW, Luccioli S. Microbial-gut interactions in health and disease. Mucosalimmune responses. Best Pract Res Clin Gastroenterol, 2004, 18: 387-404.
27 Dion ML, Poulin JF, Bordi R, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity, 2004,21:757-768.
28 Haynes BF, Hale LP, Weinhold KJ, et al. Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J Clin Invest, 1999, 103:921.
1 WHO. Coronavirus never before seen in humans is the cause of SARS. http://www.who.int/entity/esr/sasaschive/2004-04-16/en.
2 Magiorkinis G, Magiorkinis E, Paraskevis D, et al. Phylogenetic analysis of the full-length SARS-CoV sequences: evidence for phylogenetic discordance in three genomic regions. J-Med-Virol. 2004, 74: 369-372.
3 Zhao Z, Li H, Wu X, et al. Moderate mutation rate in the SARS coronavirus genome and its implications. BMC-Evol-Biol. 2004, 4: 21.
4 Song HC, Seo MY, Stadler K, et al. Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavims spike glycoprotein. J Virol, 2004, 78: 10328-10335.
5 Ying W, Hao Y, Zhang Y, et al. Proteomic analysis on structural proteins of Severe acute respiratory syndrome coronaviru. Proteomics, 2004, 4: 492-504.
6 Luo C, Luo H, Zheng S, et al. Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A. Biochem Biophys Res Commun, 2004, 321: 557-654.
7 Arbely E, Khattar Z, Brotons G, et al. A highly unusual palindromic transmembrane helical hairpin formed by SARS coronavirus E protein. J Mol Bio, 2004, 341:769-779.
8 He Y, Zhou Y, Wu H, et al. Identification of immunodominant sites on the spike protein of Severe acute respiratory syndrome (SARS) coronavirus: plications for developing SARS diagnostics and vaccines. J Immunol, 2004, 3: 4050-4057.
9 Pang H, Liu Y, Han X, et al. Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine. J Gen Virol, 2004, 85: 3109-3113.
10 Seto WH, Tsang D, Yung R, et al. Effectiveness of precautions agaist droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome(SARS). Lancet, 2003, 361: 1519-1520.
11 Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med, 2003, 348: 1967-1976.
12 Cinatl JJ, Hoever G, Morgenstern B, et al. Infection of cultured intestinal epithelial cells with severe acute respiratory syndrome coronavirus. Cell Mol Life Sc, 2004, 61: 2100-2112.
13 Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426,450-454.
14 Jeffers SA, Tusell SM, Laura GR, et al. CD209L (L-SIGN) is a receptorfor severe acute respiratory syndrome coronavirus. PNAS, 2004, 101, 15748-15753.
15 Glass WG, Subbarao K, Murphy B, et al. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol, 2004,173: 4030-4039.
16 Barnard DL, Hubbard VD, Burton J, et al. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivi Chem Chemother, 2004, 15: 15-22.
17 周先志，赵敏，王福生，等．北京地区首批SARS病人的发病特点和临床诊治．中华医学杂志，2003，83：1018-1021．
18 Liu JH, Ma SX, Ouyang X, et al. Determination and comparison of anti-SARS antibody in children and adults. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2004, 12: 217-219.
19 Zhao Z, Zhang F, Xu M, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol, 2003, 52: 715-720.
20 Zhou XZ, Yang YP, Zou ZS, et al. Diganosis and treatment severe SARS. Rev Int Set Sante Forces Ammess, 2004, 77: 63-66.
21 Lee N, Hui D, Wu A, et al. A Major Outbreak of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med, 2003, 348: 1986-1994.
22 Chau TN, Lee PO, Choi KW, et al. Value of initial chest radiographs for predicting clinical outcomes in patients with severe acute respiratory syndrome. Am J Med, 2004, 117: 249-254.
23 Chan CW, Chiu W-K, Chan CC, et al. Osteonecrosis in children with severe acute respiratory syndrome. Pediatr Infect Dis J, 2004, 23: 888-890.
1 Bomsel M. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell barrier. Nat Med, 1997, 3: 42-47.
2 Meng G, Wei X, Wu X, et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med, 2002, 8: 150-156.
3 Yahi N, Baghdiguian S, Moreau H, et al. Galactosyl ceramide (or a closely related molecule) is the receptor for human immunodeficiency virus type 1 on human colon epithelial HT29 cells. J Virol, 1992, 66: 4848-4854.
4 Bouhlal H, Chomont N, Haeffher-Cavaillon N, et al. Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells. J Immunol, 2002,169:3301-3306.
5 Van de Perre P. Mother-to-child transmission of HIV-1: the 'all mucosal' hypothesis as a predominant mechanism of transmission. AIDS, 1999, 13:1133-1138.
6 Koulinska IN, Villamor E, Chaplin B, et al. Transmission of cell-free and cell-associated HIV-1 through breast-feeding. J Acquir Immune Defic Syndr, 2006,41:93-99.
7 Liu X, Zha J, Chen H, et al. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes.J Virol, 2003, 77:3470-3476.
8 Amerongen HM, Weltzin R, Farnet CM, et al. Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS. J Acquir Immune Defic Syndr, 1991,4:760-765.
9 Owen R. M cells as portals of entry for HIV. Pathobiology, 1998, 66:141-144.
10 Fotopoulos G, Harari A, Michetti P, et al. Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc Natl Acad Sci USA, 2002, 99:9410-9414.
11 Smith PD, Meng G, Sellers MT, et al. Biological parameters of HIV-1 infection in primary intestinal lymphocytes and macrophages. J Leukoc Biol, 2000,68:360-365.
12 Meng G, Sellers MT, Mosteller-Barnum M, et al. Lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and are the likely target cell for human immunodeficiency virus type 1 in the intestinal mucosa. J Infect Dis, 2000,182:785-791.
13 Ndolo T, Rheinhardt J, Zaragoza M, et al. Alterations in RANTES gene expression and T-cell prevalence in intestinal mucosa during pathogenic or nonpathogenic simian immunodeficiency virus infection. Virology, 1999, 259:110-118.
14 Anton PA, Elliott J, Poles MA, et al. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS, 2000,14:1761-1765.
15 Poles MA, Elliott J, Taing P, et al. A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol, 2001, 75:8390-8399.
16 Geijtenbeek TBH, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell, 2000,100:587-597.
17 Engering A, Van Vliet SJ, Geijtenbeek TBH, et al. Subset of DC-SIGN(+)dendritic cells in human blood transmits HIV-1 to T lymphocytes.blood, 2002,100:1780-1786.
18 Geijtenbeek TBH, Engering A, van Kooyk Y. DC-SIGN,a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology. J Leukoc Biol, 2002, 71:921-931.
19 Karin L, Anna SS, Jayanand V, et al. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells.JEM, 2005,201:2023-2033.
20 Kwon DS, Gregorio G, Bitton N, et al. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity, 2002, 16:135-144.
21 Angela GP, Angelika G, Christine T, et al. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci USA, 2004,101:7669-7674.
22 Fantini J, Yahi N, Delezay O, et al. GalCer, CD26 and HIV infection of intestinal epithelial cells. AIDS, 1994, 8:1347-1351.
23 Kotler DP, Reka S, Borcich A, et al. Detection, localization,and quantitation of HIV-associated antigens in intestinal biopsies from patients with HIV. Am JPathol, 1991,139:823-830.
24 Neildez O, Le Grand R, Caufour P, et al. Selective quasispecies transmission after systemic or mucosal exposure of macaques to simian immunodeficiency virus. Virology, 1998,243:12-20.
25 Harouse JM, Gertie A, Tan RC, et al. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science, 1999, 284:816-819.
26 Poles MA, Elliott J, Vingerhoets J, et al. Despite high concordance, distinct mutational and phenotypic drug resistance profiles in human immunodeficiency virus type 1 mRNA are observed in gastrointestinal mucosal biopsy specimens and peripheral blood mononuclear cells compared with plasma. J Infect Dis, 2001, 183:143-148.
27 Schneider T, Jahn HU, Schmidt W, et al. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Gut, 1995, 37:524-529.
28 Clayton F, Snow G, Reka S, et al. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin Exp Immunol, 1997,107:288-292.
29 Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 1998,280:427-431.
30 Fackler OT, Schafer M, Schmidt W, et al. HIV-1 p24 but not proviral load is increased in the intestinal mucosa compared with the peripheral blood in HIV-infected patients. AIDS, 1998,12:139-146.
31 Schmidt W, Fackler OT, Schafer M, et al. Similar proviral load but increased HIV-1 p24 in the intestinal mucosa compared to the peripheral blood in HIV-infected patients. Ann NY Acad Sci, 1998, 859:276-279.
32 Finkel TH, Tudor Williams G, Banda NK, et al. Apoptosis occurs predominantly in bystander cells and not productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med, 1995,1:129-134.
33 Boirivant M, Viora M, Giordani L, et al. HIV-1 gp120 accelerates Fas-mediated activation-induced human lamina propria T cell apoptosis. J Clin Immunol, 1998,18:39-47.
34 Talal AH, Irwin CE, Dieterich DT, et al. Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr, 2001,26:208-217.
35 McGowan, Ian MD, Elliott, et al. Increased HIV-1 Mucosal Replication Is Associated With Generalized Mucosal Cytokine Activation. J Acquir Immune Defic Syndr, 2004, 37:1228-1236.
36 Olsson J, Poles M, Spetz AL, et al. Human immunodeficiency virus type 1 infection is associated with significant mucosal inflammation characterized by increased expression of CCR5, CXCR4, and beta-chemokines. J Infect Dis, 2000,182:1625-1635.
37 Clayton F, Cronin WJ, Reka S, et al. Rectal mucosal histopathology in HIV infection varies with disease stage and HIV protein content. Gastroenterology, 1992,103:919-933.