Immunopathogenesis of dengue virus infection

Dengue virus infection causes dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), whose pathogeneses are not clearly understood. Current hypotheses of antibody-dependent enhancement, virus virulence, and IFN-gamma/TNFalpha-mediated immunopathogenesis are insufficient to explain clinical manifestations of DHF/DSS such as thrombocytopenia and hemoconcentration. Dengue virus infection induces transient immune aberrant activation of CD4/CD8 ratio inversion and cytokine overproduction, and infection of endothelial cells and hepatocytes causes apoptosis and dysfunction of these cells. The coagulation and fibrinolysis systems are also activated after dengue virus infection. We propose a new hypothesis for the immunopathogenesis for dengue virus infection. The aberrant immune responses not only impair the immune response to clear the virus, but also result in overproduction of cytokines that affect monocytes, endothelial cells, and hepatocytes. Platelets are destroyed by crossreactive anti-platelet autoantibodies. Dengue-virus-induced vasculopathy and coagulopathy must be involved in the pathogenesis of hemorrhage, and the unbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS. Hemostasis is maintained unless the dysregulation of coagulation and fibrinolysis persists. The overproduced IL-6 might play a crucial role in the enhanced production of anti-platelet or anti-endothelial cell autoantibodies, elevated levels of tPA, as well as a deficiency in coagulation. Capillary leakage is triggered by the dengue virus itself or by antibodies to its antigens. This immunopathogenesis of DHF/DSS can account for specific characteristics of clinical, pathologic, and epidemiological observations in dengue virus infection.     

Immunopathogenesis of hepatitis B virus infection

Hepatitis B virus (HBV) infection is a non-cytopathic hepatotropic virus that can lead to severe liver disease including acute hepatitis, cirrhosis and hepatocellular carcinoma. Successful clearance of the virus as well as the establishment of liver disease is largely driven by a complex interaction between the virus and the host immune response. In this review, the immunological events, including both the innate and adaptive immune response are discussed in the setting of both acute and chronic HBV infection and liver disease.     

Immunopathogenesis of hepatitis C virus infection

Hepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined.     

Immunopathogenesis of coronavirus infections: implications for SARS

At the end of 2002, the first cases of severe acute respiratory syndrome (SARS) were reported, and in the following year, SARS resulted in considerable mortality and morbidity worldwide. SARS is caused by a novel species of coronavirus (SARS-CoV) and is the most severe coronavirus-mediated human disease that has been described so far. On the basis of similarities with other coronavirus infections, SARS might, in part, be immune mediated. As discussed in this Review, studies of animals that are infected with other coronaviruses indicate that excessive and sometimes dysregulated responses by macrophages and other pro-inflammatory cells might be particularly important in the pathogenesis of disease that is caused by infection with these viruses. It is hoped that lessons from such studies will help us to understand more about the pathogenesis of SARS in humans and to prevent or control outbreaks of SARS in the future.     

Immunopathogenesis of poxvirus infections: forecasting the impending storm

Variola virus, the causative agent of smallpox, is a member of the poxvirus family and one of the most virulent human pathogens known. Although smallpox was eradicated almost 30 years ago, it is not understood why the mortality rates associated with the disease were high, why some patients recovered, and what constitutes an effective host response against infection. As variola virus infects only humans, our current understanding of poxvirus infections comes largely from historical clinical data from smallpox patients and from animal studies using closely related viruses such as ectromelia, myxoma and monkeypox. The outcome of an infection is determined by a complex interaction between the type of immune response mounted by the host and by evasion mechanisms that the virus has evolved to subvert it. Disease pathogenesis is also a function of both host and viral factors. Poxviruses are not only cytopathic, causing host tissue damage, but also encode an array of immunomodulatory molecules that affect the severity of disease. The ability of the host to control virus replication is therefore critical in limiting tissue damage. However, in addition to targeting virus, the immune response can inadvertently damage the host to such a degree that it causes illness and even death. There is growing evidence that many of the symptoms associated with serious poxvirus infections are a result of a 'cytokine storm' or sepsis and that this may be the underlying cause of pathology.     

Parasite infections in AIDS

'Illnesses no one's got' was the epidemiological clue that led to the identification of AIDS as a new disease in 1981 when a rare infectious organism Pneumocystis carinii was seen in previously healthy homosexuals. Since then a wide range of parasite infections has been recognized in AIDS patients. However, these patients are not susceptible to just any passing parasite. The human immunodeficiency virus (HIV) produces a specific immune defect and only parasites that can exploit that defect will be able to flourish. In this review Diana Lockwood and Jonathan Weber explore the spectrum of parasite diseases recognized in AIDS and also consider those parasites that occur infrequently in AIDS. Analysis of parasitic infections that AIDS patients do not suffer from will yield valuable information about immune recognition and handling of these parasites.     

Inflammation in virus infections

This review addresses general aspects of the nature of the cellular response in sites of viral pathology. The virus-induced inflammatory process reflects the operation of a broad spectrum of host defence mechanisms ranging, in the phylogenetic sense, from the most primitive (e.g. simple phagocytosis) to the specific immunity characteristic of the higher vertebrates. The pattern of cellular extravasation is also determined by the nature of the particular pathogen, being influenced by such factors as the extent of viral cytopathology and the spectrum of cytokine production. The presence of substantial numbers of activated T cells and macrophages in a particular tissue may have both beneficial and deleterious consequences. We now have a relatively clear concept of the factors governing the specificity of the CD4⁺ and CD8⁺ T lymphocytes that are a central component of the cellular immune response to viruses. Much remains to be learned about the biological events that influence and characterize the effector phase of these T cells in the in vivo situation, and the interactions between various host cell populations in the target organ.     

Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections

Persistent hepatitis B virus (HBV) infection is characterized by a weak and narrowly focused CD8+ T-cell response to HBV that is thought to reflect the induction of central and/or peripheral tolerance to HBV proteins in neonatal and adult onset infections, respectively. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may lead to viral clearance in chronically infected individuals. The present study was performed to compare the relative immunogenicities and tolerogenicities of HBV structural (envelope [ENV]) and nonstructural (polymerase [POL]) proteins at the CD8+ cytotoxic T lymphocyte (CTL) level in transgenic mice that replicate HBV in the liver and secrete infectious virus into the blood, thus representing an excellent model of persistent HBV infection. Interestingly, the mice were tolerant to the ENV but not to the POL proteins at the CTL level. Furthermore, the POL-specific CTLs had no impact on HBV replication or liver function in vivo, even though they were readily induced and reached the liver after DNA immunization, reflecting their relatively low avidity and the low level at which the POL protein is expressed by the hepatocyte. Collectively, these results suggest that the factors that make POL less tolerogenic also make POL-specific CTLs relatively inefficient effector cells when they reach the target organ. Immunotherapeutic strategies to control HBV infection by inducing virus-specific CTL responses in chronically infected subjects should be evaluated in light of this observation.     

艾滋病患者侵袭性真菌感染的治疗

艾滋病患者由于严重免疫缺陷而易于并发各种机会感染和肿瘤。高效抗反转录病毒联合治疗(HAART)的出现明显改善了艾滋病患者的预后,提高了患者生存质量,随着HAART在临床的广泛使用,艾滋病患者出现各种机会感染包括侵袭性真菌感染的概率大大降低。然而,由于我国艾滋病患者明确诊断时大多处于疾病晚期,机体免疫功能极低;部分患者尽管接受了HAART,但是由于依从性、病毒耐药性等原因导致患者未能出现良好的应答反应,患者的免疫功能仍未能得到     

AIDS and its virus]

An etiological agent of AIDS is a human retrovirus called HIV. The genomic structure of HIV features regulatory genes in which tat and rev genes control the viral replication and affect cellular functions. Understanding their molecular mechanism may provide a clue to prevent the onset of AIDS from the viral carriers and to direct drug designing of AIDS.