Cytomegalovirus persistence by evasion from immune control

Cytomegaloviruses (CMV) are members of the ubiquitous family of herpesviruses. The infection is characterized by a highly variable course of disease. The virus-host balance is dependent upon the state of the immune system. Several immune mechanisms independently contribute to virus control. The virus escapes immunological clearance and persists throughout life in the infected host. CMV apparently encodes more than one function which modulate the host surveillance. Some tissues are exempt from control and allow local virus persistence. Other host-interactive genes can be directly monitored by their interaction with proteins of defined immunological function. Sequence homology indicates the existence of additional putative host-interactive genes.     

Measles: immune suppression and immune responses

Measles is a highly contagious viral disease that remains the leading vaccine-preventable cause of child mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. Several abnormalities of the immune system have been described, including changes in lymphocyte number and function, shifts in cytokine responses, immunomodulatory effects of interleukin-10, down regulation of interleukin-12, impaired antigen presentation, and altered interferon alpha/beta signaling pathways. Although the current vaccine is very effective, knowledge of the molecular basis of the immune responses to measles virus could contribute to the development of a safer, more immunogenic measles vaccine. However, the safety of new measles vaccines must be carefully investigated, as two measles vaccines have resulted in unintended immunologic consequences: atypical measles following administration of the formalin-inactivated measles vaccine and increased mortality in girls following administration of high-titer measles vaccines.     

Virus persistence and immune memory

Viral infections and live vaccines often confer long-term immunity. This article contrasts the nature of antiviral T and B cell memory and takes a critical look at the role of viral persistence in maintaining immunity.     

Vaccinia virus persistence in a child against the background of immune deficiency

A young girl, vaccinated against smallpox 6 years before suffered from a persistent vaccinia virus infection and a congenital skin disease, i.e. epidermolysis bullosa. The virus was isolated from skin lesions at the vaccination site and remote sites and repeatedly from the blood; it was not isolated from bone-marrow specimen, saliva, pharynx or urine. The titre of virus-neutralizing antibodies was low (1:10), immunoglobulins A, M and G were within age-related limits; antibodies against measles and tetanus were at protective levels, skin tests were positive. Staphylococcal antitoxin titre was extremely high. The child's mother, not vaccinated against smallpox, possessed vaccinia--virus-neutralizing antibodies at high titre (over 1:320). Examination of the child did not show any quantitative immune deficiency. Immune deviations were found in the lymphocyte blast-transformation reaction on stimulation with PHA and specific antigen, as well as in the nonspecific-suppression test. The possible genesis of the virus persistence and the role of the virus in the clinical course of the disease are discussed.     

Measles virus polypeptides in infected cells studied by immune precipitation and one-dimensional peptide mapping.

Measles virus does not turn off host cell polypeptide synthesis, making it difficult to precisely identify the polypeptides specified by the virus during the infectious cycle. By using the technique of immune precipitation with measles-specific antisera, the host cell background has been eliminated, and new observations have been made concerning measles virus polypeptides H, P, NP, F, and M. The H polypeptide is first synthesized as a monomer which is processed by further glycosylation and by the formation of disulfide-bonded dimers. Polypeptide P (70,000 daltons) has been found to occur also as a 65,000-dalton molecule, P2, and both forms of the molecule are equally phosphorylated. Polypeptide NP is processed from a cleavage-sensitive form (which undergoes cleavage during the process of isolation to form polypeptide 6 [41,000 daltons]) to a form which is resistant to this cleavage. The fusion and hemolysin polypeptide is first found in the cells as a 55,000-dalton precursor, F0, which is clearly resolved from the NP polypeptide on gel electrophoresis. The measles virus F0 protein identified in previous reports had not been resolved from the 60,000-dalton NP polypeptide. The M protein occurs in the infected cells as two distinct bands, and, as in the case of Sendai virus, one of these two M protein bands represents a phosphorylated form of the other.     

Measles virus neurovirulence and host immunity

Measles virus is highly neuroinvasive, yet host immune responses are highly effective at limiting neurovirulence in humans. We know that neurons are an important target of infection and that both IFN-γ and -β expression are observed in the measles virus-infected human brain. Rodent models can be used to understand how this response is orchestrated. Constitutive expression of the major inducible 70-kDa heat-shock protein is a feature of primate tissues that is lacking in mice. This article examines the importance of addressing this difference when modeling outcomes of brain infection in mice, particularly in terms of understanding how infected neurons may activate uninfected brain macrophages to produce IFN-β and support T-cell production of IFN-γ, a mediator of noncytolytic viral clearance. New and historical data suggest that the virus heat-shock protein 70 relationship is key to a protective host immune response and has potential broad relevance.     

Innate immune control of West Nile virus infection

West Nile virus (WNV), from the Flaviviridae family, is a re-emerging zoonotic pathogen of medical importance. In humans, WNV infection may cause life-threatening meningoencephalitis or long-term neurologic sequelae. WNV is transmitted by Culex spp. mosquitoes and both the arthropod vector and the mammalian host are equipped with antiviral innate immune mechanisms sharing a common phylogeny. As far as the current evidence is able to demonstrate, mosquitoes primarily rely on RNA interference, Toll, Imd and JAK-STAT signalling pathways for limiting viral infection, while mammals are provided with these and other more complex antiviral mechanisms involving antiviral effectors, inflammatory mediators, and cellular responses triggered by highly specialized pathogen detection mechanisms that often resemble their invertebrate ancestry. This mini-review summarizes our current understanding of how the innate immune systems of the vector and the mammalian host react to WNV infection and shape its pathogenesis.     

Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin

Measles is one of the most contagious human infectious diseases and remains a major cause of childhood morbidity and mortality worldwide. The signaling lymphocyte activation molecule (SLAM), also called CD150, is a cellular receptor for measles virus (MV), presumably accounting for its tropism for immune cells and its immunosuppressive properties. On the other hand, pathological studies have shown that MV also infects epithelial cells at a later stage of infection, although its mechanism has so far been unknown. In this study, we show that wild-type MV can infect and produce syncytia in human polarized epithelial cell lines independently of SLAM and CD46 (a receptor for the vaccine strains of MV). Progeny viral particles are released exclusively from the apical surface of these polarized epithelial cell lines. We have also identified amino acid residues on the MV attachment protein that are likely to interact with a putative receptor on epithelial cells. All of these residues have aromatic side chains and may form a receptor-binding pocket located in a different position from the putative SLAM- and CD46-binding sites on the MV attachment protein. Thus, our results indicate that MV has an intrinsic ability to infect both polarized epithelial and immune cells by using distinctive receptor-binding sites on the attachment protein corresponding to each of their respective receptors. The ability of MV to infect polarized epithelial cells and its exclusive release from the apical surface may facilitate its efficient transmission via aerosol droplets, resulting in its highly contagious nature.     

Measles virus assembly within membrane rafts

During measles virus (MV) replication, approximately half of the internal M and N proteins, together with envelope H and F glycoproteins, are selectively enriched in microdomains rich in cholesterol and sphingolipids called membrane rafts. Rafts isolated from MV-infected cells after cold Triton X-100 solubilization and flotation in a sucrose gradient contain all MV components and are infectious. Furthermore, the H and F glycoproteins from released virus are also partly in membrane rafts (S. N. Manié et al., J. Virol. 74:305-311, 2000). When expressed alone, the M but not N protein shows a low partitioning (around 10%) into rafts; this distribution is unchanged when all of the internal proteins, M, N, P, and L, are coexpressed. After infection with MGV, a chimeric MV where both H and F proteins have been replaced by vesicular stomatitis virus G protein, both the M and N proteins were found enriched in membrane rafts, whereas the G protein was not. These data suggest that assembly of internal MV proteins into rafts requires the presence of the MV genome. The F but not H glycoprotein has the intrinsic ability to be localized in rafts. When coexpressed with F, the H glycoprotein is dragged into the rafts. This is not observed following coexpression of either the M or N protein. We propose a model for MV assembly into membrane rafts where the virus envelope and the ribonucleoparticle colocalize and associate.     

森林脑炎灭活疫苗加强免疫效果及免疫持久性观察

目的评价森林脑炎灭活疫苗加强免疫效果以及免疫持久性。方法采用单中心无对照设计,在吉林省选择571名≥8岁受试者进行疫苗基础免疫,其中400名受试者进行加强免疫,加强免疫后选择54名进行免疫持久性研究。于基础免疫前及免疫后1、6和12个月分别采血,加强免疫前及免疫后1、6、12、18、24、30、36和42个月分别采血检测抗体浓度,计算抗体阳性率和抗体几何平均浓度(geometric mean concentration, GMC)。结果基础免疫后1、6和12个月,抗体阳性率分别为96.05%、86.45%、76.95%,GMC值分别为753、332和225 VIEU/mL。加强免疫后1、6和12个月,抗体阳性率分别为95.87%、94.33%、91.54%,GMC值分别为3 391、2 322和1 981 VIEU/mL。加强免疫后42个月GMC值为747 VIEU/mL。结论森林脑炎疫苗加强免疫后具有良好的免疫持久性,与基础免疫相比,加强免疫具有更好的免疫应答。     

Measles virus and immunomodulation: molecular bases and perspectives

Measles virus (MV) remains among the most potent global pathogens, killing more than 1 million children annually. The virus induces a profound suppression of immune functions that favours the establishment of, and aggravates the course of, secondary infections. By contrast, MV-specific immune responses are efficiently generated, and these clear the virus from the organism and confer a long-lasting immunity. As sensitisers of pathogen encounter and instructors of the adaptive immune response, professional antigen-presenting cells (APCs) such as dendritic cells play a decisive role in the induction and quality of the MV-specific immune response. However, key features of immune suppression associated with MV are compatible with interference with APC maturation and function, and subsequent qualitative and quantitative alterations of T-cell activation.