病毒學(xué)雙語(yǔ)版

1、© Academic Press, 2000.,Evasion of Immune Responses by Viruses,Inhibition of MHC I-Restricted Antigen Presentation:CTLs can only respond to foreign antigens presented by MHC I complexes on the target cell.A numbe

2、r of viruses interfere with MHC I expression or function to disrupt this process & evade the CTL response.Such mechanisms include downregulation of MHC I expression by adenoviruses & interference with the antige

3、n processing required to form an MHC I-antigen complex by herpesviruses.,© Academic Press, 2000.,Evasion of Immune Responses by Viruses,Inhibition of MHC II Restricted-Antigen Presentation:MHC-II antigens are essen

4、tial in the adaptive immune response in order to stimulate the development of antigen-responsive clones of effector cells.Herpesviruses & papillomaviruses interfere with the processing & surface expression of MH

5、C II-antigen complexes, inhibiting the CTL response.Inhibition of Natural Killer Cell Lysis:The poxvirus Molluscum contagiosum encodes a homologue of MHC I which is expressed on the surface of infected cells but is una

6、ble to bind an antigenic peptide, thus avoiding killing by NK cells which would be triggered by the absence of MHC I on the cell surface.Similar proteins are made by other viruses such as HHV-5 (CMV), & herpesviruse

7、s in general appear to have a number of sophisticated mechanisms to avoid NK cell killing.,© Academic Press, 2000.,Evasion of Immune Responses by Viruses,Inhibition of Cytokine Action:Cytokines are secreted polypep

8、tides that co-ordinate important aspects of the immune response, including inflammation, cellular activation, proliferation, differentiation, & chemotaxis.Some viruses are able to inhibit the expression of certain c

9、hemokines directly.Herpesviruses & poxviruses encode "viroceptors" - virus homologs of host cytokine receptors which compete with cellular receptors for cytokine binding but fail to give trans-membrane sig

10、nals.High-affinity binding molecules may also neutralize cytokines directly, & molecules known as "virokines" block cytokine receptors again without activating the intracellular signalling cascade.,©

11、Academic Press, 2000.,Evasion of Immune Responses by Viruses,Interference with ApoptosisVirus Resistance to Interferons:Epstein-Barr virus EBER RNAs are similar in structure & function to the adenovirus VA RNAs.T

12、he EBNA-2 protein also blocks interferon-induced signal transductionVaccinia virus is known to show resistance to the antiviral effects of interferons.One of the early genes of this virus, K3L, encodes a protein which

13、is homologous to eIF-2? which inhibits the action of PKR. In addition, the E3L protein also binds dsRNA & inhibits PKR activationPoliovirus infection activates a cellular inhibitor of PKR in virus-infected cellsRe

14、ovirus capsid protein ?3 is believed to sequester dsRNA & therefore prevent activation of PKR,© Academic Press, 2000.,Evasion of Immune Responses by Viruses,Evasion of Humoral Immunity:Although direct humoral i

15、mmunity is less significant than cell-mediated immunity, the anti-viral action of ADCC & complement make this a worthwhile target to inhibit.The most frequent means of subverting the humoral response is by high freq

16、uency genetic variation of the B cell epitopes on antigens to which antibodies bind.This is only possible for viruses which are genetically variable, e.g. influenza virus & HIV.Herpesviruses use alternative strateg

17、ies such as encoding viral Fc receptors to prevent Fc-dependent immune activation.,© Academic Press, 2000.,Evasion of Immune Responses by Viruses,Evasion of the Complement Cascade:Poxviruses, herpesviruses & r

18、etrovirus families encode mimics of normal regulators of complement activation proteins, e.g. secreted proteins which block C3 convertase assembly & accelerate its decay.Poxviruses can also inhibit C9 polymerization

19、, preventing membrane permeabilization.,© Academic Press, 2000.,Virus-Host Interactions,For all viruses, pathogenic or non-pathogenic, the first factor which influences the course of infection is the mechanism &

20、 site of entry into the body:,© Academic Press, 2000.,The Skin:,Mammalian skin is a highly effective barrier against viruses.The outer layer (epidermis) consists of dead cells & therefore does not support virus

21、 replication.Very few viruses infect directly by this route unless there is prior injury such as minor trauma or puncture of the barrier, such as insect or animal bites or subcutaneous injections.Some viruses which do

22、use this route are herpes simplex virus & papillomaviruses, although these viruses probably still require some form of disruption of the skin such as small abrasions or eczema.,© Academic Press, 2000.,Mucosal Me

23、mbranes:,The mucosal membranes of the eye & genitourinary (GU) tract are much more favourable routes of access for viruses to the tissues of the body.This is reflected by the number of viruses which can be sexually

24、 transmitted; virus infections of the eye are also quite common.,© Academic Press, 2000.,The Alimentary Canal:,Viruses may infect the alimentary canal via the mouth, oropharynx, gut, or rectum, although viruses whic

25、h infect the gut via the oral route must survive passage through the stomach, an extremely hostile environment with a very low pH & high concentrations of digestive enzymes.The gut is a highly valued prize for virus

26、es - the intestinal epithelium is constantly replicating & there is a good deal of lymphoid tissue associated with the gut which provides many opportunities for virus replication.Moreover, the constant intake of foo

27、d & fluids provides ample opportunity for viruses to infect these tissues.To counteract this problem, the gut has many specific (e.g. secretory antibodies) & non-specific (e.g. stomach acids & bile salts) de

28、fence mechanisms.,© Academic Press, 2000.,The Respiratory Tract:,The respiratory tract is probably the most frequent site of virus infection.As with the gut, it is constantly in contact with external virus particle

29、s which are taken in during respiration.As a result, the respiratory tract also has defences aimed at virus infection - filtering of particulate matter in the sinuses, & cells & antibodies of the immune system p

30、resent in the lower regions.Viruses which infect the respiratory tract usually come directly from the respiratory tract of others, since aerosol spread is very efficient: 'coughs & sneezes spread diseases'.,

31、© Academic Press, 2000.,The Natural Environment is a Considerable Barrier to Virus Infections.,Most viruses are relatively sensitive to heat, drying, ultraviolet light (sunlight), etc, although a few types are quite

32、 resistant to these factors.This is particularly important for viruses which are spread via contaminated water or foodstuffs - not only must they be able to survive in the environment until they are ingested by another

33、host, but as most are spread by the faecal-oral route, they must also be able to pass through the stomach to infect the gut before being shed in the faeces.One way of overcoming environmental stress is to take advantage

34、 of a secondary vector for transmission between the primary hosts.,© Academic Press, 2000.,Insect Vectors Offer Protection from the Environment,© Academic Press, 2000.,Virus Transmission,Viruses without a secon

35、dary vector must rely on continued host-to-host transmission, & have evolved various strategies to do this:Horizontal transmission: The direct host-to-host transmission of viruses.This strategy relies on a high ra

36、te of infection to maintain the virus populationVertical transmission: The transmission of the virus from one generation of hosts to the next.This may occur by infection of the foetus before, during, or shortly after

37、birth (e.g. during breastfeeding).More rarely, it may involve direct transfer of the virus via the germ line itself, e.g. retroviruses.In contrast to horizontal transmission, this strategy relies on long-term persisten

38、ce of the virus in the host rather than rapid propagation & dissemination of the virus.,© Academic Press, 2000.,Primary Replication,Having gained entry to a potential host, the virus must initiate an infection b

39、y entering a susceptible cell (primary replication).This initial interaction frequently determines whether the infection will remain localized at the site of entry or spread to become a systemic infection.In some cases

40、, virus spread is controlled by infection of polarized epithelial cells & the preferential release of virus from either the apical (e.g. influenza virus - a localized infection in the upper respiratory tract) or baso

41、lateral (e.g. rhabdoviruses - a systemic infection) surface of the cells.,© Academic Press, 2000.,Infection of Polarized Epithelium,© Academic Press, 2000.,Systemic Spread,Following primary replication at the s

42、ite of infection, the next stage may be spread throughout the host.In addition to direct cell-cell contact, there are two main mechanisms for spread throughout the host:Via the bloodstream: Viruses may get into the b

43、loodstream by direct inoculation, for example, by arthropod vectors, blood transfusion, or intravenous drug abuse (sharing of non-sterilized needles).Via the nervous system: Spread of virus to the nervous system is us

44、ually preceded by primary viraemia.,© Academic Press, 2000.,Clearance vs. Persistance,Virus clearance is mediated by the immune system.However, viruses are moving targets which rapidly respond to pressure from the

45、immune system by altering their antigenic composition (whenever possible).The classic example of this phenomenon is influenza virus, which displays two genetic mechanisms that allow the virus to alter its antigenic cons

46、titution:Antigenic drift: This involves the gradual accumulation of minor mutations (e.g. nucleotide substitutions) in the virus genome which result in subtly altered coding potential & therefore altered antigenici

47、ty, leading to decreased recognition by the Antigenic shift: In this process a sudden & dramatic change in the antigenicity of a virus occurs owing to reassortment of the segmented virus genome with another genome

48、of a different antigenic type.,© Academic Press, 2000.,Antigenic Variation in Influenza Virus,© Academic Press, 2000.,InfluenzaPandemics,© Academic Press, 2000.,The Course of Virus Infections,Patterns of

49、virus infection can be divided into a number of different types:Abortive infection: occurs when a virus infects a cell (or host), but cannot complete the full replication cycle. Therefore, this is a non-productive infec

50、tion.Acute infection: many common virus infections (e.g. 'colds') - relatively brief infections, where the virus is usually eliminated completely by the immune system.Chronic infection: These are the converse o

51、f acute infections, i.e. prolonged & stubborn. The best studied example is lymphocytic choriomeningitis virus (LCMV, an arenavirus) infection in mice.Latent virus infections typically persist for the entire life of

52、the host, e.g. herpes simplex virus (HSV).,© Academic Press, 2000.,Chronic LCMV Infection:,© Academic Press, 2000.,Prevention & Therapy of Virus Infections,There are two aspects of the response to the threa

53、t of virus diseases: prevention of infection & treatment of disease.The former strategy relies on two approaches: public & personal hygiene, which perhaps plays the major role in preventing virus infection (e.g.

54、 provision of clean drinking water & disposal of sewage; good medical practice such as the sterilization of surgical instruments) & vaccination, which makes use of the immune system to combat virus infections.Mo

55、st of the damage to cells during virus infections occurs very early, often before the clinical symptoms of disease appear.This makes the treatment of virus infection very difficult, & therefore, in addition to being

56、 cheaper, prevention of virus infection is undoubtedly better than cure.,© Academic Press, 2000.,Virus Vaccine Design,To design effective vaccines, it is important to understand both the immune response to virus inf

57、ection & the stages of virus replication that are appropriate targets for immune intervention.To be effective, vaccines must stimulate as many of the body's defence mechanisms as possible.In practice, this usua

58、lly means trying to mimic the disease, without of course causing pathogenesis - for example, the use of nasally administered influenza vaccines & orally administered poliovirus vaccines.To be effective, it is not ne

59、cessary to get 100% uptake of vaccine.'Herd immunity' results from the break in transmission of a virus which occurs when a sufficiently high proportion of a population has been vaccinated.This strategy is most

60、 effective where there is no alternative host for the virus, e.g. measles, & in practice is the situation that usually occurs since it is impossible to achieve 100% coverage with any vaccine.,© Academic Press, 2

61、000.,DNA Vaccines,These are the newest type of vaccine & consist of only a DNA molecule encoding the antigen(s) of interest & possibly, costimulatory molecules such as cytokines. The concept behind these vaccine

62、s is that the DNA component will be expressed in vivo, creating small amounts of antigenic protein which serve to prime the immune response so that a protective response can be rapidly generated when the real antigen is

63、encountered. In theory, these vaccines could be manufactured quickly & should efficiently induce both humoral & cell-mediated immunity.,© Academic Press, 2000.,Subunit Vaccines,These consist of only some co

64、mponents of the virus, sufficient to induce a protective immune response but not enough to allow any danger of infection.In general terms, they are completely safe, except for very rare cases in which adverse immune rea

65、ctions may occur.Unfortunately, at present, they are also the least effective & most expensive type of vaccines.The major technical problems associated with subunit vaccines are their relatively poor antigenicity &

66、amp; the need for new delivery systems, such as improved carriers & adjuvants.There are several categories of such vaccines:Synthetic vaccines, such as short, chemically synthesized peptides.Recombinant vaccines,

67、produced by genetic engineering.Virus vectors, i.e. recombinant virus genomes genetically manipulated to express protective antigens from (unrelated) pathogenic viruses.,© Academic Press, 2000.,Inactivated Vaccines

68、,Produced by exposing the virus to a denaturing agent under precisely controlled conditions. The objective is to cause loss of virus infectivity without loss of antigenicity.Inactivated vaccines have certain advantages

69、, such as generally being effective immunogens (if properly inactivated), being relatively stable, & carrying little or no risk of vaccine-associated virus infection (if properly inactivated).It is not possible to p

70、roduced inactivated vaccines for all viruses, since denaturation of virus proteins may lead to loss of antigenicity, e.g. measles virus.Although relatively effective, 'killed' vaccines are sometimes not as effec

71、tive at preventing infection as 'live' virus vaccines, often because they fail to stimulate protective mucosal & cell-mediated immunity to the same extent.These vaccines may contain virus nucleic acids, whic