J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from J. clin. Path., 25, Suppl. (Roy. Coll. Path.), 6, 121-131
Immune responses in persistent virus infections
A. C. ALLISON From the Clinical Research Centre, Harrow, Middlesex
Persistent virus infections either show steady and cedures that powerfully suppress cell-mediated relentless progress-scrapie, visna, or maedi-or immunity, also decrease antibody production, persistence with reactivation, as does varicella-zoster. especially where cooperation of thymus-dependent In either case host defence mechanisms are unable (T) with antibody-producing (B) cells is required for to control the infection. To understand the under- an efficient response, which is the case with some lying defects it is necessary to know what limits the viral antigens. It is therefore necessary to examine progress of virus infections under normal conditions. the effects of selective restoration of immune re- Several factors contribute to host resistance against sponses in immunosuppressed animals. Passive pro- viruses, and it is becoming apparent that their rela- tection by serum antibody provides highly suggestive tive importance varies from one virus infection to evidence that antibody can provide the critical factor another. The main findings will be reviewed in this controlling an infection. If antibody alone provides paper, together with available observations on no protection but transfer of specifically sensitized immune responses to persistent viruses. The simplest lymphoid cells does protect, this is strong evidence way to achieve progressive infections is for the agent that cell-mediated immunity plays a major defensive responsible to be and as far role-although extravascular production of or non-immunogenic, this, IgM copyright. as we know, is true of scrapie and related agents. ofcytophilic antibody in recipients could be involved. Speculations on why immune responses are ineffec- The results of animal experiments complement tive in other persistent virus infections can be remarkably well observations which have been made offered. Immunopathological reactions to virus on human patients with immunodeficiency syn- infections are also attracting current interest. Since dromes. Although there are many gaps in knowledge, they contribute to the lesions observed in persistent a general picture is emerging. The first major line virus infections, they are also briefly considered in of defence is the inherent resistance of cells at the this paper. primary site of infection; this enables cells to over- come exposure to most viruses from other species http://jcp.bmj.com/ Mechanisms of Resistance against Viruses and, where there are individual inherited differences, to certain homologous viruses also. With infections The term 'immunity' can be used in a broad sense of seromucous surfaces such as the respiratory or to describe any form of resistance against a potential- alimentary tracts, the major second line of defence ly pathogenic organism or toxin. Immunity against is secretory antibody, which is synthesized and viruses has many components, including resistance released locally.
of individual host cells to infection, local factors such Frequently viruses spread from local sites of on October 1, 2021 by guest. Protected as temperature or acidity, formation of interferon, multiplication to macrophages, which may be local resistance of macrophages and other leucocytes, and (eg, alveolar or subcutaneous) or lining the sinuses specific humoral and cell-mediated immune re- of lymph nodes, liver, and spleen. Macrophages pro- sponses. The situation is obviously complex, but my vide an important barrier to the spread of virus colleagues and I have been attempting to find out infections; this barrier is ineffective in very young whether it is possible to show that in particular virus- animals and in certain mature animals with in- host combinations some resistance factors are more herited susceptibility to particular virus infections. important than others. The third major defence system is circulating anti- We have used several techniques to eliminate one body, which frequently limits spread of viruses or more resistance factors. Unfortunately, none of through the blood stream and their multiplication in the available immunosuppressive techniques is target organs such as the brain, liver, or heart. sufficiently selective to give unambiguous informa- Serum antibody is effective against many viruses, but tion by itself. Even neonatal thymectomy and ad- some-such as herpesviruses, poxviruses and certain ministration of antilymphocytic serum (ALS), pro- myxov-ruses-can spread despite the presence of 121 J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from 122 A. C. Allison antibody; cell-mediated immunity plays an im- up by macrophages and damage them. Intravenous portant protective role in these cases. It is of interest injection of yellow fever virus in adult mice is well that several slow virus diseases fall into this category. tolerated, but the same injection after administration Whether interferon plays a significant role in defence of silica particles results in a lethal virus encephalitis. under conditions of natural intection is still unknown This can be prevented by passive administration of although it can limit virus multiplication under antibody as late as 48 hours after infection. Studies certain rather special conditions. High temperatures with fluorescent antibodies showed that by 48 hours can protect susceptible hosts from some virus in- there were foci of virus infection in the brain, so that fections. Interactions of these factors have recently antibody must have been able to control infection been reviewed (Allison, 1972a). In this paper com- even at that stage. This is not surprising, since anti- ments will be restricted to circulating antibodies and body is known to protect against the effects of intra- cell-mediated immunity, defects of which are prob- cerebral inoculation of many viruses, including ably most relevant to slow virus infections. arthropod-borne viruses like yellow fever virus (Nathanson and Cole, 1970). CIRCULATING ANTIBODY Observations on increased severity of many virus Circulating antibody has long been regarded as a infections of the central nervous system following major defence mechanism against virus infections, immunosuppression have been reviewed by Nathan- and evidence which has accumulated during the past son and Cole (1970), eg, paralytic disease produced few years supports this interpretation for most by Japanese B encephalitis virus in spider monkeys viruses that produce systemic as opposed to local (Ateles) treated with cyclophosphamide. Similarly (seromucous surface) infections. The most direct Zlotnik, Smith, Grant, and Peacock (1970) found evidence comes irom the use of immunosuppressive that cyclophosphamide altered the pathological agents, such as cyclophosphamide, which can con- picture of virus encephalitis and greatly increased vert infections that are normally well tolerated into central nervous system damage produced by arbo- lethal infections. An example from the work of viruses in monkeys that were normally resistant. B. Zisman and myself is shown in Table I. Infection There was little mononuclear reaction-which normally produces the characteristic perivascular copyright. cuffing-but neuronal necrosis and spongy degenera- Group Number % Mortality tion were prominent. Untreated control 16 0 Weiner, Cole, and Nathanson (1971) administered Cyclophosphamide (72 hr after cyclophosphamide to mice after immunization with virus) 16 100 Cyclophosphamide + antibody inactivated arboviruses to induce specific unrespon- (4 and 15 days after virus) 14 0 siveness. The capacity of the mice to produce anti- body the same I against arboviruses, administered Table Mortality ofadult CBA mice after intraperitoneal afterwards as a live http://jcp.bmj.com/ injection of Coxsackie B-3 virus (Zisman and Allison, shortly challenge, was abolished unpublished) and the animals died after extraneural inoculation, although they made antibody against other viruses and survived extraneural challenge. These experi- with Coxsackie B virus kills newborn mice but not ments demonstrate the immunological specificity of- adult mice, unless they are immunosuppressed with the reaction, although they do not distinguish cyclophosphamide. Then a high and persisting between a role of antibody and of cell-mediated viraemia is found, together with large amounts of immunity. on October 1, 2021 by guest. Protected virus in target organs, including the heart and The observations which have been reviewed in this pancreas, and the animals die of myocarditis and section suggest that wit-h enterovirus and arthropod- pancreatitis. Administration of serum antibody to borne virus infections circulating antibody plays an the immunosuppressed mice as late as four days after important protective role, limiting the spread of virus infection markedly reduces the amounts of viruses from the primary site of infection to highly virus in the blood stream and target organs and pro- susceptible target organs, such as the brain and heart,. tects the mice. Interferon levels parallel the concen- and the multiplication of viruses in those organs. tration of virus in the circulating blood and are Evidence that this may also be true in man comes highest in mice destined to die, so it seems unlikely from observations that children with severe hypo- that interferon plays a major protective role. gammaglobulinaemia but intact cell-mediated imr- We have also analysed the relative roles of macro- munity are more liable to develop paralytic polio- phages and antibody in defence of adult mice against myelitis after exposure to vaccine strains than are yellow fever virus infection (Zisman, Wheelock, and normal children (Table I1). The importance of cir- Allison, 1971). Silica particles are selectively taken culating antibody in preventing the spread of polio- J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from Immune responses in persistent virus infections 123
Immunodeficiency Virus Infection Reference bear viral antigens on their surfaces, and these can Aggravated be recognized by sensitized lymphocytes which attack and destroy the cells, thereby interrupting the 1-fypogammaglobulin- Paralytic Schur et al (1970) aemia with intact poliomyelitis cycle of virus multiplication. This is discussed further cell-mediated in the section on immunopathology. However, immunity lymphocyte transformation may also work against Deficient cell- Vaccinia Fulginiti et al (1968) the host: many viruses cannot grow in small lympho- mediated immunity O'Connell et al (1964) cytes are transformed by phytohaemag- (± normal immuno- unless they globulins) Herpes simplex Cooper et al (1968) glutinin or an immune reaction (Bloom, Jimenez, Kretschner et al (1969) and Marcus, 1970). Varicella zoster Hayes et al (1965) If cell-mediated immunity plays a protective role Lux et al (1969) in virus infections of experimental animals, thym- Cytomegalo- Miller and Schieken (1967) ectomy and/or treatment with antilymphocytic virus Haworth et al (1967) serum (ALS) should aggravate the disease. Human Cooper et al (1968) patients with hypogammaglobulinaemia but intact Measles Nahmias et al (1 967) cell-mediated immunity should not suffer from Cooper et al (1968) severe infections with these viruses, whereas in in- Table I1 Virus infections increased in severity in human patients with defective cell-mediated immunity patients with different types of immunodeficiency fections should be severe and often progressive. Experiments on increasing severity of virus infec- tions by thymectomy and ALS are summarized in virus from the gut to the central nervous system Table III. It will be seen that the infections aggra- accounts for the efficacy of killed virus vaccines. vated by these procedures are due to herpesvirus and Neonatal thymectomy does not increase the sus- poxviruses, whereas arbovirus and enterovirus in- ceptibility of mice to enterovirus infections, in con- fections are not increased in severity. This is con- trast to herpesvirus or poxvirus infections, as dis- sistent with the view that circulating antibody can cussed in the next section (Table III). limit enterovirus and arbovirus infections, whereas copyright. cell-mediated immunity is required for resolution of CELL-MEDIATED IMMUNITY poxvirus and herpesvirus infections. Evidence that viruses can elicit cell-mediated immune responses has been summarized elsewhere (Allison, 1972b). This is shown by the usual criteria, Virus Age No. of Treatnment ° including delayed hypersensitivity following intra- (weeks) Mice Mortality dermal injection of purified virus (although there is Herpes simplex 4 25 NRS 0
usually an acute allergic reaction as well), transfer 14 Thymectomy 71 http://jcp.bmj.com/ of reactions to non-sensitized recipients by cells but 13 ALS 100 not by serum, stimulation of lymphocyte trans- Yellow fever 4 58 None 16 4 formation in the presence of virus-infected cells, and 24 ALS 16-6 the liberation of macrophage migration inhibitory Coxsackie B-3 6 25 None 0 factor. Although work on cell-mediated immunity 22 Thymectomy 0 has been much less systematic than that on antibody, Ectromelia Young 26 NRS 20 there is no reason to doubt that cell-mediated im- (Blanden, 1970) adults 26 ALS 100 mune responses are elicited at least by those viruses on October 1, 2021 by guest. Protected with antigens that infiltrate the plasma membranes Table III Effect of suppression of cell-mediated of infected cells, eg, poxviruses, herpesviruses, immunity on virus infections of mice (Zisman and myxoviruses, and tumour-inducing viruses. Allison, unpublished) There are at least three ways in which cell- NRS = normal rabbit serum; ALS = rabbit antimouse-lymphocyte mediated immunity could confer protection against serum viruses. Transformation of lymphocytes into blast cells by viral and other antigens leads to the produc- As summarized in Table II, patients with uncom- tion of interferon (Glasgow, 1970). A cell-mediated plicated severe hypogammaglobulinaemia recover immune reaction against a viral or heterologous normally from vaccination against smallpox and antigen is associated with macrophage 'activation'- from measles and varicella infections. Congenital an increase in the content of lysosomal enzymes and abnormalities in which defective cell-mediated im- capacity to kill intracellular parasites, including munity is prominent include ataxia-telangiectasia, viruses. Finally, cells in which viruses are growing Swiss agammaglobulinaemia, and the syndromes of J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from 124 A. C. Allison Wiskott-Aldrich, Gitlin, Nezelof, and di George. In antigens. In addition host-specified antigens of all these, virus infections are a recurring and often embryonic, Forssman, or blood-group type may fatal complication. Fulginiti, Kempe, Hathaway, appear on the surface of infected cells and induce Pearlman, Sieber, Eller, Joyner, and Robinson (1968) immune responses. described progressive vaccinia in patients with many For purposes of analysis, immunopathological of these syndromes, particularly Nezelof's syndrome reactions can be considered in three main classes: in which immunoglobulin levels and specific anti- (1) reactions mediated by antibodies against infected body-synthesizing capacity are near normal. Patients cells; (2) reactions mediated by immune cells against with the Wiscott-Aldrich syndrome are particularly virus-specific antigens; (3) reactions due to immune susceptible to infections produced by cytomegalo- complexes consisting of antibody and virus-specific virus, measles, and especially herpes simplex viruses antigen. In addition, viruses may participate in the (Cooper, Chase, Lowman, Krivit, and Good, 1968). development of autoimmune reactions. Patients with cartilage-hair hypoplasia, which is associated with a defect of cell-mediated immunity ANTIBODY-MEDIATED IMMUNOPATHOLOGICAL but normal antibody levels, have unusually severe REACTIONS varicella infections (Lux, Johnston, August, Say, The strongest evidence that antiviral antibody and Penchaszadeh, Rosen, and McKusick, 1969). complement can injure virus-infected cells comes Hodgkin's disease and some other debilitating from experiments in vitro. It has been shown that diseases, cancer chemotherapy, and immunosup- infection of cells with viruses that do not produce pressive therapy after renal homografting, all of cytopathology (rabies or LCM) or with viruses that which depress cell-mediated to a greater extent than eventually do produce cytopathology (herpes sim- humoral immunity, increase susceptibility to infec- plex, vaccinia, influenza, and Newcastle disease tions, particularly by cytomegalovirus (Craighead, viruses) results in the appearance of new antigens on 1969), herpes simplex virus (Montgomerie, Becroft, the surface of the infected cells and that the inter- Croxson, Doak, and North, 1969) and zoster, as action of specific antiviral antibody and complement discussed further below. with these antigens can damage the cells (Wiktor, Kuwert, and Koprowski, 1968; Brier, Wohlenberg, copyright. Immunopathology of Virus Infections Rosenthal, Mage, and Notkins, 1972). In the absence of either specific antiviral antibody or complement, Although in most circumstances immunological such injury does not take place. The degree of reactions are beneficial, they sometimes initiate or immunological injury may be influenced by a aggravate tissue damage. Viruses may produce number of factors including the density of viral pathological changes in several ways, some of which antigens on the surface of infected cells; the inherent are independent of immune reactions. Viruses may susceptibility of the cells to lysis by complement; the directly damage cells or tissues, they may bring nature concentration and of the antiviral antibody, http://jcp.bmj.com/ about hyperplasia or malignancy, or they may more ie, complement-fixing vs. non-complement-fixing; or less selectively inhibit cell division, eg, picodna- and the ratio of cytolytic to non-cytolytic antibody viruses. Nevertheless, it is likely that immune re- in a particular serum. Other factors, such as the actions frequently make some contribution to patho- phase of the mitotic cycle or coinfection with a logical changes observed in virus infections, as well second virus, might influence the appearance of viral as playing a major part in recovery. Some virus antigens and effects of antibody on cells. If a particu- infections, such as lymphocytic choriomeningitis lar virus produces few antigenic sites or if these sites (LCM), produce little or no tissue damage unless are widely separated, complement-mediated cell on October 1, 2021 by guest. Protected accompanied by an immune response; immuno- destruction may not occur. Increased density of pathological reactions may then be so severe as to virus-specific antigens on the cell surface would en- kill the infected animal. hance the likelihood of doublet formation with IgG Cells infected with viruses may develop new sur- antiviral antibody and this in turn might increase the face antigens and thus become targets for antibody amount of complement-mediated cell destruction. or cell-mediated immune reactions. These are viral Fluctuations in the density of viral antigens on the envelope antigens in the case of myxo-, paramyxo-, surface of infected cells might be a particularly rhabdo-, areno-, toga-, andleuco-viruses which mature important factor in the pathogenesis of slow viruses. by budding from the cell surface. Virus-specific Exposure to small amounts of antiviral antibody or antigens may also appear on the surface of cells in- to non-complement-fixing antibody might result in fected with certain non-budding viruses such as pox- endocytosis of membrane containing viral antigen, a viruses and herpes viruses, and cells transformed by process termed antigenic modulation (see Taylor, viruses may bear tumour-specific transplantation Duffus, Raff, and de Petris, 1971). J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from Immune responses in persistent virus infections 125 The attachment of antibody to the surface of the neonatal thymectomy, irradiation, antilymphocytic infected cell might have other consequences. On the serum, or cytotoxic drugs, mice remain well in spite one hand, the attachment of antiviral antibody of extensive infection. In contrast, mice infected neo- might accelerate killing or phagocytosis of the in- natally or congenitally show widespread infection fected cell by activated macrophages. On the other with virus, but only a slight immune response to hand, antiviral antibody or antigen-antibody com- infection. They remain well during most of their life, plexes might prevent sensitized lymphocytes from but slowly accumulate immune complexes in kidney recognizing or reacting with the viral antigens and glomeruli, as described in the next section. thereby inhibit the cell-mediated immune response. Attempts have been made to determine whether In virus infections, this might prove to be the the antibody- or cell-mediated component of the counterpart of 'blocking antibody' or 'immuno- immune response causes the pathological changes in logical enhancement', favouring virus persistence. mice infected as adults with LCM virus. In vivo Under certain circumstances the destruction of experiments were carried out by Cole and Nathanson, virus-infected cells by antiviral antibody and com- who gave cyclophosphamide to adult mice infected plement may be more beneficial than harmful to the with LCM virus. The immune response was in- host. Antibody-mediated cell damage may be one of hibited and a persistent nonpathogenic infection the mechanisms by which the host resists those established. When immune spleen cells were inocu- viruses that avoid neutralization by spreading direct- lated into these mice acute pathological changes and ly from cell to cell. Destruction of cells which are death were seen, comparable to those occurring in producing virus would inhibit virus replication and the natural infection. The transfer of immune serum release or expose the infectious virus within the cell was ineffective, and it was concluded that the trans- to neutralizing antibody. Thus, in viral infections, ferred cells had reacted with infected host cells to antibody-mediated cell destruction might fulfil part give a cell-mediated immunopathological disease. In of the role that has been postulated for cell-mediated contrast to these results, transfer of immune spleen immunity and may serve as a complementary or cells to congenitally infected carrier mice has failed supplementary defence mechanism. to give any clinical or histological evidence of tissue In vivo evidence that antibody plays a role in the damage. High titres of neutralizing and complement- copyright. pathogenesis of virus infections is less convincing. fixing antibody were produced in the recipient carrier Depletion of complement by cobra venom decreased mice, so that under these circumstances antibody, the lethal effects of LCM in adult mice, and injec- too, was not pathogenic (Lehmann-Grubbe, tions of antibody into the cerebrospinal fluid of 1971). LCM carrier mice produced meningeal inflammation In-vitro systems have been used to demonstrate (Oldstone and Dixon, 1970). However, in mice the action of sensitized lymphoid cells on virus- carrying LCM after adult infection with administra- infected cells. Spleen cells obtained from immune Monjan, animals added to cells persistently infected with tion of cyclophosphamide (Cole, Gilden, http://jcp.bmj.com/ and Nathanson, 1971) administration of antibody measles or mumps virus were found to destroy the did not produce disease. When mice infected with latter (Speel, Osborn, and Walker, 1968). In the Langat virus (an arbovirus) were given antibody, case of mumps virus, the cytotoxic action of the some aggravation of disease was reported (Webb, immune spleen cells could be prevented by pre- 1969). However, the timing of the antibody ad- treatment of target cells with antibody. Damaging ministration was critical, and it seems likely that effects of sensitized lymphocytes on cells carrying antibody usually protects the host rather than in- LCM virus have also been reported (Lundstedt, creasing the severity of virus infections. 1969; Oldstone and Dixon, 1969), but the results on October 1, 2021 by guest. Protected have not been consistent or reproducible. CELL-MEDIATED IMMUNOPATHOLOGY Sensitized lymphocytes, after reacting specifically The most fully studied laboratory model for cell- with viral antigen in tissues, release a variety of mediated immunopathology has been LCM virus mediators. These mediators bring about retention infection of mice. In adult mice with LCM there is and activation of macrophages in the affected area. virus replication in many tissues, including the Activated macrophages show increased capacity to viscera and the meninges. The infection is non- take up and kill various organisms, including viruses, cytopathic, and mice remain well until the onset of protozoa, and bacteria. They may also kill intact cells an immune response five to seven days after infec- bearing viral antigens on their surfaces. In this way tion, when inflammatory cell infiltrations occur in the recruited macrophages, perhaps with the help of the sites of viral growth in viscera and in the cell-bound antibody, appear to play a major anti- meninges leading to pathological changes, sickness, viral role in the infected area. At the same time they and death. If the immune response is inhibited by can contribute to the production of lesions. J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from 126 A. C. Allison
IMMUNOPATHOLOGICAL EFFECTS OF ANTIGEN- spread necrotizing arteritis, with bound viral antigen, ANTIBODY COMPLEXES immunoglobulin, and complement in blood vessel It is well known that persistence of antigen-antibody walls. It seems likely that this follows local multi- complexes in the circulation can lead to symptoms plication of virus rather than secondary deposition of serum sickness, including glomerulonephritis, of circulating immune complexes. Thus factors other vasculitis, skin rash, arthralgia, and arthritis. than the presence of complexes in the circulation Recently it has been shown in animals that viruses determine their localization and the severity of the can persist in the circulation in the form of virus- immunopathological reactions which they produce. antibody complexes, and that the deposition of these One of the interesting associations to emerge complexes in the kidney can lead to the development during the past few years has been the presence of of an immune-complex type of glomerulonephritis. Australia antigen in about 60% of patients with Infectious virus-antibody complexes have been periarteritis nodosa (Trepo and Thivolet, 1970; found in the circulation of animals infected with Gocke, Hsu, Morgan, Bombardieri, Lockshin, and lactic dehydrogenase virus, Aleutian mink disease, Christian, 1971). In five fatal cases of hepatitis, murine leukaemias, and probably equine infectious Australia antigen, immunoglobulin, and comple- anaemia (Table IV). Glomerulonephritis has been ment were found in the intima of arterioles showing changes typical of periarteritis (Nowoslawski, Brzosko, Krawczyn'ski, and Madalen'ski, 1972). A case of immune Virus Infectious Virus Glomerular Complexes complex nephritis has been reported Ab Complexes in Complexes in Walls with deposition of Australia antigen, IgG, and com- Circulation plement in the glomeruli (Combes, Stastny, Shorey, Lymphocytic Eigenbrodt, Barrera, Hull, and Carter, 1971) and at choriomeningitis + + + ? necropsy of four fatal cases of hepatitis Australia Aleutian mink disease ± antigen, IgG, IgM, and complement were found in + ++ + + glomerular capillaries (Nowoslawski et al, 1972). Murine leukemogenic + 4- - From observations on synovial tissues, Alpert et al Equine infectious (1971) suggest that immune complexes with Australia copyright. anaemia + + antigen contribute to the urticaria and arthritis Human hepatitis ? + + sometimes associated with hepatitis. Lactic dehydrogenase + + Hypersensitivity in Virus Infections Table IV Presence of complexes of viral antigen and antibody in circulating blood, renal glomeruli, and blood Reports of local and systemic reactions in recipients vessel walls of inactivated measles vaccine when subsequently inoculated with live virus vaccine (Buser, 1967; http://jcp.bmj.com/ Scott and Bonanno, 1967) or experiencing natural demonstrated in each of these diseases, but with infection (Nader, Horwitz, and Rousseau, 1968) sug- varying degrees of severity. In all cases viral antigen, gest the importance of hypersensitivity reactions in specific antiviral antibody, and complement have virus infections. In the vaccinated subjects atypical been found in the kidney. Severe glomerulonephritis exanthema and swelling and erythema at the site of has been found in LCM chronic carrier mice. The infection developed over three to eight days. Evidence degree of glomerulonephritis depends on the strain that this is an Arthus-type reaction has been pre- of the mouse, the amount of LCM virus, and the sented by Bellanti, Sanga, Klutinis, Brandt, and on October 1, 2021 by guest. Protected amount of antiviral antibody. A high proportion of Artenstein (1969), who found bound immuno- the immunoglobulin eluted from diseased kidneys is globulin, measles antigen, and complement com- antibody to LCM (Oldstone and Dixon, 1971). ponents in skin biopsies from the sites of local Aleutian disease of mink is also characterized by a reaction. severe glomerulonephritis. All mink appear to be Chanock, Parrott, Kapikian, Kim, and Brandt susceptible to the virus but those homozygous for (1968) have proposed a similar explanation for the the Aleutian gene suffer the most severe disease with severity of respiratory syncytial virus infection in heavy deposition of virus, antibody, and complement babies. Lack of secretory antibody (which is not in the glomeruli (Porter, Larsen, and Porter, 1969). received from the mother) would allow establish- In contrast, lactic dehydrogenase virus, in which ment of a local infection, and circulating maternal there is a persistent high viraemia, produces only IgG antibody could form complexes with virus mild renal disease (Porter and Porter, 1971) and no antigen in the pulmonary tissue and produce an vasculitis. In Aleutian mink disease there is a wide- Arthus reaction. J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from Immi(ne responses in persistent virus infections 127 Scrapie gammaglobulinaemia, sometimes of monoclonal (myeloma-like) nature. Glomerulonephritis, de- Although the agent producing scrapie is classified as generative arterial lesions, and proliferation of intra- a slow virus, it shows many remarkable properties, hepatic bile ducts are commonly seen. including extreme resistance to radiation (Latarjet, Porter et al (1969) have shown that Aleutian Muel, Haig, Clarke, and Alper, 1970) and apparent disease virus replicates rapidly, and attains high absence of immunogenicity. No antibody has been titres, especially in the liver. Viral antigen is confined demonstrable by neutralization, complement fixa- to the cytoplasm ofmacrophages in spleen and lymph tion, precipitation, or immunofluorescence (Gibbs, nodes and Kupffer cells in the liver. Very high levels Gajdusek, and Morris, 1965; Chandler, 1959). There of antibodies (measured by indirect immuno- are no mononuclear infiltrates of lesions suggestive fluorescence against viral antigen) were found. of a cell-mediated immune response. Neonatal Secondary deposits of viral antigen, antibody, and thymectomy (Gibbons and Hunter, 1967) or thym- complement are marked in the renal glomeruli where ectomy, lethal irradiation, and reconstitution with they exhibit the bumpy appearance characteristic of foetal liver cells, which markedly depletes thymus- immune complexes. Bound immunoglobulin and derived (T) lymphocytes, had no effect on the incuba- complement have also been found in arteriolar walls. tion period or pathology ofscrapie in mice (McFarlin, Raff, Simpson, and Nehlsen, 1971). This suggests Lactic Dehydrogenase Virus that cell-mediated immunity neither contributes to the pathogenesis of scrapie nor plays a significant This is a virus infection of mice which, once estab- role in the host's defence against the agent. lished in newborn or adult animals, persists for life. Infectious virus continues to circulate in the plasma. Equine Infectious Anaemia It is combined with antibody and can be neutralized by antiserum against mouse immunoglobulin This disease is restricted to Equidae and is character- (Notkins, Mahar, Scheele, and Goffman, 1966). The ized by persistence of virus, haemolytic anaemia virus replicates in macrophages (Evans and Salaman, with C3-coated erythrocytes, hypergammaglobulin- 1965). Immune complexes are found in the kidneys copyright. aemia, deposition of y-globulin and C3 in the renal (Porter and Porter, 1971), but they are much less glomeruli (Banks and Henson, 1969), and decreased striking than in lymphocytic choriomeningitis virus. circulating C3 levels. The clinical course is variable; Whether a cell-mediated immune response is some horses have severe haemolytic disease while mounted against this virus has not been investigated. others become asymptomatic. Infected horses remain viraemic for life, despite the presence of neutralizing Visna-maedi and complement-fixing antibody in the serum Dr Palsson describes elsewhere in the present
(McGuire, Crawford, and Henson, 1971). By volume this complex of progressive infections of the http://jcp.bmj.com/ immunofluorescence viral antigen is demonstrable in central nervous system and lungs of sheep. Relevant the cytoplasm of peripheral blood leucocytes, to the present discussion is the fact that virus infec- macrophages lining blood or lymph sinuses, and tion continues to spread despite the presence of other sites. The virus thus apparently replicates in neutralizing antibody in serum. Possibly cell- macrophages. The anaemia may result from attach- mediated immunity plays a part in controlling this ment of viral antigen-antibody-complement com- myxovirus-like agent (as in measles) and in Icelandic plexes to erythrocytes, with their subsequent sheep specific cell-mediated immunity is ineffective. removal from the circulation. A deliberate search for cell-mediated immunity, on October 1, 2021 by guest. Protected using virus-infected cells, and for blocking serum Aleutian Mink Disease factors would be well worth while. Since virus is readily recovered from mononuclear cells in cere- Aleutian disease is a chronic virus infection of mink, brospinal fluid, most of which are macrophages, virus which has caused serious economic losses to com- may be able to replicate in macrophages. Since this mercial ranchers. 'Mutation' mink homozygous for would contribute to the persistent infection despite a pale coat colour (Aleutian) gene are particularly the presence of antibody, it would be worth investi- susceptible to the disease but other mink also develop gating systematically. chronic infections. Once the infection is established, virus can be recovered from the serum, organs, and Measles and Subacute Sclerosing Panencephalitis urine for the remainder of the animal's life. The pri- (SSPE) mary lesion is a systemic proliferation of plasma cells, and this is associated with marked hyper- Subacute sclerosing panencephalitis is a slow infec- 5 J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from 128 A. C. Allison tion of the central nervous system of children with Electron micrographs of the brain of one patient measles virus (see Connolly, this symposium). In who died, taken by Dr A. Dayan, showed numerous view of the evidence summarized in the section on intranuclear structures indistinguishable from cell-mediated immunity that this reaction plays an measles nucleocapsids. The second child is still under important part in controlling measles infections, one investigation and details will be published elsewhere. possible explanation for persistent measles infection Thus severe SSPE-like neuropathology may occur as of the central nervous system would be that the a complication of immunodeficiency. patient has a generalized deficit of cell-mediated An interesting animal model has been described by immunity or a specific deficit in cell-mediated im- Wear and Rapp (1971). Humanmeaslesvirusadapted munity directed against viral antigens on infected to hamster brain replicated to high titres and pro- cells. Presumably these would be envelope rather duced encephalitis when inoculated into unprotected than nucleoprotein antigens. The limited evidence newborn hamsters. However, measles antibodies which has been published is conflicting. acquired from immunized mothers blocked acute It has long been known that measles infections encephalitis but not intracellular virus replication in temporarily suppress cell-mediated immune re- the central nervous system. The infection remained actions against unrelated antigens, eg, tuberculin; latent until the animals were treated with cyclo- this is true of infections with vaccine as well as phosphamide, when the majority developed per- naturally occurring strains of the virus. However, sistent myoclonic tremors. Virus was isolated from patients usually recover their capacity to produce these animals for at least 90 days after infection. delayed hypersensitivity within a few weeks. These observations suggest that maternally acquired Kolar (1968) described a reduced lymphocyte antibody suppresses but does not eliminate the virus response to phytohaemagglutinin in two patients infection, and that the latent virus can be reactivated with subacute sclerosing panencephalitis. Gerson and by immunosuppressive treatment. Whether the acti- Haslam (1971) reported that four boys with SSPE vation is due to effects on specifically sensitized had impaired expression of delayed hypersensitivity lymphocytes is not yet clear. to skin test antigens and delayed rejection of skin allografts. In three of the four IgA levels were sub- Varicella Zoster copyright. normal. In contrast, Jabbour, Roane, and Sever (1969) found that all eight SSPE patients tested had It is now generally accepted that the same virus positive skin responses to Candida; two of three causes varicella or chickenpox and herpes zoster (see patients tested became sensitized to dinitrochloro- McCarthy, this symposium). The latter might be due benzene. Skin tests with measles antigen (at best a to the persistence of varicella-zoster virus in a latent procedure difficult to interpret) were negative. form following chickenpox infection or it might be Saunders, Knowles, Chambers, Caspary, Gardner- due to reinfection. Miller and Brunell (1970) have
Medwin, and Walker (1969) not only found a summarized reasons for supporting the former view. http://jcp.bmj.com/ normal lymphocyte response tophytohaemagglutinin An epidemiological investigation of 108 patients in one patient with SSPE but state that trans- with zoster showed that (1) only four had a possible formation of lymphocytes in the presence of recent exposure to varicella or zoster; (2) there was measles antigen was increased. Dr M. J. Dillon no increase in zoster cases corresponding to the and Professor J. F. Soothill (Institute of Child seasonal peak of varicella; and (3) the fewest cases Health) have found normal lymphocyte transforma- of zoster were contributed by subjects with the tion by phytohaemagglutinin in eight cases of SSPE greatest likelihood of being exposed to varicella. (private communication). Thus there is at present no Subjects with varicella have a primary immune on October 1, 2021 by guest. Protected consistent evidence for an overall impairment of cell- response, with both IgM and IgG antibodies against mediated immunity in SSPE, or of an absence of viral antigens, whereas those with zoster have a reaction to measles antigen. Evidence on the latter secondary response, with only IgG antibodies point is, however, weak. Attempts should be made to (Leonard, Schmidt, and Lennette, 1970). obtain consistent stimulation in vitro of lymphocytes Thus available evidence suggests that varicella- from convalescent subjects with measles virus- zoster virus can remain latent in the body after infected cells. These could then be compared with chickenpox infection, and can emerge when host responses from SSPE patients, and tests could also resistance wanes. In considering resistance against be made for blocking factors in SSPE serum. the virus, it appears that there are two components. We have observed a condition like SSPE but with Antibody can protect against the initial infection. progressive blindness as well in two related boys with Immune globulin from zoster patients has been combined immunodeficiency syndromes, including found, in double-blind studies, to prevent varicella marked deficiency of all immunoglobulin classes. in exposed children (Brunell, Ross, Miller, and Kuo, J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from Immune responses in persistent virus infections 129 1969). However, once the infection has become 1969). Cytomegalovirus infections have been trouble- established, administration of antiviral antibody has some in renal transplant patients (Montgomerie et al, no real beneficial effect. Patients develop localized 1969) and in patients with renal lymphoreticular zoster despite rapid rises in levels of antibody against malignancies treated with cytotoxic drugs. The ex- the virus in peripheral blood, and the same is true of perimental animals and human subjects in which most patients with generalized zoster. Two patients cytomegalovirus infections are activated may have with cytotoxic therapy for malignant disease had serum antibody against the virus, suggesting again delayed antibody responses, but this may have been that serum antibody alone is insufficient to control part of a widespread deficit in their immune re- the infection. sponses. A mother developed zoster one month following the birth of twinv. (Gibbs, Shapiro, Comment Cassidy, and Brunell, 1970). The twins were not infected although their 4-year-old sibling developed Some tentative generalizations can be made about varicella following exposure to the mother. Gibbs the immunology of persistent virus infections. and his colleagues conclude that although maternal 1 With scrapie, mink encephalopathy, kuru, and antibody synthesis was sufficient to protect her twins Creutzfeld-Jacob disease there does not appear to be by passive transfer across the placenta, it was in- a host immune response at all, although in at least sufficient to protect her against reactivation of a some cases the agent transmitting the disease is latent varicella-zoster virus infection. found in high titre in the lymphoreticular system. It seems likely that the most effective defence Hence immunological factors neither control nor mechanism once varicella-zoster virus infection has complicate the disease. become established is cell-mediated immunity. Dr 2 Certain virus infections, once established, are never P. A. Brunell, who is spending a sabbatical year with eliminated, and viraemia persists until the death of us, has found that lymphocytes of subjects con- the host. This is true, for example, of Aleutian mink valescing from varicella show marked stimulation of disease, equine infectious anaemia, and lactic de- DNA synthesis in the presence of varicella-infected hydrogenase virus infection of mice, all established cells, but not uninfected control cells. Sonicates of in adult animals, and of murine infections with copyright. infected cells stimulated the lymphocytes much less certain leukaemogenic viruses or lymphocytic chorio- well. This should enable us to establish whether the meningitis established in newborn mice. Sometimes specific cell-mediated immune response against vari- (as in Aleutian mink disease and equine infectious cella antigens on infected cells is depressed in patients anaemia) this is accompanied by hypergamma- with zoster. Many such patients, especially those globulinaemia and high levels of antiviral antibody. with lymphomas and other malignant diseases Often virus circulates in the form of complexes with treated with cytotoxic drugs, have non-selective de- antibody which are still infectious, but which can be
pression of lymphocyte reactivity (decreased skin rendered non-infectious by treatment with anti- http://jcp.bmj.com/ reactions to test antigens and in vitro response to globulin serum. Complexes of viral antigen and anti- mitogens-see Rifkind, 1966). The possibility that body are deposited in the renal glomeruli or arterial varicella antigen-antibody complexes or other serum walls, giving rise to glomerulonephritis and pan- factors specifically block the effects of lymphocyte- arteritis. With lactic dehydrogenase virus, this com- mediated immunity is also worth investigating. plication is slight; with Aleutian mink disease, equine infectious anaemia, lymphocytic chorio- Cytomegalovirus meningitis, and leukaemogenic viruses under certain conditions it is severe. Human hepatitis virus infec- on October 1, 2021 by guest. Protected Host-specific cytomegaloviruses establish latent tions are occasionally accompanied by periarteritis, infections in man and many other mammals, includ- with Australia antigen and antibody in the blood ing the monkey, guinea pig, rat, hamster, and mouse. vessel walls, and immune complexes are occasionally Serological surveys show that more than 80% of found in renal glomeruli. human subjects above the age of 35 have been in- Why some of these virus infections can persist in fected with cytomegalovirus. Normally, disease (of the presence of high levels of neutralizing antibody the liver and brain) is produced only in infants with in the serum is not yet understood. One factor may congenital infections, possibly from mothers with be the ability of some of the viruses in question (eg, primary subclinical infections during pregnancy. The Aleutian mink disease, equine infectious anaemia, virus may remain latent in salivary gland and other lactic dehydrogenase virus, LCM) to replicate in tissues and emerge after immunosuppressive treat- macrophages, including Kupffer cells and cells ment both in guinea pigs (Smith and Vellios, 1950) lining splenic sinuses. Possibly complexes of virus and in man (Cangir and Sullivan, 1966; Craighead, and antibody removed from the circulation by J Clin Pathol: first published as 10.1136/jcp.s3-6.1.121 on 1 January 1972. Downloaded from 130 A. C. Allisoni in cells without R. A. (1968). Wiskott-Aldrich syndrome. An immunologic macrophages multiply these destroy- deficiency disease involving the afferent limb of immunity. ing them. The other distinctive property of viruses in Amer. J. Med., 44, 499-513. this group is that they do not kill the cells in which Craighead, J. E. (1969). Immunologic response to cytomegalovirus infection in renal allograft recipients. Anmer. J. Epidemiiiol., 90, they replicate. The lesions which they produce are 506-513. largely immunopathological. Deforest, A., and Klein, M. (1968). The immunoglobtulin response in recurrent herpes simplex infection in man. Fed. Proc., 27, 734. 3 Viruses which remain latent for long periods and Dixon, F. J., Oldstone, M. B. A., and Tonietti, G. (1971). Pathogenesis may then be reactivated include herpesviruses of immune complex glomerulonephritis of New Zealand mice. and and measles J. exp. Med., 134, 65s-71s. (herpes simplex varicella-zoster) (in Ellison, S. A., Carton, C. A., and Rose, H. M. (1959). Studies of subacute sclerosing panencephalitis). These viruses recurrent herpes simplex infections following section of the probably remain latent in the nervous system and trigeminal nerve. J. infect. Dis., 105, 161-167. Evans, R., and Salaman, M. H. (1965). Studies on the mechanism of cell-mediated immunity plays a major part in con- action of Riley virus. III. Replication of Riley's plasma trolling their spread, which occurs in the presence of enzyme-elevating virus in vitro. J. exp. Med., 122, 993-1002. Fulginiti, V. A., Kempe, C. H., Hathaway, W. E., Pearlman, D. S., neutralizing antibody. Diminution of the effective- Sieber, 0. F., Eller, J. J., Joyner, J. W., and Robinson, A. ness of cell-mediated immunity against the virus (1968). Progressive vaccinia in immunologically deficient (because of of T cell-mediated responses, individuals. In Inimunologic Deficiency Diseases in Man depression (Birth Defects: Original Article Series, vol. 4, no. 1) edited either general or virus-specific) probably allows by D. Bergsma, pp. 128-151. National Foundation, Washing- reactivation of the infection, although the observa- ton D.C. Gerson, K. L., and Haslam, R. H. A. (1971). Subtle immunologic tions so far made on these points are by no means abnormalities in four boys with subacute sclerosing pan- definitive. encephalitis. New Engi. J. Med., 285, 78-82. Gibbons, R. A., and Hunter, G. D. (1967). Nature of the scrapie agent. Nature (Lond.), 215, 1041-1043. References Gibbs, C. J. Jr., Gajdusek, D. C., and Morris, J. A. (1965). Viral characteristics of the scrapie agent in mice. In Slow, patent, Allison, A. C. (1972a). Immunity against viruses. Sci. Basis Med. and Temperate Virus Infections (NINDB Monograph, no. 2), Anu. Rev., pp. 49-73. edited by D. C. Gajdusek, C. J., Gibbs, Jr., and M. Alpers, pp. Allison, A. C. (1972b). The role of membranes in the replication of 192-202. National Institute of Neurological Diseases and animal viruses. Int. Rev. exp. Pat/i., in press. Blindness, Washington, D.C. Allison, A. C., Denman, A. M., and Barnes, R. D. (1971). Co- Gibbs, R. C., Shapiro, E., Cassidy, H., and Brunell, P. A. (1970). operating and controlling functions of thymus-derived lympho- Possible mechaiisms for maintaining immunity to varicella-
cytes in relation to autoimmunity. Lancet, 2, 135-140. zoster virus. Anmer. J. Dis. C/iild., 120, 456-457. copyright. Alpert, E., Isselbacher, K. J., and Schur, P. H. (1971). The patho- Glasgow, L. A. (1970). Interrelationships of interferon and immunity genesis of arthritis associated with viral hepatitis. Complement- during viral infections. J. gen. Physiol., 56, Suppl. (July), 212s- component studies. New EngI. J. Med., 285, 185-189. 226s. Banks, K. L., and Henson, J. B. (1969). Glomerular deposition of Gocke, D. J., Hsu, K., Morgan, C., Bombardieri, S., Lockshin, M., gamma globulin and complement (C'3) in equine infectious and Christian, C. L. (1971). Vasculitis in association with anemia. Fed. Proc., 28, 752. Australia antig!n. J. exp. AMed., 134, 330s. Bellanti, J. A., Sanga, R. L., Klutinis, B., Brandt, B., and Artenstein, Gudnadottir, M., and Palss6n, P. A. (1965). Host-virus interaction in M. S. (1969). Antibody responses in serum and nasal secretions visna-infected sheep. J. Ininmunol., 95, 1116-1120. of children immunized with inactivated and attenuated measles- Haworth, J. C., Hoogstraten, J., and Taylor, H. (1967). Thymic virus vaccines. New Engl. J. Med., 280, 628-633. alymphoplasia. Arc/h. Dis. C/ilidh., 42, 40-54. Blanden, R. V. (1970). Mechanisms of recovery from a generalized Hayes, J. A., Been, T. E., Valentine, E. J., and Bras, G. (1965). A
virus infection: mousepox. 1. The effezts of anti-thymocyte case of fatal dissemination of varicella. J. Pat/h. Bact., 90, 328- http://jcp.bmj.com/ serum. J. exp. Med., 132,1035-1054. 333. Bloom, B. R., Jimenez, L., and Marcus, P. 1. (1970). A plague assay Jabbour, J. T., Roane, J. A., and Sever, J. L. (1969). Studies of for enumerating antigen-sensitive cells in delayed type hyper- d-layed dermal sensitivity in patients with subacute sclerosing sensitivity. J. exp. Med., 132, 16-30. panencephalitis. Neurology (Minneap.), 19, 929-931. Brier, A. M., Wohlenberg, C., Rosenthal, J., Mage, M., and Notkins, Johnson, R. T. (1 964). The pathogenesis of herpes virus encephalitis. A. L. (1972). Inhibition or enhancement of immunological 1. Virus pathways to the nervous system of suckling mice injuryofvirus-infectedcells. Proc. nat. Acad. Sci. (Was/h.), in demonstrated by fluorescent antibody staining. J. ex
neutropenia and abnormal cellular immunity in cartilage-hair complexes in the kidneys of mice infected with lactic dehydro- hypoplasia. New Engl. J. Med., 282, 231-236. genase virus. J. Imnmunol., 106, 1264-1266. McFarlin, D. E., Raft; M. C., Simpson, E., and Nehlsen, S. 1H. (1971). Rifkind, D. (1966). The activation of varicella-zoster virus infections Scrapie in immunologically deficient mice. Nature (Lond.), 233, by immunosuppressive therapy. J. Lab. clin. Med., 68, 463-474. 336. Saunders, M., Knowles, M., Chambers, M. E., Caspary, E. A., McGuire, T. C., Crawford, T. B., and Henson, J. B. (1971). Immuno- Gardner-Medwin. D., and Walker, P. (1969). Cellular and fluorescent localization of equine infectious anemia virus in humoral responses to measles in subacute sclerosing pan- tissue. Amer. J. Pat/i., 62, 283-294. encephalitis. Lancet, 1, 72-74 Miller, L. H., and Brunell, P. A. (1970). Zoster, reinfection or activa- Schur, P. H., Borel, H., Gelfand, E. W., Alper, C. A., and Rosen, F. S. tion of a latent xirus? Amer. J. Med., 49, 480-483. (1970). Selective gamma-G globulin deficiencies in patients Miller, M. E., and Schieken, R. M. (1967). Thymic dysplasia. A with recurrent pyogenic infections. New Engl. J. Med., 283, separable entity from 'Swiss agammaglobulinemia'. Amner. J. 63 1-634. med. Sci., 253, 741-750. Scott, T. F. M., and Bonanno, D.E.(1967). Reactions to live-measles- Montgomerie, J. Z., Becroft, D. M. O., Croxson, M. C., Doak, P. B., virus vaccine in children previously inoculated with killed and North, J. D. K. (1969). Herpes-simplex-virus infection virus-vaccine. New Engl. J. Med., 277, 248-250 after renal transplantation. Lancet, 2, 867-871. Smith, M. G., and Vellios, F. (1950). Inclusion disease or generalized Nader, R. P., Horwitz, M. S., and Rousseau, J. (1968). Atypical exan- salivary gland virus infection. Arch. Path., 50, 862-884. them following exposure to natural measles: eleven cases in Speel, L. F., Osborn, J. E., and Walker, D. L. (1968). An immuno- children previously inoculated with killed vaccine. J. Pediat., cytopathogenic interaction between sensitized leukocytes and 72, 22-28. epithelial cells carrying a persistent noncytocidal myxovirus Nahmias, A., Griffith, D., Salsbury, C., and Yoshida, K. (1967). infection. J. Imniunol., 101, 409-417. Thymic aplasia with lymphopenia, plasma cells, and normal Stevens, J. G., Nesburn, A. B., and Cook, M. L. (1972). Latent herpes immunoglobulins: relation to measles virus infection. J. Amer. simplex virus from trigeminal ganglia of rabbits with recurrent nmed. Assc., 201, 729-734. eye infection. Nature [new Biol.], 235, 216-217. Nathanson, N., and Cole, G. A. (1970). Immunosuppression and Taylor, R. B., Duffus, W. P. H., Raff, M. C., and de Petris, S. experimental virus infection of the nervous system. Advanc. (1971). Redistribution and pinocytosis of lymphocyte surface virus Res., 16, 397-448. immunoglobulin molecules induced by anti-immunoglobulin Notkins, A. L., Mahar, S., Scheele, C., and Goffman, J. (1966). antibody. Nature [new Biol.], 233, 225-229. Infectious virus-antibody complex in the blood of chronically Trepo, C., and Thivolet, J. (1970). 1-epatitisassociated antigen and infected mice. J. exp. Med., 124, 81-97. periarteritis nodosa (PAN). Vox Sang. (Basel), 19, 410-411. Nowoslawski, A., Brzosko, W. J., Krawczyhski, K., and Madaleniski, Wear, D. J., and Rapp, F. (1971). Latent measlesvirusinfectionof the K. (1972). Australia antigen and hepatitis. Pathogenic con- hamster central nervous system. J. nimniuno/., 107, 1593-1598. siderations and practical implications. Rec. Advanc. clin. Pat/i., Webb, Hf. E. (1969). The pathogenesis of the viral encephalitides. In in press. Virus Diseases and the Nervous Systeni, edited by C. W. M. O'Connell, C. J., Karzon, D. T., Barron, A. L., Plaut, M. E., and Whitty, J. T. Hughes, and F. 0. MacCallum, pp. 169-177. Ali, V. M. (1964). Progressive vaccinia with normal anti- Blackwell, Oxford. bodies: a case possibly due to deficient cellular immunity.
Ann. intern. Med., 60, 282-289. Weiner, L. P., Cole, G. A., and Nathanson, N. (1971). Virus-specific copyright. Oldstone, M. B. A., and Dixon, F. J. (1969). Pathogenesis of chronic immunologic depression in mice following combined im- disease associated with persistent lymphocytic choriomenin- munization and cyclophosphamide-induced immunosuppres- gitis viral infection. 1. Relationship of antibody production to sion. J. Ininiunol., 106, 427-430. disease in neonatally infected mice. J. exp. Med., 129, 483-505. Wiktor, T. J., Kuwert, E., and Koprowski, H. (1968). Immune lysis Oldstone, M. B. A., and Dixon, F. J. (1971). Immune complex of rabies virus-infected cells. J. Imniunol., 101, 1271-1282. disease in chronic viral infections. J. exp. Med., 134, 32s-40s. Zisman, B., Wheelock, E. F., and Allison, A. C. (1971). Role of Porter, D. D., Larsen, A. E., and Porter, H. G. (1969). The patho- macrophages and antibody in resistance of mice against yellow genesis of Aleutian disease of mink. 1. In vivo viral replication fever virus. J. Imnmunol., 107, 236-243. and the host antibody response to viral antigen. J. exp. Med., Zlotnik, I., Smith, C. E. G., Grant, D. P., and Peacock, S. (1970). The 130, 575-593. effect of immunosuppression on viral encephalitis, with special Porter, D. D.. and Porter, H. G. (1971). Deposition of immune reference to cyclophosphamide. Brit. J. exp. Path., 51, 434-439. http://jcp.bmj.com/ on October 1, 2021 by guest. Protected