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Immune Responses in Persistent Virus Infections 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
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