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Chapter 19Virus-induced Immunosuppression

and .

Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132.

Introduction

The History of Measles Virus

Measles virus (MV) naturally infects only humans and occasionally other primates (33). Because of the absence of a reservoir other than humans and the ability to induce lifelong immunity, MV can only maintain itself in human populations of greater than 200,000 individuals capable of sustaining a continuous person-to-person transmission (10). Thus, measles is a relatively new disease of humans, most likely evolving from an animal morbillivirus such as rinderpest virus of cattle (64).

Measles, as a disease of civilization, most likely first appeared in the early population centers of northern Africa, Mesopotamia, and India (33; A. Zahoor, 1997, http://www.erols.com/zenithco/razi.html). An Arab physician first recognized measles as distinct from smallpox in the 9th century. European and Far Eastern records show epidemics of illnesses characterized by a rash between A.D. 1 and 1200. European records of the 11th and 12th centuries show repeated epidemics identified as measles. Measles was first described as a disease of childhood in 1224 (33). Francis Home, a Scottish physician, formally showed measles to be caused by an infectious agent, by transmitting the disease via blood from measles patients to naïve individuals, in 1757 (71). James Lucas, an English surgeon, first described complications of measles in 1790 (54). Peter Panum, a young Danish physician, described the highly contagious nature, the 14-day incubation period, and the induction of lifelong immunity and postulated a respiratory route of infection for measles in 1846 (68).

In Vienna, von Pirquet first described measles virus-induced immunosuppression, as represented by the disappearance of delayed-type hypersensitivity (DTH) skin test responses to tuberculin in 1908 (84). This tuberculin skin response was only transiently impaired during the course of acute measles infection (84). von Pirquet's work with measles virus provided the first evidence that viruses have the ability to suppress the immune system.

Part of the difficulty encountered in examining measles virus is its limited host range. It was not until Goldenberger and Anderson (30) successfully passaged measles virus in macaque monkeys that any sort of laboratory system for the examination of measles existed. Research on measles virus has greatly advanced since Enders and Peebles (21) successfully grew measles virus in tissue culture. Enders et al. (20) went on to develop a live virus vaccine for measles, which was further attenuated to produce the Schwarz vaccine used today (77). When used in a vigorous immunization regimen, this vaccine dramatically reduced the incidence of measles in the United States and other countries.

A Description of Measles Virus

MV belongs to the family Paramyxoviridae, subfamily Paramyxovirinae, genus Morbillivirus (72). Other members of the Morbillivirus genus, specifically canine distemper virus and rinderpest virus, have also been shown to cause immunosuppression (50, 60).

MV is an enveloped, negative-sense, single-stranded, nonsegmented RNA virus with a genome of approximately 15,890 nucleotides (Fig. 1). The viral genome comprises six genes separated by conserved noncoding sequences containing termination, polyadenylation, and initiation signals. MV replicates in the cytoplasm of infected cells (90). The viral genome is transcribed into seven monocistronic mRNAs, resulting in a gradient of mRNA abundance. Control regions comprising 50 nucleotides at the 3′ end and 50 nucleotides at the 5′ end, termed the leader and trailer, respectively, function in transcription to control viral gene expression and in replication to initiate encapsidation (52). The seven mRNAs are translated into eight proteins, most of which are structural and found in the virion (90).

Figure 1. MV genome.

Figure 1

MV genome. The structure of the MV RNA and resultant viral proteins is shown.

The hemagglutinin (H) protein is a type II integral membrane glycoprotein that is incorporated as a spike in the virus envelope. This protein mediates attachment to cells through a cellular receptor (52). The H protein can cause the agglutination of primate erythrocytes and can elicit neutralizing antibodies (52, 90). The MV hemagglutinin protein is different from other paramyxovirus hemagglutinins in that the MV H protein does not contain neuraminidase activity (90).

The fusion (F) protein is a type I integral membrane glycoprotein that is also incorporated as a spike in the virus envelope (52). This protein mediates the fusion of the viral envelope to the cell plasma membrane. It also has the ability to fuse cells into syncytia and thus spread the virus intercellularly. The F protein, like the H protein, also elicits antibodies (90). The F protein is translated as an F0 precursor that is cleaved by a cellular protease, furin in the trans-Golgi, into F1 and F2, which are linked by a disulfide bond (12, 89). Some nonpermissive host cells are unable to cleave F0 and thus produce noninfectious virions (26, 90). The N-terminal 20 amino acids of the F protein are a highly conserved, hydrophobic region named the fusion peptide. This fusion peptide inserts into target membranes allowing membrane fusion to proceed (52).

The nucleoprotein (N) is associated with the RNA along with two other proteins, L and P, to form the nucleocapsid. The nucleocapsid does not disassemble upon infection of cells, but acts as a template for RNA synthesis. The transcribed RNA, which is mRNA, is translated into viral proteins. When the concentration of the N protein reaches a critical level, there is a switch from transcription of viral mRNAs to replication of full-length, positive-sense viral RNA, which in turn acts as a template for the production of full-length, negative-sense viral genomic RNA (90).

The large (L) protein is the least abundant viral protein, with only 50 copies per virion. The L protein, together with the P protein, forms the viral polymerase/transcriptase. The L protein also encodes the guanylyl- and methyl-transferase activities required for mRNA capping (52).

The phosphoprotein (P), together with the L protein, forms the viral polymerase. The gene that encodes the P protein also encodes two other proteins, C via an internal initiation site for translation and V via the insertion of a nontemplated G nucleotide during transcription that results in a frameshift (90). The C and V proteins are thought to act to either speed up or slow down viral replication by either decreasing mRNA synthesis, C, or decreasing genome replication, V (52).

The matrix (M) protein is the most abundant protein in the virion. The M protein is peripherally associated with the nucleocapsid and the cell plasma membrane, where H and F proteins are located. The M protein inhibits transcription of the nucleocapsid during viral assembly, and the resultant virion is released by budding from the plasmid membrane (52).

Measles Virus-induced Immunosuppression

Immunologic Paradox

MV infection produces an immune system paradox. MV infection, while inducing lifelong immunity, also suppresses the immune system leading to an increase in susceptibility to other, secondary infections (24, 67, 91). In vitro research has shown that MV infection of cell cultures makes the cells more susceptible to a secondary bacterial invasion (13). The immune suppression appears coincident with the marked activation of the immune system, in the form of MV-specific responses, which in turn is coincident with the onset of clinical disease, i.e., rash. Immune suppression can continue for many weeks after the apparent recovery from measles (47). Therefore, MV infection results in both immune activation and immune suppression at the same time. Immune suppression is apparent in vivo in such forms as the loss of the DTH skin test response, the impairment of the production of antibody and cellular immune responses to new antigens, reactivity of tuberculosis, and remission of immune mediated diseases such as juvenile rheumatoid arthritis (15, 16, 84, 95). Immune suppression is apparent in vitro in such forms as suppressed lymphoproliferative responses to mitogens, abnormal lymphokine production, and inhibition of antigen-specific proliferation of T lymphocytes (9, 40, 87).

Secondary bacterial, protozoal, or viral infections occur because of immunosuppression by MV infection. These infections can result in pneumonia, chronic pulmonary disease, otitis media, laryngotracheobronchitis, adult respiratory distress syndrome, hepatitis and diarrhea (7, 29). Secondary infections are more common in underdeveloped countries. These secondary infections account for most of the morbidity and mortality associated with acute measles (7). Much research has been done to determine whether a correlation exists between malnutrition and/or overcrowding, which in turn results in a more intensive exposure to measles, and measles mortality (1, 2, 4, 5, 28). A natural epidemic of measles virus in a rhesus monkey colony showed that enteric organisms normally carried in healthy individuals became serious pathogens during the viral infection (58). Some of the bacteria that can be involved in superinfections in measles patients are Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Morganella morganii, Pseudomonas aeruginosa, Chlamydia trachomatis, and Streptococcus pyogenes (7, 56, 94). Some of the viruses that can be involved in superinfections include adenovirus and herpes simplex virus (7, 88, 92). Although acute measles infection causes a relatively high mortality, there was no increase in mortality of those who survived a measles infection found in the postmeasles period as compared with uninfected community controls (6).

Recovery from MV infection depends on both the cell-mediated immune system and the humoral immune system (3). The role of the cell-mediated immune system in MV infection has been known since the work of Burnet (14). He described the course of MV infection in individuals with immunological abnormalities. In individuals with congenital agammaglobulinemia, lack of humoral immunity, measles follows its normal course, whereas in individuals with cortisone-treated acute leukemia, lack of cell-mediated immunity, measles results in fatal giant cell pneumonia without a rash (14). Kiepiela and colleagues demonstrated that MV causes a defect in the T-cell population, specifically the T-helper cell population, the severity of which could be correlated with the severity of the measles disease (46). Patients with a severe depletion of the T-helper cell population had an elevated level of the complement component C3, which in turn is an index of a poor prognosis (46).

The role of humoral immunity in MV infection was explored by determining the beneficial therapeutic effects of antibodies and the correlation between outcome and antibody response (3). It has been found that passive immunization with pooled normal human immunoglobulin will abort the disease if given promptly and will modify the disease if given a few days later, as well as modify or interfere with measles immunization (51, 79, 90). Also, maternal antibodies are sufficient to protect infants from MV infection (8, 11). Antibodies in a natural infection are first detectable when the rash appears (70, 74), and the failure to mount an adequate antibody response results in a poor prognosis (17). The antibody titers after vaccination can be as much as 10 times lower than the titer induced by natural infection, yet long-term immunity is still induced (90).

Models of Immunosuppression

Although MV-induced immunosuppression has been known since the days of von Pirquet (84), the mechanisms involved remain elusive. Many groups around the globe are studying MV-induced immunosuppression. The next section and Table 1 summarize the many approaches being used by various groups to determine the mechanism of MV-induced immunosuppression.

Table 1. Potential mechanisms of MV-induced immunosuppression.

Table 1

Potential mechanisms of MV-induced immunosuppression.

Fujinami and colleagues have approached the problem of MV-induced immunosuppression by examining the affect of MV infection on T and B cells. They have studied the production of cytokines by T lymphocytes and the role of a soluble factor in suppression (9, 27, 81). The study examining cytokine production determined that there is no generalized inhibition of cytokine production leading to generalized immunosuppression (9). MV infection of antigen-specific activated T cells caused no significant alteration in the production of interferon gamma (IFN-γ), interleukin-2 (IL-2), IL-6, or IL-10, although there was a 50% reduction in the production of IL- 4. However, the expression of the IL-2 receptor alpha (IL-2Rα) subunit was decreased in infected, antigen-specific activated T cells. The block in expression of the IL-2Rα subunit by activated T cells may be one mechanism for the suppression of proliferation following MV infection (9).

Through the study of in vitro infected peripheral blood mononuclear cells (PBMC), it was shown that the virus-infected cells secreted an immunosuppressive factor, which was not IFN-γ, IFN-α, or prostaglandin E (75). Studies by Fujinami's group have further examined the role of a soluble factor in immunosuppression, and these studies show that both MV-infected T and B cells produce a soluble factor, present in the supernatants, which in turn can suppress the proliferation of uninfected T and B cells (27, 81). The suppression of proliferation by the supernatants is not due to infectious virus, IL-10, or transforming growth factor beta (TGF-β). The soluble factor is larger than 100 kDa; however, trypsin digestion reveals an antiproliferative activity associated with a factor of less than 10 kDa, and heat treatment at 56°C results in loss of activity. These data support the idea that the soluble factor may be a new cytokine (81). This soluble factor also has the ability to mirror the effects of MV infection of B cells, which results in the inhibition of antigen presentation (27).

Griffin and colleagues have approached the problem of MV-induced immunosuppression by examining the immune responses during MV infection. Various studies of humans have shown that the T-cell-driven immune response is activated during measles infection. There is an elevation in the plasma levels of the soluble forms of the T-cell surface molecules CD4, CD8, IL-2R, and β2-microglobulin and of the T-cell products IL-2, IL-4, and INF-γ (34, 3639). The plasma also contains elevated levels of proliferating CD8 T cells (86). Therefore, immunosuppression is occurring even though substantial immune activation is present. The MV-specific immune response that is induced is effective in clearing the virus and in inducing long-term immunity. Analysis of the in vitro abnormalities suggests defects in the responses of both monocytes and lymphocytes which may be due to infection of these cells leading to cell lysis, via apoptosis, or functional alterations (22, 32). Increases in IL-1 and decreases in tumor necrosis factor alpha (TNF-α) may result from direct infection of monocytes (87). Although T cells have not been shown to be infected in vivo, the numbers of T cells decrease during measles even though a normal proportion of CD4 and CD8 lymphocytes is maintained; therefore, abnormalities in T-cell responses may be secondary to other changes (86). One of the mechanisms suggested for immunosuppression is the presence of elevated levels of IL-4 which functions to suppress macrophage activation and DTH responses (34, 87). The analysis of the cytokine pattern present during MV infection suggests an initial type 1 immune response during viral clearance followed by a prolonged type 2 response; DTH responses depend on the production of type 1 cytokines (43).

Karp and colleagues have approached the problem of MV-induced immunosuppression by examining the role of IL-12 and the complement system during MV infection. IL-12 activity is critical for both protective and pathological cellular immune responses, and as such, is tightly regulated (61). The prime producers of IL-12 in vivo are monocytes/macrophages and dendritic cells (DCs), which are also the main immune cells productively, infected with MV in vivo (44). MV infection of primary human monocytes suppresses the stimulated production of IL-12 (45). This suppression of IL-12 did not appear to be dependent on either an endogenous soluble inhibitor or a productive infection with MV. A direct interaction between MV and CD46, the cellular receptor for MV, was suggested to cause the suppression of IL-12 production even if no productive MV infection results (45). This hypothesis is supported by the suppression of IL-12 production seen as a result of antibody-mediated cross-linking of CD46 on the surface of primary human monocytes. Likewise, complement activation products that interact with CD46 also suppress the stimulated production of IL-12 (45). MV also suppresses the production of IL-12 by DCs (25). The ability of MV infection to suppress the production of IL-12 may be one mechanism by which MV induces immunosuppression, because IL-12 is required for most DTH responses (44). This requirement for IL-12 in DTH responses may in turn be due to the requirement for IL-12 in the development of type 1 immune responses (43). However, suppression of IL-12 does not explain the in vitro lymphoproliferative defects caused by MV infection, nor has the suppression of IL-12 yet been shown to occur in vivo (44, 61).

Oldstone and colleagues have approached the problem of MV-induced immunosuppression by examining both the in vitro lymphoproliferative defect and the host-pathogen interactions. The suppressed lymphoproliferative responses to mitogens in vitro has been shown to be caused by a block in the cell cycle at late G1 or G0 (57, 59, 62).

The host-pathogen interactions are being examined via transgenic mice. Mice transgenic for CD46, the human MV receptor, have been used to study the pathogenesis of MV infection (69). Immunosuppression in the transgenic mice has been shown to occur as seen by: (i) a reduction of the CD8+ cytotoxic T lymphocyte (CTL) response against viral challenge with viruses such as lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV), (ii) the inability to generate antibodies against antigens, and (iii) the susceptibility of the transgenic mice to secondary bacterial infections (69).

Horvat and colleagues have approached the problem of MV-induced immunosuppression by examining the role of MV proteins in the generation of immunosuppression in vivo (55). They have studied the DTH response mediated by CD4+ T cells and the contact hypersensitivity (CHS) response mediated by CD8+ T cells, two types of T-cell-dependent inflammatory reactions. They demonstrated that inactivated MV (thus absence of viral replication) efficiently suppresses these inflammatory responses in mice after the MV envelope proteins, F and H, and N protein have interacted with their cellular receptors, CD46 and FcγR, respectively. CD46 appears to be expressed on DCs as well as an additional cell type, while FcγR is expressed on DCs (55).

Two groups, Yanagi and colleagues and Richardson and colleagues, have approached the problem of MV-induced immunosuppression by examining the receptor used by MV to bind to cells. CD46 has been identified as the MV receptor yet MV strains isolated in B95a cells or human B cell lines did not grow in CD46+ cell lines (18, 49, 63). Through the use of two different versions of functional expression cloning, the human signaling lymphocytic activation molecule (SLAM) gene was identified as the cellular receptor for MV strains that cannot use CD46 (41, 82). Unlike CD46, which is ubiquitously expressed, SLAM is constitutively expressed on immature thymocytes, CD45ROhigh memory T cells, and some B cells and is induced on activated T and B cells (53, 93). The pattern for SLAM expression is consistent with the lymphoid tropism of MV infection. Binding of MV to SLAM on the cell surface may cause either the destruction of SLAM+ cells or may impair the lymphocyte activation by affecting the signals induced through SLAM, resulting in immunosuppression (93). Type 1 immune cells express more SLAM than type 2 immune cells; therefore, the destruction of SLAM+ cells could favor the type 1 to type 2 immune response shift suggested previously (41).

Servet-Delprat and colleagues approached the problem of MV-induced immunosuppression by examining Fas-mediated apoptosis of MV-infected DCs and activation of bystander uninfected DCs in vitro (78). They determined that the Fas-mediated apoptosis, induced by MV replication, of infected DCs helps mediate the release of infectious MV particles. They also found that apoptotic MV-infected DCs induce the maturation of uninfected DCs via a bystander mechanism of contact with or engulfment of infected apoptotic DCs. These two occurrences may explain how both a specific immune response to measles (DC activation) and immunosuppression (DC apoptosis) can occur simultaneously after MV infection (78).

Klagge and colleagues approached the problem of MV-induced immunosuppression by also examining DCs and the affect of MV infection on them in vitro (48). They determined that the release, induced by MV infection, of INF-α/β by DCs contributes to DC maturation. However, MV-infected DCs expressing the MV F and H glycoproteins on their surface inhibit mitogen-induced proliferation of T cells. Therefore, the immunosuppressive activity of the glycoproteins on the cell surface appears to overcome the promotion of DC maturation by soluble mediators (48). This same group showed that the expression of the MV F and H glycoproteins on peripheral blood lymphocytes (PBLs), used as presenter cells, reduced the proliferation of naïve PBLs to various stimuli by means of surface contacts (76).

Potential Therapies

Measles itself can be treated by the administration of immunoglobulin, as discussed above, and interferon, vitamin A, and ribavirin (42, 56). Interferon is thought to reduce virus replication by inhibiting infection of uninfected cells by virions (31). For reasons that are as yet unexplained, the administration of vitamin A decreases the mortality due to MV infection. Ribavirin, a synthetic nucleoside analog structurally related to guanosine and inosine, has in vitro activity against MV replication (56). Measles pneumonia may be life threatening in immunocompromised adults, and ribavirin has been used in vivo to treat measles pneumonia in oncology and HIV-infected patients, and in immunocompetent individuals (23, 42, 73, 80).

The secondary infections, which occur as a result of MV-induced immunosuppression, can themselves be treated. Secondary infections due to bacteria can be treated with antibiotics. Secondary infections due to viruses can be treated with antiviral drugs.

The most efficient way to treat measles, and the resultant immunosuppression and secondary infections, is by prevention. Prior to the introduction of the measles vaccine, the United States alone had almost 4 million cases of measles annually. Following the introduction of the measles vaccine in the United States, the incidence of measles decreased dramatically, to a low of 1,497 cases in 1983 (56). Measles has not been eradicated, however. Outbreaks continue to occur in the United States in preschool-age children who have not received vaccination and in adolescents of high school and college age who have received only a single dose of the vaccine (56). On the basis of the presence of these outbreaks, a two-dose vaccination schedule was implemented in the United States in 1989, and a two-dose vaccination schedule is supported worldwide by the World Health Organization (56, 83). Through the use of the two-dose vaccination strategy, it is feasible to raise the level of vaccination coverage such that the virus transmission is interrupted and measles could be essentially eradicated (65, 66). Eradication of measles is feasible because measles is only transmitted from human to human, so 100% vaccination is not necessary. It is only necessary to increase the overall immunity level to a level where the number of susceptible individuals in the population is too low to sustain measles virus transmission (19).

Summary

Many laboratories are studying the immunosuppression induced by MV infection. One theory about the mechanism is that the viral infections shift the immune response to a type 2 immune response (32, 35, 85). This mechanism was explored further to demonstrate that the interaction of MV with its cellular receptor, CD46, results in the suppression of IL-12 which is required for type 1 immune responses (43, 45). Another theory about the mechanism is that an as-yet-unidentified soluble factor is able to inhibit lymphoproliferation (27, 81). Other groups are addressing the role that the MV proteins play in immunosuppression (48, 55, 76), while others are examining the role of the alternate MV receptor, SLAM, in immunosuppression (41, 82). Yet another group is examining the Fas-mediated apoptosis of MV-infected DCs as a means of explaining the presence of both a specific immune response and immunosuppression (78). Regardless of the extensive work that has been done on MV-induced immunosuppression, the exact molecular mechanism remains unresolved and may be multifactorial.

Acknowledgments

We thank Kathleen Borick for preparation of the manuscript.

This research is supported by NMSS grant RG29258.

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