Complement-dependent control of viral dynamics in pathogenesis of human immunodeficiency virus and simian immunodeficiency virus infection

Molecular Immunology 38 (2001) 241– 247 www.elsevier.com/locate/molimm

Review

Complement-dependent control of viral dynamics in pathogenesis of human immunodeficiency virus and simian immunodeficiency virus infection Laco Kacani a,*, Heribert Stoiber a, Cornelia Speth a, Zolta´n Ba´nki a, Klara Tenner-Racz b, Paul Racz b, Manfred P. Dierich a a

Institute of Hygiene and Social Medicine, Ludwig Boltzman Institute for AIDS Research, Uni6ersity of Innsbruck, Fritz Pregl-Straße 3, A-6010 Innsbruck, Austria b Department of Pathology, Bernhardt Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, D-20359 Hamburg, Germany

Abstract Since the first contact with the host, human immunodeficiency virus (HIV) exploits the complement system to reach maximal spread of infection. HIV has adapted many strategies to avoid complement-mediated lysis and uses the opsonization with complement fragments for attachment to complement receptors (CR). From the pathogen’s perspective, binding to CR-expressing cells is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Moreover, complement-mediated trapping on CR+ cells permits HIV to infect surrounding cells even in the presence of an excess of neutralizing antibodies. Thus, complement activation initiates the assumption of power over the host’s immune system by HIV and thus augments viral spread and replication throughout the body. On the other hand, natural hosts of primate lentiviruses, such as sooty mangabeys, African green monkeys and chimpanzees, are generally considered to be resistant to the development of AIDS, despite persistent viral replication. This review focuses on the possible link between the resistance to disease and species-specific diversity in function of human and monkey complement system. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Complement; Human immunodeficiency virus; Simian immunodeficiency virus; AIDS; Human; Monkey; Pathogenesis

1. Human immunodeficiency virus pathogenesis and interaction with human complement system Like other pathogens, human immunodeficiency virus (HIV) directly activates the classical complement pathway even in the absence of antibodies (Dierich et al., 1993; Marschang et al., 1993; Stoiber et al., 1997). The antibody-independent activation of the classical complement pathway occurs already during the acute phase of HIV infection, before virus-specific antibodies appear. The direct interaction of HIV envelope protein gp41 with the C1-subcomponent C1q leads to complement activation and deposition of C3 fragments on the viral surface (Ebenbichler et al., 1991; Thielens et al., 1993; Stoiber et al., 1994). In addition to gp41, gp120 * Corresponding author. Tel.: + 43-512-507-3404; fax: + 43-512507-2870. E-mail address: [email protected] (L. Kacani).

molecules activate the complement cascade, probably through binding of mannose-binding lectin and activation of the lectin pathway (Haurum et al., 1993; Susal et al., 1994). During and after seroconversion, HIV-specific antibodies enhance the activation and deposition of complement fragments on the surface of virions (Spear et al., 1993a; Saarloos et al., 1995). However, a large proportion of virions exhibit an intrinsic resistance towards complement-mediated virolysis (Marschang et al., 1993; Saifuddin et al., 1995; Stoiber et al., 1996). Similar to other retroviruses, HIV particles bud from the plasma membrane of infected cells. During this budding process, virions acquire the cell membrane of the host with its membrane-anchored host proteins, additionally to their own envelope glycoproteins gp120 and gp41. Among them, complement regulatory proteins such as decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) or

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CD59 have been found on the surface of HIV (Montefiori et al., 1994; Marschang et al., 1995; Saifuddin et al., 1995; Frank et al., 1996; Stoiber et al., 1996). Moreover, factor H binds to the viral envelope, thereby enhancing the protection of HIV against complementmediated damage (Stoiber et al., 1996), i.e. keeping complement activation under a certain threshold necessary to induce lysis of virions. Already first studies on sections of infected lymphoid tissue (LT) have shown that CD4+ cells in the T cell zone produce HIV, but the major part of virions is attached extracellularly to follicular dendritic cells (FDC) in germinal centres (GC) (Armstrong and Horne, 1984; Tenner-Racz et al., 1985; Racz et al., 1986). Immunohistochemical studies of LT established the FDC network as significant HIV reservoir in all phases of infection (Fox et al., 1991; Embretson et al., 1993; Pantaleo et al., 1993; Schacker et al., 2000). Moreover, quantitative image analysis demonstrated that viral RNA extracellularly bound to FDC is over 50-fold more abundant than viral RNA in productively infected cells (Haase et al., 1996). Accordingly, FDCassociated virions represent more than 90% of total body virus pool during the presymptomatic and late stage of infection (Pantaleo et al., 1998; Haase, 1999). FDC are essential constituents of LT, where they form a three-dimensional network and trap antigens on their surface. Several mechanisms have been supposed to mediate extracellular trapping of HIV in GC. In addition to Fcg receptors, CR are generally recognized as the main effector molecules for trapping of antigens in GC (reviewed in Tew et al. (1997)). FDC express substantial amounts of CR1 and CR2, in addition to lesser amounts of CR3. This unique pattern of CR expression allows FDC to interact with all major C3 fragments, namely C3b, iC3b and C3d. In addition, B cells expressing CR1 and CR2, may significantly contribute to trapping of HIV-immune complexes (Speth et al., 1997; Stoiber et al., 1997; Moir et al., 2000). Using isolated FDC, extracellular HIV trapping was shown to be complement-dependent at least in vitro (Joling et al., 1993). Recently, we have studied contribution of particular complement receptors (CR) to HIV trapping in vivo. CR2 was identified as the main binding site for HIV in GC of infected individuals. Moreover, mAb blocking the CR2 – C3d interaction has been shown to detach 60– 70% of HIV from FDC network (Kacani et al., 2000). Further experiments shall clarify the contribution of Fcg receptors and other molecules to HIV trapping in GC. The accumulation of HIV in LT triggers a series of events that represent a normal immune response against pathogens. As typical for an antigen-specific immune response, HIV induces activation of a variety of immunocompetent cells, including macrophages, T lymphocytes and B cells. Activated CD4+ and CD8+ T

cells migrate into lymphoid follicles and stimulate B cell proliferation, antibody production and isotype switching. FDC bind HIV-immune complexes (virus opsonized with Ab and complement fragments) that serve as antigen-specific stimuli for affinity maturation of B cells (Burton et al., 1997; Cohen et al., 1997). In addition, HIV causes an intense polyclonal activation of B cells, as manifested by hypergammaglobulinaemia, elevated serum levels of immune complexes and increased numbers of immunoglobulin-secreting cells (Schnittman et al., 1986; Fauci, 1988). However, HIV-specific immune response is never efficient enough to eradicate the virus completely. This persistence of HIV causes permanent immune activation that is accompanied by dramatic changes in histopathology of LT. The number of CD8+ T cells increases significantly in GC, where CD8+ T cells are otherwise rare (Janossy et al., 1985; Racz et al., 1986; Racz et al., 1989). Follicular hyperplasia or formation of exuberant GC and persistent generalized lymphadenopathy are the histopathologic counterparts of this state of immune activation in early stage of disease (Tenner-Racz et al., 1985; Racz et al., 1986; Embretson et al., 1993). Expansion of FDC network is responsible for enhanced trapping and accumulation of HIV in GC (Pantaleo et al., 1994). Moreover, FDC maintain trapped HIV in an infectious form in vivo for month (Heath et al., 1995; Smith et al., 2001). It is likely that close physical proximity between FDC, B cells and CD4+ T cells in GC promote new infection of target T cells (Racz et al., 1989; Do¨ pper et al., 2000). In addition, cytokine-rich microenvironment and permanent immune activation generate a pool of target cells within GC that is capable to support virus replication. It was demonstrated that a large proportion of CD4+ T cells present in GC are activated and infected with HIV (Embretson et al., 1993). Furthermore, GC CD4+ T cells have been shown to be an important site of HIV replication in vivo (Hufert et al., 1997; Tenner-Racz et al., 1998). Recently, HIV transmission from FDC and B cells to CD4+ T cells was studied using cocultivation of purified cell populations in vitro. In this system, HIVimmune complexes immobilized on FDC efficiently infected T cells, even in the presence of neutralizing Ab (Heath et al., 1995). Similarly, opsonized HIV particles trapped on the surface of B cells infected CD4+ T cells (Do¨ pper et al., 2000; Jakubik et al., 2000). Infection of T cells was observed also in the absence of exogenous activation, suggesting that B cells carrying complementcoated HIV on their surface provide enough costimulatory signals for activation of CD4+ T cells upon cocultivation (Do¨ pper et al., 2000). In conclusion, initial events associated with the primary immune response towards HIV paradoxically create favourable conditions for viral replication and spread of infection.

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The molecular mechanism of HIV transmission from FDC and B cells to T cells is not clear, nor the role of CR on CD4+ T cells in this process. Low levels of CR1 and CR2 expression have been reported on subsets of T cells (Wilson et al., 1983; Cohen et al., 1989; Fischer et al., 1991) and opsonization of the HIV particles with complement enhances infection of T cells up to tenfold (Robinson et al., 1990; Boyer et al., 1991; Delibrias et al., 1993). Whether CR can replace CD4 or chemokine coreceptor as essential contributors of viral entry, remains to be elucidated. As HIV infection progresses, there is a shift in the histopathologic pattern from follicular hyperplasia to follicular involution. Already during early stages of HIV infection initial signs of follicular involution and fragmentation may be detected within individual GC. In the intermediate stage of HIV infection, FDC network is disrupted and lymphoid follicles diminish. This shift in histopathology is associated with infiltration of CD8+ T cells and macropages into GC, whereas the number of CD4+ T cells decreases (Janossy and Bofill, 1985; Tenner-Racz et al., 1985; Racz et al., 1986). Simultaneously, changes occur in the distribution of virus. Destruction of FDC network leads to decrease of HIV trapping in GC, whereas the level of infectious virions increases in circulation. Sequestration of infected cells within LT also becomes less efficient during follicular involution (Embretson et al., 1993; Pantaleo et al., 1994). Finally, lymph node architecture is completely destroyed and most of LT is replaced by fibrotic tissue and fatty infiltration. At this time, the number of CD4+ T cells in blood declines below 200 CD4+ T cells/ml and generalized immunosuppression occurs. Trapping of virus at this stage is completely absent or limited to those areas of LT, where isolated FDC are still present, whereas the number of cells replicating virus is generally increased (Pantaleo et al., 1993, 1994). Thus, intact FDC network serves as a filter keeping HIV attached, whereas disruption of lymphoid follicles leads to release of virus and redistribution of cells between LT and the periphery. It is generally accepted that lysis of HIV by complement is a mechanism of viral clearance from blood (Sullivan et al., 1996). However, a large proportion of virions resists complement-mediated virolysis, even in the presence of HIV-specific antibodies (Marschang et al., 1993; Stoiber et al., 1996). Such opsonized particles can bind on CR-expressing cells in peripheral blood. B cells isolated from peripheral blood of HIV+ individuals have been shown to carry HIV-immune complexes on their surface. Circulating B cells bind opsonized virions through CR2 and this interaction has been shown to be complement-dependent in vivo (Moir et al., 2000). These findings strongly suggest that B cells are similar to FDC in their capacity to serve as extracellular reservoirs for HIV (Do¨ pper et al., 2000; Jaku-

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bik et al., 2000; Moir et al., 2000). Since B cells possess the capability to circulate in peripheral blood and to migrate through tissues, their contribution to spread of virus during different stages of HIV infection should be reconsidered (Moir et al., 2000).

2. Simian immunodeficiency virus infection and interaction with monkey complement HIV-1 appears to have evolved from cross-species transfer of simian immunodeficiency virus (SIV) from chimpanzee (Gao et al., 1999), whereas HIV-2 arose probably from cross-species transmission of SIV-infected sooty mangabeys (Chen et al., 1996; Hahn et al., 2000). Therefore, many monkey models are increasingly exploited to find mechanisms of protective immunity to AIDS. In the last 10 years, more than 30 SIV strains have been isolated from a variety of monkey species (Hirsch et al., 1995). For most isolates, no evidence of AIDS in the naturally infected monkey species (sooty mangabey, African green monkey, chimpanzee) could be found and most of the AIDS-inducing infections resulted from heterologous SIV, i.e. transmission of SIV across species. In host species, that have not experienced long-term endemic infection by the primate immunodeficiency viruses such as humans and Asian macaques, HIV or SIV infection is associated with decline of CD4+ T cells and progression towards AIDS (reviewed in Norley and Kurth (1997)). Conclusively, the knowledge of mechanisms responsible for resistance towards progression of disease in natural hosts promises a chance for development of new strategies to prevent and treat HIV infection in humans (Letvin, 1991). Similar to human complement, the monkey complement system is efficiently activated by all SIV strains tested so far (Montefiori et al., 1990; Spear et al., 1993a,b). Moreover, SIV uses identical strategies to avoid complement-mediated virolysis. DAF, MCP and CD59 are incorporated into the viral envelope during budding of SIV from infected cell (Montefiori et al., 1994). Furthermore, complement-dependent enhancement of SIV infection has been demonstrated with sera obtained from infected or immunized macaques and chimpanzee (Robinson et al., 1989; Montefiori et al., 1990). Although the first interaction between monkey complement and SIV is very similar across species, clinical outcome of SIV infection depends on the infected monkey species (Letvin, 1991; Norley and Kurth, 1997). Most AIDS-related studies have been performed using rhesus macaques infected with SIVmac. Pathogenic SIVmac arose from accidental transmission of natural SIV from sooty mangabeys (SIVsm) to rhesus macaques (Daniel et al., 1985). Following intravenous

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or mucosal inoculation, SIVmac isolates induce a disease pattern very similar to that of human AIDS. After 1– 2 weeks of primary viremia, CD4+ T cells gradually decline during 3 months to 3 years of asymptomatic phase. Whatever the primary site of infection, SIVmac rapidly disseminates over the majority of lymphoid organs with the catastrophic effects on the lymph node architecture. Histopathological changes are identical with that found in HIV infected humans: follicular hyperplasia is associated with virus trapping in GC and CD8+ T cell infiltration (Chakrabarti et al., 1994; Rosenberg et al., 1997). Similar to the situation in humans, the progressive breakdown of lymphoid follicles is associated with the development of opportunistic infections and full-blown simian AIDS. It is controversial whether SIVmac trapping in GC of infected animals is complement-dependent and which receptor is responsible for this effect. Repeated administration of cobra venom factor to rhesus MAC challenged with SIVmac did not reduce viral trapping in GC (Schmitz et al., 1999). However, it is not clear whether complement depletion to B5% of baseline haemolytic activity in blood of rhesus monkeys is sufficient to interfere with opsonization of SIVmac virions. Further experiments are currently under way to elucidate this mechanism. African green monkeys and sooty mangabeys can maintain long-term, persistent infection with SIV without developing AIDS and thus provide an important model for understanding mechanisms of natural host resistance to disease. Although SIVagm and SIVsm replicate to high levels in these two species, trapping of SIV in GC, follicular hyperplasia, or follicle destruction have never been detected (Beer et al., 1996; Norley and Kurth, 1997; Rey-Cuille et al., 1998; Broussard et al., 2001). African green monkeys and sooty mangabeys appear to exist in a non-pathogenic equilibrium with their virus, wherein active replication is tolerated without development of disease (Broussard et al., 2001). Immunological studies suggest that infected but asymptomatic animals fail to mount significant antiviral immune responses and show far lower levels of generalized immune system activation (Norley and Kurth, 1997). Unfortunately, no data are available concerning the complement status of infected animals and lack of viral trapping in GC. HIV-inoculated chimpanzees are resistant to the development of AIDS despite an active and persistent infection. Among more than 150 experimentally infected animals only 4 have been defined to progress towards AIDS after \ 10 years of infection (Novembre et al., 1997; O’Neil et al., 2000). Importantly, HIV trapping was detected in GC of 3 animals with the highest viral load, highlighting that attachment of HIVimmune complexes to FDC network is crucial to progression of disease. In contrast to HIV-infected

humans, most HIV-positive chimpanzees maintain normal numbers of CD4+ T cells, harbour low plasma virus loads, display only transient virus deposition in GC and a paucity of virus-expressing cells (Bogers et al., 1998; O’Neil et al., 2000). In these non-progressors, some of the lymph nodes may exhibit moderate follicular hyperplasia with some infiltrating CD8+ T cells, but there is no evidence of follicular fragmentation (Koopman et al., 1999). With the exception of four documented cases of progression, HIV-infected chimpanzees remain healthy, similar to human long-term non-progressors (Nath et al., 2000; O’Neil et al., 2000).

3. Conclusions A lack of HIV deposition in GC may be a key determinant of protection against progression to AIDS. We hypothesize that already small quantitative differences in the function of the complement system can provide a plausible explanation for distinct clinical outcome of lentiviral infection in natural and heterologous hosts. In all primates, soluble immune complexes bind to CR1 on erythrocytes through C3b and subsequently they are cleared from circulation in the liver. In addition, human CR1 functions as a cofactor for factor I-mediated cleavage of C3b to iC3b, which ultimately leads to release of immune complexes from the surface of erythrocytes. Such iC3b-opsonized HIVimmune complexes can bind to CR2+ FDC network in LT or to B cells in peripheral blood (Joling et al., 1993; Do¨ pper et al., 2000; Kacani et al., 2000; Moir et al., 2000). In this regard, chimpanzee as well as other primate erythrocytes were reported to posses much higher capacity to bind immune complexes than human erythrocytes (Edberg et al., 1992; Nickells et al., 1995) and alternatively spliced CR1 molecules on chimpanzee erythrocytes only weakly support the cleavage of C3b to iC3b (Edberg et al., 1992; Birmingham et al., 1994). On the basis of our preliminary data, we speculate that a slight shift in processing of complement fragments on the virion surface might establish a non-pathogenic equilibrium between host and virus, and thus could determine the clinical outcome of infection. These studies promise to define the immunological correlates of progression towards AIDS and may help to envision new strategies for treatment of HIV infection.

Acknowledgements This work was supported in part by grants from the Austrian Science Found (P14661-PAT), the 5th framework of the EU (QLK 2-1999-01215), the LudwigBoltzmann Institute for AIDS Research and the State of Tyrol.

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