Elsevier

Molecular Immunology

Volume 42, Issue 2, February 2005, Pages 213-228
Molecular Immunology

Review
HIV-infection of the central nervous system: the tightrope walk of innate immunity

https://doi.org/10.1016/j.molimm.2004.06.018Get rights and content

Abstract

Infection of the central nervous system (CNS) by HIV is a frequent and sometimes very early event in the course of HIV pathogenesis. Possible consequences are diverse symptoms of neurological dysfunction, but also the establishment of a lifelong latent viral reservoir in the brain. Whereas in the periphery innate and adaptive immunity are equal partners, the blood–brain barrier (BBB) with its restricted access of peripheral immune effectors shifts this balance in favour of the local innate immunity. Four main elements of cerebral innate immunity are discussed in the present article, including two cell types with immunological functions and two soluble immune systems: (1) the stimulation of microglial cells as the predominant brain-resident immune cell and the main local reservoir for the virus; (2) the reaction of astrocytes in response to viral infection; (3) the activation of the local complement system as important soluble immune cascade; and (4) the role of chemokines and cytokines which help to conduct and cross-link the interplay between the different immune elements. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. A dual role of these components with both harmful and protective effects further enhances the complexity of the mutual interactions.

Introduction

The human immunodeficiency virus induces a fatal infection in man with now over 40 million infected persons worldwide. Infection of the central nervous system (CNS) can be proven in about 80% of the HIV-positive individuals and occurs presumably via infected monocytes, macrophages and/or T-cells that traverse the blood–brain barrier (BBB) (Brack-Werner, 1999). Severe neurological complications as a consequence of infection afflict about 25% of adults and half of children with AIDS (Price et al., 1988, Gray et al., 1996). Neurological symptoms include meningitis, neuropathies and AIDS dementia complex (ADC) with cognitive, motor and behavioural dysfunctions. Typical neuropathological hallmarks are atrophy, multinucleated giant cells, reactive astrogliosis, microgliosis, loss of neurons and inflammatory infiltrates consisting of lymphocytes and macrophages (Budka, 1991). Although the incidence of ADC has declined since the introduction of highly active antiretroviral therapy (HAART), this reduction is less marked than for other major AIDS-related diseases (Dore et al., 1999). Prolonged survival for people with HIV could even lead to an increased prevalence of AIDS-associated dementia. The high number of affected patients, along with the restricted penetration of most antiviral drugs through the BBB, emphasizes the relevance of a detailed knowledge about the resident immune effectors in the HIV-infected brain.

Under the selective pressure imposed by a variety of infectious microbes and the relative absence of adaptive immune cells like T- and B-cells, the brain has developed an arsenal of resident innate immune elements including microglia, astrocytes, complement and chemokines/cytokines. Whereas the normal uninfected CNS lacks significant immunological activity, these elements can contribute in concert to the clearance of pathogens from the brain after infection. However, excessive activation might contribute to tissue damage, since the brain is very sensitive against chronic inflammation. This sensitivity creates the necessity to include both inflammatory and anti-inflammatory mediators in the antiviral defence. Our review aims to highlight the four main arms of innate immunity and their functional network in the course of HIV pathogenesis.

Mononuclear phagocytes constitute an important part of the innate immune response and play an essential role in the defence of infectious agents. On the other hand, it has been postulated that they contribute to the pathogenesis of a variety of neurodegenerative disorders. During HIV-infection, their significance is further emphasized by the fact that they represent a major target for a productive infection.

In the brain, three distinct types of cells represent the mononuclear phagocyte lineage which differ in their functions under normal and pathological conditions. Parenchymal microglial cells are the most important cellular component of the immune response within the brain and act as central regulator of nonspecific inflammation and antigen-specific adaptive immune response (Aloisi et al., 2001). Also, as microglia can be activated to express the necessary surface molecules for antigen presentation (MHCII, CD40 and CD80), they are considered the most potent endogenous antigen-presenting cell in the CNS. This hematopoetic cell type is dispersed throughout the cerebral tissue with a very low turnover, representing about 12% of the total cell numbers in the brain (Sedgwick et al., 1991a, Sedgwick et al., 1991b). The second cell type are perivascular and meningeal macrophages which line the endothelium of cerebral blood vessels and meninges, respectively (Williams et al., 2001). They are bone marrow-derived cells, which are steadily replenished from the periphery. During inflammation, these two resident microglial populations are complemented by infiltrating macrophages, which invade the brain parenchyma from the periphery. Perivascular and infiltrating macrophages phenotypically and functionally resemble typical tissue-specific mononuclear phagocytes. All three types of mononuclear phagocytes have been shown to be infected in HIV-patients (Cosenza et al., 2002). However, their different origin, turnover and metabolism bear different implications on the pathogenesis of HIV-induced neurological disease as discussed below.

Under physiological conditions, parenchymal microglia are ubiquitously present in a highly ramified form, exhibiting a quiescent state and lacking endocytic and phagocytic activity. Many of the macrophage-specific receptors and ligands that are essential for performing functions of the innate immune response are expressed at very low levels. However, upon contact with e.g. LPS, DNA with CpG motifs, viruses, or upon insult of the brain or subtle changes in their microenvironment, microglia are able to respond rapidly and become highly activated (Anderson, 2000, Sopper et al., 1996, Lokensgard et al., 2001). Beside by Toll-like receptors (TLRs) microglia can also recognize an infecting agent through binding of opsonizing complement fragments or antibodies, since microglia constitutively express complement receptors as well as Fcγ receptors (Barnum, 1999, Peress et al., 1993); by means of these receptors microglia mediate efficient elimination of opsonized pathogens and damaged cells (Mosley and Cuzner, 1996, Witting et al., 2000).

During activation microglia change to a more rounded phenotype with reduced processes. Surface receptors like CD14 or TLRs are upregulated (Cosenza et al., 2002, Rivest, 2003, Bsibsi et al., 2002) and effector molecules such as proteases, cytokines, and complement components are produced (Aloisi et al., 2001). Ultimately, microglia are capable to exert the complete spectrum of mononuclear phagocyte functions. A variety of cell-cell interactions and soluble molecules regulate the activation status of microglia exerting stimulatory or inhibitory signals. Intact neurons, for example, are able to suppress activation of microglia (Neumann et al., 1996) partly through production of neurotrophins (Neumann et al., 1998) or through the interaction between neuronal CD200R and CD200 on the microglial surface (Hoek et al., 2000). Astrocytes have also been shown to downregulate microglia activity (Liu et al., 1994, Sievers et al., 1994, Eder et al., 1997). Interaction between microglial CD40 and its ligand CD154 expressed on activated T-cells leads to bidirectional activation as it promotes inflammatory responses by microglia and provides a strong costimulatory signal to T-cells (Benveniste et al., 2004). Similarly, the complement anaphylatoxins C3a and C5a induce microglia activation through their specific receptors (Nataf et al., 1999). A network of pro- and anti-inflammatory cytokines and chemokines also exerts a profound effect on the microglial activation state, modulating antimicrobial and antigen-presenting functions, migration, proliferation and cytokine/chemokine secretion (Benveniste, 1998, Rivest, 2003, Si et al., 2002, Rappert et al., 2002, Pereira et al., 2003, Mizuno et al., 2003). Recently, it has been shown that microglia are even able to sense peripheral inflammation which produce a preactivated state that helps to ensure rapid reaction once pathogens invade the brain (Rivest, 2003).

The central role of monocytic phagocytes in the brain is reflected by the numerous roles in the HIV infection of the CNS.

  • (1)

    HIV-infected infiltrating macrophages, as well as T-cells can act as “Trojan horses” and transport HIV into the brain. As a cargo HIV gets access to the brain early after infection during primary viraemia (Davis et al., 1992, Chakrabarti et al., 1991, Demuth et al., 2000). Thus, the penetration of macrophages through the BBB is a central event for the viral spreading into the brain and lays the foundations of the typical neurological dysfunction of HIV-infected patients.

  • (2)

    Parenchymal microglia, perivascular and infiltrating macrophages have been shown to be productively infected by HIV-1, HIV-2 and simian immunodeficiency virus (SIV) (Michaels et al., 1988, Cosenza et al., 2002, Morner et al., 2003, Sopper et al., 2002). Since the viral life cycle cannot be completed in other cells of the CNS, monocytes/microglia is the cell lineage which establishes the viral burden. At early time points, only few productively infected parenchymal microglia cells can be found, and the intrathecal viral replication is fuelled by infiltrating and perivascular macrophages continuously replenished from the periphery (Gartner, 2000, Williams et al., 2001). In the late stage of infection careful analysis of the phenotype and location of infected cells demonstrated that the majority of productively infected cells are parenchymal microglia (Cosenza et al., 2002).

    Several groups have shown that microglia can be infected with HIV and SIV in vitro (Jordan et al., 1991, Sopper et al., 1996) as they express CD4 and chemokine receptors for viral entry (Perry, 1987; He et al., 1997). As demonstrated in different animal models microglia selects for neurovirulent strains (Hein et al., 2003, Babas et al., 2003); these viruses isolated from the brain display reduced dependence on CD4 and increased affinity for CCR5 (Martin et al., 2001, Gorry et al., 2002), possibly to compensate for low CD4 expression on microglia, which however is increased after activation and in brains of HIV-infected patients (Perry and Gordon, 1987, Dick et al., 1997).

  • (3)

    Parenchymal microglia as long-lived cells represent an important viral reservoir in the body and can store archival virus sequences (Ryzhova et al., 2002). It seems that microglia get infected very early in the course of the infection but harbor the virus in a latent state. Viral replication is then restricted for a long period of time by both the resident innate immune system and an intrathecal virus-specific immune response (Sopper et al., 1998). Only as the control by immune system wanes, viral replication can be increasingly reactivated via different pathways, for example through local secretion of proinflammatory cytokines (Wilt et al., 1995). Also infiltrating immune cells or cytokines inundating from the periphery could provide the necessary stimuli (Gartner, 2000).

  • (4)

    Viral infection results in microglia activation with all its neuroprotective and neurodetrimental aspects. Microglia activation can be found very early after infection (Chakrabarti et al., 1991) and increases with the course of the infection. It seems not to be dependant on the presence of HIV antigens (Weis et al., 1994) and is regarded by some to be the best histopathological correlate for ADC (Glass et al., 1995). In addition, viral replication in microglia leads to further activation of these cells (Sopper et al., 1996).

    Microglia in general perform neuron-supporting functions (Streit, 2002). They are involved in maintaining the homeostasis of the extracellular fluid, as they are able to take up excessive neurotransmitters (Nakajima et al., 2001) and participate in the production of neurotrophic factors (Gilad and Gilad, 1995). Their neuroprotective properties become even more evident upon activation since the glutamate transporters and scavenger molecules are upregulated and the production of nerve growth factors and neurotrophins is augmented leading to the removal of excitotoxins and dead cells and regeneration of damaged neurons.

    On the other hand, activated microglia are hypothesized to initiate a series of events ultimately leading to neurodegeneration and neurological symptoms seen in HIV-dementia patients (Kaul et al., 2001). In order to fulfill their functions microglia have to migrate to the site of damage, upregulate effector functions of the innate immune response, sequester and coordinate cells of the adaptive immune response, help to destroy pathogens and even normal cells destined to die (Streit, 2002) and finally remove cellular debris. All these actions are associated with the production of effector molecules like proteases, oxide radicals and cytokines, many of which are potentially harmful for the exquisitely vulnerable neurons (Schwartz, 2003).

    This dual role of activated microglia with both neuronal protection and damage is seen for many aspects. Microglia activation leads to the secretion of excitatory amino acid (EAA) like glutamate and quinolinate (Koutsilieri et al., 1999, Nottet et al., 1996) and increased levels of these excitotoxins have been found in the cerebrospinal fluid of patients with ADC (Heyes et al., 1992, Ferrarese et al., 2001). On the other side, EAA-transporters and glutamine synthetase are upregulated in microglia, possibly counterbalancing the deleterious effects of microglia activation (Gras et al., 2003).

    Oxidative stress is another pathway possibly responsible for neurodegeneration in ADC (Mollace et al., 2001). Several groups have demonstrated increased expression of the inducible nitric oxide synthase in microglia and of endproducts of oxidative stress in demented patients (Boven et al., 1999). In addition, viral products released from infected microglia like gp120 and tat might also contribute to the increased oxidative stress in the brain of HIV-patients (Mollace et al., 2001). On the other side microglia upregulate superoxide dismutase, one of the components of the antioxidant defense machinery (Boven et al., 1999).

    These findings demonstrate the capacity of microglia to counteract the negative effects of infection and immune activation. These efforts seem to be efficient throughout most phases of the disease. Only with the overwhelming viral replication late in infection, the defense mechanisms of the innate immune response in the brain become increasingly activated and the neurodegenerative functions of microglia prevail.

  • (5)

    Viral infection leads to secretion of proinflammatory cytokines/chemokines and complement components by microglia, a link to the other arms of innate cerebral immunity. The cerebral infection by HIV modulates the production of a wide array of cytokines and chemokines, which attract or activate other immune cells or directly interfere with neuronal functions (Table 1). These cytokines/chemokines display both neurotoxic as well neuroprotective effects as described further below (Shohami et al., 1999, Saha and Pahan, 2003).

Astrocytes are the most numerous cell type in the brain and fulfil a variety of different functions. They are described as generator of the BBB, guardians and nurturers of the neurons, as taking care of maintenance of homeostasis, as inducers of migration of neuroblasts and of axon growth (Brack-Werner, 1999). Although multinucleated giant cells and microglia are the main target cell for HIV in the brain, astrocytes were also shown to be infected. The lack of CD4 surface antigen makes the precise way of viral attachment unclear; alternative receptors like galactosyl ceramide might play a role (Brack-Werner, 1999). Due to the abundance of astrocytes in the brain, this cell type represents a considerable reservoir for HIV. The malfunction of Rev in astrocytes hardly allows the production of progenitor virus, but high levels of the regulatory proteins Nef, Rev and Tat are detected (Brack-Werner, 1999).

Astrocytes also fulfil a number of immunological functions. These functions are made possible by the capacity to synthesize a variety of messenger molecules and to form an intercellular contact network with their processes. This capacity implies a crucial role of this cell type in cerebral HIV-infection.

  • (1)

    Being an integral part of the BBB with their endfeet astrocytes inhibit the passage of most pathogens into the brain. In the case of HIV, however, this direct contact with virus and/or with infiltrating HIV-infected blood cells at the BBB can result in astrocytic infection as a very early event in HIV neuropathogenesis. The exposition to viral proteins like gp120 or Tat stimulates the expression of the adhesion molecules ICAM-1 and VCAM-1 in astrocytes (Woodman et al., 1999, Toneatto et al., 1999). Expression of these adhesion proteins by astrocytes serves to target leukocytes to the CNS parenchyma; it thus might enhance antiviral immune response but also facilitate the infiltration of infected cells into the brain and enhance viral burden (Woodman et al., 1999). Astrocytes also secrete soluble factors which modulate the adhesion of T-cells to endothelium; treatment of brain-derived endothelial cells with astrocytes-conditioned medium results in an enhancement of adhesion of T-cells to endothelium (Joseph et al., 1997).

  • (2)

    Astrocytes can synthesize most components of the complement cascade (Speth et al., 2002a, Gasque et al., 2000). Although the constitutive synthesis is low, inflammatory mediators like cytokines can enhance the production. Furthermore, direct incubation with HIV highly stimulates the expression of complement factors C2 and C3 in astrocytes (Speth et al., 2001, Speth et al., 2002a, Speth et al., 2002b). In vivo studies using brain sections of SIV-infected rhesus macaques confirm the induction of C3 in astrocytes compared to the synthesis in brain material from uninfected monkeys (Speth et al., 2004). Via enhanced complement synthesis after infection astrocytes guarantee the presence of the first line of immune defence with lysis of virions, immune cell activation and attraction of microglia, peripheral T-cells and macrophages as main complement functions. Furthermore, astrocytes express receptors for complement activation products and are thus sensitive for the numerous biological effects of complement fragments (see below). This sensitivity is modulated by HIV, since the viral Nef protein alters the synthesis of CD88, the receptor for C5a, which is a central molecule for cell activation and chemotaxis (Kohleisen et al., 1999).

  • (3)

    Astrocytes are one main player to keep the brain an immunoprivileged site. In the normal brain the contact with astrocytes maintains microglia in a dormant ramified state (Brack-Werner, 1999). It has been demonstrated in in vitro experiments that ameboid microglial cells ramify to quiescent state when they are cultured on astrocytes (Liu et al., 1994, Sievers et al., 1994, Tanaka and Maeda, 1996) or treated with astrocyte-conditioned medium (Eder et al., 1997, Eder et al., 1997). In addition, the capacity of microglia to present antigens is reduced by astrocytes through downmodulation of MHC class I and MHC class II molecules (Eder et al., 1999, Tanaka et al., 1999). It has also been reported that astrocytes are able to suppress microglial phagocytosis (DeWitt et al., 1998) as well as the production of the proinflammatory cytokine interleukin-12 (Aloisi et al., 1997). Not only microglial activation, but also the functionality of infiltrating monocytes may be impaired by astrocytes. Supernatant from astrocyte cultures was shown to be a very potent agent in reducing the levels of MHC class II as well as ICAM-1 expression, implicating that astrocytes seem to provide soluble factors that have the capacity to deactivate hematogenous monocytes (Hailer et al., 2001).

    In the HIV-infected brain one might speculate about two consequences about this anti-inflammatory function of astrocytes. On the one hand, astrocytes might downmodulate the antiviral activity of both infiltrating microglia and infiltrating phagocytes. On the other hand, in the later stages of infection the virus-induced functional impairment of astrocytes might be overridden by strong pro-inflammatory signals, resulting in microgliosis as a prominent feature of cerebral HIV infection.

  • (4)

    Astrocytes can present internal antigens via MHC class I molecules, and a variable proportion of adult human astrocytes also express MHC II molecules even under basal culture conditions as shown by double immunostaining (Yong et al., 1992). Astrocytes are considered to be semi-professional antigen-presenting cells. When activated by IFN-γ astrocytes upregulate the production of MHC class I and II as well as costimulatory B7- molecules and can present antigens to CD4+ Th1 cells and CD8+ T cells, respectively (Sedgwick et al., 1991a, Sedgwick et al., 1991b, Cornet et al., 2000). The activation status of astrocytes and their expression level of MHC II are essential for a functional response. High levels of MHC II on activated astrocytes promote immune stimulation and proliferation of CD8+ and CD4+ T-cells, whereas minimal levels of MHC II, typically found on uninduced astrocytes, result in hyporesponsiveness of T-cells and deactivation of monocytes/macrophages within the CNS to prevent neuroinflammatory processes (Hailer et al., 1998, Sun et al., 1997, Cornet et al., 2000).

    HIV affects the presentation of internal antigen by astrocytes. The regulatory Nef protein downmodulates the surface expression of MHC I in astrocytes by promoting the accumulation of MHC I molecules in intracellular organelles (Swann et al., 2001) and accelerating the endocytosis at the plasma membrane (Schwartz et al., 1996). This downmodulation of HLA is essential for the protection of infected cells from CTL killing (Collins et al., 1998, Yang et al., 2002). Since Nef is produced in considerable amounts in astrocytes and is secreted from the cells, the infection of astrocytes can also influence the antigen presentation of neighbouring cells; this might be a general mechanism for immune evasion and for establishment of a persistent infection in the brain.

  • (5)

    Astrocytes were shown to possess phagocytic activity, although they are less potent than microglia (Magnus et al., 2002). Astrocytic cells have the capacity to ingest apoptotic lymphocytes, and their phagocytic activity is dependent on the number of dying T cells. Apoptosis of T lymphocytes is a common pathway to terminate an inflammatory reaction and to prevent the leakage of potentially harmful contents of dying cells (Ren and Savill, 1998). Furthermore, the ingestion of apoptotic cells actively suppresses the subsequent generation of proinflammatory cytokines and can support anti-inflammatory cytokine production (Fadok et al., 1998, Voll et al., 1997). This knowledge makes it an interesting hypothesis that phagocytosis by astrocytes might aim to limit the HIV-induced inflammatory reaction in the brain, another mechanism to keep the brain an immunopriviledged site. Furthermore they could participate in removal of cell debris (Morcos et al., 2003) generated by the neurotoxic activity of cerebral HIV infection.

  • (6)

    Astrocytes are also a main producer of cytokines in the brain. Being capable to produce both inflammatory and anti-inflammatory cytokines and chemokines (John et al., 2003, Dong and Benviste, 2001) they can modulate the mediator network in the brain under normal conditions as well as in HIV pathogenesis. A variety of astrocytes-derived cytokines/chemokines are known to be modulated in their expression in the HIV-infected brain (Table 1). Potential consequences might be immune cell attraction through BBB and activation or deactivation of microglia and infiltrating immune cells (see below).

  • (7)

    Astrocytes suppress the expression of HIV in monocyte-derived macrophages by the secretion of soluble factors (Hori et al., 1999). In contrast, the direct physical interaction of astrocytes with macrophages induces the rapid expression of HIV (Hori et al., 1999). In summary astrocytes regulate in a complex manner the viral burden in the brain and thus the development of HIV-1-associated cognitive/motor complex.

Complement is one of the phylogenetically most ancient arms of immunity, which normally guarantees an immediate and potent limitation of infection (Speth et al., 1999). It is a universal defence system which fights against a large diversity of pathogens. Complement comprises a set of soluble proteins arranged as an activation cascade of interacting components which finally results in the generation of a membrane attack complex (MAC), forming a lytic pore in the membrane of the pathogen or the infected cell. Nearly all complement factors were shown to be synthesized also in the brain, although the normal expression level in the normal brain is low (Speth et al., 2002b).

Three different pathways can initiate the sequential activation cascade. The classical pathway starts the complement cascade after antibody-dependent or antibody-independent interaction of the pathogen with complement factor C1q. In the alternative pathway, the recognition of foreign surface structures by complement itself followed by deposition of C3b induces an amplification loop generating C3 fragments. Mannan-binding lectin (MBL) is the starter molecule of the lectin pathway when it interacts with carbohydrate structures on the surface of the pathogen. All these three activation pathways result in the cleavage of C3, the central multifunctional element of the complement cascade. Further cleavage steps result in the insertion of the multimerized complement protein C9 into the attacked membrane to destroy osmotically the microorganism or the infected cell. All three pathways can be activated by HIV, either antibody-dependently or, in the absence of antibodies, by direct interaction of the viral envelope proteins gp41 and gp120 with the starter molecules of the complement cascade (Speth et al., 1997).

The potentially devastating action of complement implies the necessity to implant a strict control by a set of both soluble (e.g. factor H) and membrane-bound regulatory molecules (e.g. CD55, CD46 and CD59) which prevent or at least reduce the complement attack. Further biological activities of various complement factors or fragments are mediated by the complement receptors CR1, CR2, CR3, C3aR and C5aR. These receptors are widely found in the brain with CR1 and CR2 expressed on astrocytes, CR3 on microglia, and C5aR and C3aR on astrocytes, microglia and neurons, indicating that the majority of brain cells is responsive towards complement activation products (Menet et al., 1999, Gasque et al., 2000).

In the HIV-infected brain, complement synthesis and complement activation can influence and interact with numerous immunological and virological processes:

  • (1)

    Complement might be responsible for increased viral spreading into and within the brain. Interaction of opsonized HIV with complement receptor-positive cells was shown to result in enhancement of cell infection due to improved targeting of the opsonized virions. Such a complement-dependent increase in cellular infection was observed for monocytes (Reisinger et al., 1990, Thieblemont et al., 1995) and for T cell lines (Boyer et al., 1991, Montefiori et al., 1996). Since infection of the brain is supposed to occur by infiltration of infected macrophages and T-cells into the brain, complement-supported infection of peripheral blood cells might also affect the infection rate of the central nervous system.

    The better interaction between iC3b-opsonized virions and complement receptor-positive cells might not only enhance the infection of peripheral immune cells, but also of CR3-positive microglia. Furthermore, the opsonization of virions with complement fragments might also allow the contact to CR1- and CR2-bearing astrocytes with a similar enhancement of astrocyte infection or with a better retention of the virus on the surface and subsequent transmission to microglia.

  • (2)

    In contrast to the enhancement of cellular infection, complement can also participate in the limitation of viral load. Activation of the complement cascade can result in direct lysis of invading pathogens or infected cells by formation of MAC. However, it is known from the periphery that HIV acquires the complement regulator proteins CD55, CD46 and CD59 from the host cell during budding (Stoiber et al., 1996). Furthermore, opsonization of HIV with complement fragments might support the phagocytosis by microglia or astrocytes.

  • (3)

    The anaphylatoxins C3a and C5a, cleavage products of complement factors C3 and C5, and the soluble form of the MAC can exert various biological functions in the brain (Speth et al., 2002b): (i) C3a and C5a are potent attractors of peripheral immune cells, resulting in enhanced infiltration of (potentially infected) monocytes/macrophages into the brain; C5a is known to be chemotactic also for microglia and astrocytes and hence, could contribute to their migration to the site of inflammation/infection; (ii) an activation of signalling cascades in astrocytes and microglia has been shown for C3a, C5a and MAC; thus these complement products might contribute to the typical reactive astrocytosis and microgliosis in HIV-neuropathogenesis, but also stimulate the viral transcription which is dependent on the activation status of the host cell; (iii) modulation of molecule expression and release, e.g. of proinflammatory IL-6; (iv) induction (C5a) or inhibition (MAC) of cellular processes like apoptosis, and cell cycle progression.

  • (4)

    Chronically activated complement might also contribute to AIDS-associated neurodegeneration. The discrepancy between the relatively small number of HIV-infected brain cells and the severity of neurological dysfunctions suggests the presence of molecules which mediate the brain damage. Several hints argue for a potential role of complement as such a detrimental mediator. Indications for a general role of complement in neurodegenerative processes came from a variety of neuropathological conditions like Alzheimer’s disease, Huntington’s disease, Pick’s disease, multiple sclerosis and stroke which were all associated with chronic complement activation and enhanced synthesis (for review, see Speth et al., 2002b, Gasque et al., 2000). Potential mechanisms of secondary brain damage following CNS infections and involving the complement system, can include: (i) opsonization of the surrounding brain cells and phagocytosis by macrophages/microglia; (ii) complement-dependent bystander lysis following the formation of the MAC. Neurons are extremely sensitive against complement attack since they express only limited amounts of the membrane-bound negative regulator CD59 (Singhrao et al., 2000), and the viral envelope protein gp41 can further down-modulate the expression of CD59 on neurons (Chong and Lee, 2000); (iii) oxidative stress through stimulation of respiratory burst activity by complement-derived fragments. Sublytic doses of the MAC are known to induce the release of arachidonic acid and its metabolites, and these molecules have been proposed to be important factors of neurological injury (Power and Johnson, 1995); (iv) C5a was reported to induce apoptosis of neuronal cells (Farkas et al., 1998a, Farkas et al., 1998b).

For all these functions sufficient levels of complement within the brain are a prerequisite. The BBB with its function as a molecular sieve restricts passage of complement factors from the plasma, making the local synthesis of complement a central point. Whereas the spontaneous constitutive expression of complement is low in the CNS, the synthesis can be markedly upregulated by inflammatory cytokines (Gasque et al., 2000, Speth et al., 2002b). Furthermore, viral infection by HIV directly upregulates the expression of complement factors C2 and C3 in astrocytes and of C3 in neurons (Speth et al., 2001, Speth et al., 2002a). Detailed studies of the relevant mechanism resulted in the identification of a regulatory element within the promoter of the C3 gene as being responsive to the stimulatory influence of HIV-1 (Bruder et al., 2004). These results fit well to other data, showing increased levels of C3 in the CSF of HIV-infected patients with neurological symptoms in vivo compared to CSF from uninfected individuals (Jongen et al., 2000). Furthermore, recent own immunohistochemical analyses revealed significant complement production in the brain of HIV-infected patients compared with uninfected control tissue (Speth et al., unpublished). Not only the synthesis of soluble complement proteins is modulated by HIV but also the expression of cellular complement receptors. The viral protein Nef was demonstrated to upregulate the expression of C5aR on astrocytes, a potential mechanism to make this cell type more sensitive against the action of anaphylatoxins (Kohleisen et al., 1999). Further studies will give deeper insight into the protective and/or detrimental role of complement in the HIV-infected brain.

Many of the functions of immune cells like microglia and astrocytes are mediated through their production of cytokines and chemokines. These soluble factors represent a central mean of crosstalk either between the brain cells or between brain cells and infiltrating haematogenous cells. Cytokines are a large and diverse group of small polypeptides with pleiotropic activity, i.e. the ability to perform a broad range of effects on different cell types. Chemokines are a subclass of cytokines possessing chemotactic activity.

Different cytokines/chemokines have partly overlapping, partly synergistic or antagonistic functions; regulating mutually their synthesis in a complex manner, they form a tight network of cerebral signalling elements. Besides infiltrating peripheral immune cells brain-resident neurons, astrocytes, microglia and oligodendrocytes are important producer of these molecules in the brain. Furthermore, all cell types in the brain possess the corresponding receptors which provide responsiveness for a large variety of different cytokines/chemokines. (Miller and Meucci, 1999).

The synthesis of cytokines in the damaged brain is similar to a pyramid, with increasing pathology leading to a recruitment of more and more cytokines (Raivich et al., 1999). An overview of those cytokines which are modulated in their expression in the HIV-infected brain is given in Table 1 and includes both pro-inflammatory and anti-inflammatory cytokines/chemokines. The virus-host interactions and the release of viral proteins lead to cytokine and chemokine imbalance which then contributes to neuropathologic manifestations of the infection including microgliosis, astrocytosis and neuronal dysfunction or death. The immunological role of cytokines in the HIV-associated neuropathogenesis includes several either proven or speculative aspects which will be reviewed in the following.

  • (1)

    Cytokines/chemokines are central regulators for the infiltration of blood-derived immune cells through the BBB. Potential consequences are on the one hand an improved immune defence within the brain. Deficits in lymphocyte recruitment and/or trafficking into the brain are discussed to be associated with high viral load and onset of HIV-associated dementia (Poluektova et al., 2001). On the other hand, the cytokine/chemokine-mediated immune cell attraction might be a trigger for cerebral infection due to the enhanced infiltration of HIV-infected monocytes/macrophages and T-cells as Trojan horses into the brain.

    Chemokines/cytokines can modulate the infiltration from the periphery by two different mechanisms. Chemokines possess considerable chemotactic activity towards monocytes/macrophages and T-cells (Wong and Fish, 2003), as shown, e.g. for MCP-1 and SDF-1 (Wu et al., 2000). Furthermore, inflammatory cytokines/chemokines like TNF-α and interleukins, which are known to be upregulated in HIV neuropathogenesis, can modulate the expression of adhesion molecules on brain endothelial cells (Dietrich, 2002). The cytokine-driven expression level of the intercellular adhesion molecule ICAM-1 on brain microvascular endothelial cells is of special importance, since it is directly correlated with the adhesion and extravasation of leukocytes across the BBB (Cannella et al., 1990, Couraud, 1998).

  • (2)

    Cytokines and chemokines orchestrate the immune defence with activation or inactivation of astrocytes and microglia. Th2-derived cytokines like IL-4 and IL-10, which are both known to be upregulated in the brain by HIV infection (see Table 1) induce a ramification of microglia and a reduction of their adhesion molecule expression, whereas pro-inflammatory cytokines like IFN-γ, IFN-α and TNF-α enhance microglial adhesion to laminin and thus determine the extent of microglial infiltration into and retention at the site of injury (Milner and Campbell, 2002, Wirjatijasa et al., 2002). Pro-inflammatory cytokines like IFN-γ upregulate the expression of MHC class II and the co-stimulatory molecule B7-1 on astrocytes and microglia and thus the capacity to present antigen and to activate T-cells efficiently (Girvin et al., 2002). Also infiltrated T cells and monocytes can be activated via binding of brain-derived chemokines to their corresponding receptors. This cytokine-driven cell activation and excessive inflammation might be a central mechanism of brain damage in the HIV-infected brain. Furthermore, the cytokine-induced inhibition of normal cell function or direct induction of apoptosis might play a role in the development of HIV neuropathogenesis (Brack-Werner, 1999, Wesselingh and Thompson, 2001).

  • (3)

    Cytokines modulate the transcription of HIV and the production of progenitor virions in brain cells. TGF-β-associated signalling proteins can change the activity of the viral LTR in astrocytes (Coyle-Rink et al., 2002). IL-4 and IL-10 enhanced the replication of HIV in microglia (Wang et al., 2002). Other reports describe that HIV replication was induced when CNS cell cultures were stimulated by a combination of pro-inflammatory cytokines including IFN-γ, IL-1β and TNF-α (Janabi et al., 1998, Swingler et al., 1992). Since the cerebral expression of these cytokines is enhanced after HIV-infection, there seems to be a vicious circle for the mutual stimulation of viral replication and cytokine synthesis.

  • (4)

    A number of inflammatory cytokines is able to upregulate the low constitutive expression of complement in brain cells (Speth et al., 2002b). IFN-γ is the most effective cytokine to enhance the synthesis of most complement proteins by astrocytes, microglia and neuronal cells (Haga et al., 1996, Gasque et al., 1992, Gasque et al., 1993), but also other cytokines like TNF-α, IL-1β and IL-8 are potent inducers of C3 expression in astrocytes (Rus et al., 1992). Interestingly, not only the expression of the components of the complement cascade can be stimulated by inflammatory cytokines, but also the synthesis of negative regulators of complement activation; IFN-γ and TNF-α enhance the production of negative regulators of complement activation like factor H and C1-inhibitor (Thomas et al., 2000; Gasque et al., 1993) and thus provide an effective counterbalance for their induction of complement factors.

  • (5)

    Cytokines can modulate the synthesis of chemokine receptors which represent essential co-receptors for HIV attachment to the host cell, thus implying an altered infectability of the cells. Inflammatory cytokines regulate the expression of the chemokine receptor CXCR4 in astrocytes (Wu et al., 2000, Han et al., 2001). Similarly, the expression of the HIV co-receptor CCR5 was described to be enhanced in microglia under the influence of cytokines (Wang et al., 2002).

  • (6)

    Chemokines as the natural ligands can directly compete with HIV for binding to the co-receptors. This competition between the viral envelope protein gp120 and chemokines underlines the significance of chemokine levels in the brain (Kitai et al., 2000). Furthermore, binding of HIV gp120 to chemokine receptors cannot only mediate binding of the virions and their fusion with the host cell, but even elicit signals through the chemokine receptors and act as chemokine agonist (Davis et al., 1997, Meucci et al., 1998, Weissman et al., 1997). Similarly gp120 has been shown to activate signalling pathways through the chemokine receptors in neurons and astrocytes (Lee et al., 2003).

Since the cerebral infection with HIV modulates the expression of a large variety of cytokines/chemokines (Table 1) a detailed analysis would go beyond the scope of this article. In the following we concentrate on some single cytokines/chemokines which might contribute to the HIV-associated neuropathogenesis.

Macrophage chemoattractant protein (MCP-1; CCL2) is a CC chemokine produced by macrophages, microglia, activated astrocytes and endothelial cells (Sozzani et al., 1995, Rollins, 1996). There is an accumulation of MCP-1 in the CSF of AIDS patients with dementia, and the MCP-1 levels correlate well with the degree of dementia (Cinque et al.; Mengozzi et al., 1999, Weiss et al., 1999). This increase may be at least partly due to viral Tat protein, since the incubation with Tat upregulates the expression of MCP-1 in microglial cells (Pu et al., 2003).

The correlation between MCP levels and dementia can be based on two effects of MCP-1: the promotion of immune cell infiltration and the cell activation. MCP-1 potently recruits monocytes and T-cells into the brain (Sozzani et al., 1995, Rollins, 1996), and results from a macaque model provide evidence that high levels of MCP-1 in the CSF are directly associated with higher macrophage/microglia infiltration (Zink et al., 2001). Similarly, MCP-1 induces transmigration of lymphocytes and monocytes across in vitro models of the BBB, a co-culture of astrocytes and endothelial cells (Wu et al., 2000, Weiss et al., 1999). Possible consequences might be a macrophage-based support of the local immunity, but also the attraction of infected macrophages and therefore the promotion of virus dissemination within the brain. The other putative contribution of MCP might be due to the cell activation capacity of MCP-1. Macaques with increased concentration of MCP-1 in their CSF also show significantly higher expression of macrophage/microglia and astrocytes activation marker. (Zink et al., 2001). Thus, MCP-1 might contribute to astrocytosis and microgliosis as characteristic inflammatory hallmarks of HIV neuropathogenesis. On the other hand, MCP-1 can protect human neurons and astrocytes from Tat-induced apoptosis and may thus play a role as protective agent against toxic effects (Eugenin et al., 2003).

Fractalkine (CX3CL1) is found in a variety of tissues, but unlike other chemokines, it is expressed at higher levels in the CNS than in the periphery (Bazan et al., 1997). Its production in human astrocytes and neurons is increased following incubation with HIV virions or purified envelope protein gp120 (Erichsen et al., 2003). Furthermore, fractalkine is upregulated in CSF samples collected from cognitively impaired HIV-infected patients compared to samples from HIV-patients without neurological impairment (Erichsen et al., 2003, Pereira et al., 2001). Fractalkine as important neuronal chemokine is hypothezised to serve as damage signal to recruit macrophages and microglia to the site of injury, serving to induce brain inflammation (Harrison et al., 2001, Erichsen et al., 2003). This hypothesis is supported by the finding that monocyte infiltration into the brain correlates extremely well with the occurrence of HIV-associated dementia (Nottet, 1999). Similar to MCP-1, the precise role of fractalkine is not yet clear since some studies indicate fractalkine as neuroprotective molecule (Pan et al., 1997, Tong et al., 2000). Fractalkine substantially ameliorates gp120-induced neuronal apoptosis in neurons and protects neurons from the neurotoxic activity of viral Tat protein (Meucci et al., 1998, Tong et al., 2000). Thus, the upregulation of fractalkine in HIV encephalitis can attract monocytes as immunologically active cells and interfere with neuronal apoptosis induced by viral gp120 or Tat; the increased infiltration of monocytes however, might promote inflammatory processes and thus neuronal injury.

Stromal cell-derived factor-1α (SDF-1α) belongs to the alpha chemokines. Its expression has been described in neuronal, astroglial and microglial cells of the CNS (Ohtani et al., 1998). It regulates processes like leukocyte and hematopoietic precursor migration, cell growth and cerebellar development (Zou et al., 1998). SDF-1α is the natural ligand of the chemokine receptor CXCR4, which has been localized to microglia, astrocytes and neurons and serves as a co-receptor for HIV-1. This receptor-sharing with HIV makes the cerebral SDF-1a expression an important parameter. SDF-1α expression has been described to be elevated by HIV both in vitro by incubation of brain cell cultures with HIV or Tat and in vivo in the brain of HIV-infected patients with encephalitis (Zheng et al., 1999, Langford et al., 2002, Rostasy et al., 2003). The upregulation of SDF-1 might help to protect brain cells from infection by shifting the competition between binding of SDF-1 and gp120 in favour of SDF-1. Rats receiving SDF-1a were indeed protected against the apoptotic effect of gp120 (Corasaniti et al., 2001a, Corasaniti et al., 2001b).

The two-faced role of cytokines/chemokines is also found for SDF-1α. It has been postulated that SDF-1α, similar to gp120, might contribute to neuronal death via CXCR4 binding and subsequent signaling cascades (Hesselgesser et al., 1998). In addition, since SDF-1α induces astrocytes proliferation (Bonavia et al., 2003), its enhanced expression might contribute to the typical astrocytosis in HIV encephalitis. SDF-1α induces the transmigration of lymphocytes and monocytes across the BBB (Wu et al., 2000), therefore participating in antiviral defence as well as in (potentially harmful) inflammatory reaction.

The cytokine interleukin-10 (IL-10) has a widespread anti-inflammatory action with an influence on a variety of immune elements. Its cerebral synthesis can be stimulated by incubation of astrocytes or neurons with the envelope protein gp41, and increased levels are also revealed in rat brains expressing viral gp160 (Speth et al., 2000, Gemma et al., 2000). The cerebral synthesis of IL-10 is one tool to keep the brain an immunopriviledged site and to suppress excessive immune reaction, thereby preventing the immunopathological effects of an uncontrolled inflammation and immune-mediated injury of the brain. IL-10 exerts its anti-inflammatory effect on different levels. It can be supposed to inhibit an effective T helper cell response to antigens in the brain, as it is shown for the periphery (Schols and De Clercq, 1996, Daftarian et al., 1995). Furthermore, enhanced IL-10 expression has been related to monocyte/macrophage functional impairment (Rosenberg and Fauci, 1990). Treatment of brain-resident microglia with IL-10 down-modulates the expression of MHC class II and of the costimulatory molecules B7-1 and B7-2, which are essential for antigen presentation and T-cell stimulation (Frei et al., 1994, Menendez-Iglesias et al., 1997). In addition, IL-10 inhibits microglial proliferation (Kloss et al., 1997) and attenuates astroglial reactivity (Balasingam and Yong, 1996). This extensive anti-inflammatory mode of action implicates that increased IL-10 levels might disturb in general the antiviral immune response, thus protecting the brain from excessive inflammation, but also favouring viral spread in the brain. Beside its immune-suppressing action, IL-10 induces a dose-dependent increase of nerve growth factor secretion and can provide a neurotrophic support to injured neurons in the HIV-infected brain (Brodie, 1996).

Section snippets

Conclusion

All components of the cerebral innate immunity play a multifaceted role in HIV-induced neuropathogenesis with both protective and detrimental aspects. As described above, they do not act separately from each other but form a complex functional immunity network (Fig. 1). Cytokines induce the synthesis of complement in brain cells and complement activation products enhance the synthesis of pro-inflammatory cytokines in astrocytes (Gasque et al., 2000). Cytokines/chemokines and complement factors

Acknowledgements

This study was supported by the Ludwig-Boltzmann-Society, FWF (project 15375), the Österreichische Nationalbank (project 9374), the BMSG and the State of Tyrol. S. Sopper was supported by the German competence network HIV/AIDS funded by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (01 KI 0211).

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