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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283495a26
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Emerging role for complement in HIV infection

Huber, Georg; Bánki, Zoltán; Lengauer, Susanne; Stoiber, Heribert

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Division of Virology, Innsbruck Medical University, Innsbruck, Austria

Correspondence to Heribert Stoiber, Division of Virology, Innsbruck Medical University, Innsbruck, Austria Tel: +43 512 9003 71701; fax: +43 512 9003 73701; e-mail:

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Purpose of review: New evidence is provided that the complement system is not only an effective component of the innate immunity, but is also involved in bridging innate and adaptive immune response to control retroviral infections.

Recent findings: The complement contributes to the control of retroviral replication by various strategies, such as complement-mediated lysis, triggering of B-cell responses by trapping the virus on follicular dendritic cells in the germinal center or enhancing of antigen presentation and thus the induction of virus-specific cytotoxic T lymphocytes. HIV has evolved mechanisms to escape from complement-meditated neutralization and counteracts these immune responses by escaping from lysis, using follicular dendritic cells as anchor to generate a latent viral reservoir and enhancing the infection of antigen-presenting cells.

Summary: This review will discuss the complex interactions of complement and complement receptors with retroviruses and review the escape mechanisms, which protect this virus family from complement-mediated destruction.

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For decades, the complement system is known for its contributions in the innate immune defense by the induction of complement-mediated lysis (CML) and its role in tagging pathogens for phagocytosis. Recent publications indicate that complement plays an additional role in the induction and maintenance of the adaptive immune response. In addition to enhancing antibody responses, complement is involved in antigen presentation and thus the induction of robust and specific cytotoxic T-lymphocyte (CTL) responses against HIV and other retroviruses. HIV responds to the attacks mediated by the complement system directly or indirectly with different escape strategies, which are discussed below.

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The complement system

The complement as a major part of the immune system acts as the innate surveillance of foreign intruders, for example fungi, worms, bacteria and viruses [1,2]. Up to date almost 50 soluble or membrane-bound proteins are involved in the complement cascade and its regulation, from the initial start by recognition of pathogenic surfaces to the final formation of the membrane attack complex (MAC) [3••].

Depending on the trigger, complement activation takes place at three different pathways: the classical, the alternative and the lectin pathway; they all merge in the activation of C3, the pivot point within the complement cascade [1].

Classical pathway is activated by binding of C1-complex, a multidomain protein consisting of pentameric C1q and C1s2r2, clustering to at least two immunoglobulins bound to cell walls of pathogens [4], apoptotic cells or by the pentraxin family members [5–7]. Thereby C1-complex recruits C2 and C4, thus generating the classical pathway C3-convertase C4bC2a, which activates C3 by cleaving it into C3a and C3b [2,8].

In contrast to the often referred to as antibody-depended classical pathway, the lectin pathway is activated by distinct pattern recognition molecules [9•,10], for example carbohydrates, lipopolysaccharides (LPS), mannans or dsRNA featured by microbes, but not by the host [10]. Therefore, the identification occurs via the mannose-binding-lectin protein family (MBL) and ficolins [2,8]. After recognition of these pathogenic surface molecules, MBL-associated serine proteases (MASPs) are activated. The following proteolytic cascade resembles the classical pathway in cleavage of C2 and C4 by establishing the enzyme complex C4bC2a (C3-convertase).

The alternative pathway is constitutively active at low levels and needs no exogenic trigger [11]. Initiated by the spontaneous hydrolysis of the C3 internal thioester bond resulting in C3(H2O), the active group becomes exposed to stabilizing factor B (fB), which serves as substrate for factor D (fD) resulting in C3(H2O)Bb. This early C3-convertase of alternative pathway cleaves additional C3 to C3b and C3a. The activated C3b integrates in the preceding cycle to form C3bBb resulting in the full C3-convertase of alternative pathway, stabilized by Properdin (P) [12]. By this C3-amplification loop, more and more C3b is recruited and covalently attached to the microbial surface [11]. Thus, a rapid opsonization is guaranteed.

After opsonization of the pathogenic surface with C3b, a multiprotein complex is formed with either C4bC2a or C3bBb, by which C5 is cleaved into C5a and C5b. The release of C5b initializes the downstream steps to MAC formation [13]. During this process C6–C9 are sequentially recruited forming and integrating a pore-like structure within the pathogen's cell-membrane resulting in the affected cell's homeostatic breakdown [1,8].

There are many regulating membrane-bound and fluid phase proteins to protect the host's tissue from complement-mediated damage. The identification of pathogenic surface patterns occurs by distinguishing nonself and self [14], including a set of so-called regulators of complement activation (RCA). In fluid phase, mainly C3-convertase is controlled by inactivation through its cleavage by factor I (fI), factor H (fH), factor H-like protein 1 (FHL-1) and C4-binding protein (C4BP). Inactivation on the cell surface is achieved by decay-accelerating factor (DAF), membrane cofactor protein (MCP) or complement receptor 1 [15,16•]. Non-RCA proteins claim at the very start of the cascade in case of classical pathway and lectin pathway with C1-inhibitor (C1-inh) by inactivating C1r, C1s and MASP1/2. The MAC formation itself is inhibited by CD59 binding and thus, inhibiting C5b-8 complexation on and C9 polymerization into the membrane [13]. Carboxypeptidase N inactivates the cleavage-derived anaphylatoxins C3a and C5a during the cascade [17,18] and, thus, prevents inflammatory signals to chemoattractive cells such as granulocytes or antigen-presenting cells (APCs). Furthermore, in addition to the protein level, the regulation is also tissue-specific and controlled at the level of transcription [19,20].

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Complement activation by HIV

A direct activation of the complement system is shown for several viruses. HIV triggers the classical pathway, in the absence of HIV-specific antibody by binding of the viral envelope protein gp41 to C1q [21,22]. In addition, MBL, the triggering molecule of the lectin pathway, interacts with HIV [23]. MBL binds to the virus via high mannose carbohydrates on gp120 and the interaction of MBL with HIV depends on sialylation [23]. Nevertheless, these complement interactions in the absence of antibodies do not exceed the activation threshold necessary to induce CML. Thus, HIV remains opsonized with C3-fragments in HIV-infected individuals (Fig. 1a) [24,25]. Nevertheless, the masking of viral epitopes by deposition of C3-fragments on the viral envelope reduces the infectivity of complement-receptor-negative T cells in vitro[26,27] and in monkey experiments [28]. This neutralization mechanism has been described for other viruses too [29] and may contribute, at least in part, to lower viral loads during the acute HIV infection. After seroconversion, HIV-specific antibodies further enhance complement activation [30]. Several antibodies that induce CML of HIV have been described [31–33]. In vivo, such CML-inducing antibodies are supposed to contribute to the control of the viral spread during the acute phase of infection in humans and SIVΔ-nef immunized macaques [34,35]. Mainly nonneutralizing antibodies seem to dominate this process [34,36]. The responses are thought to be found in the chronic phase of infection, too [34,36–39]. Thus, CML is suggested to contribute to the control of viral loads in HIV-1-infected individuals (Fig. 1b). However, substantial amounts of the virus seem to be resistant against the lytic attacks by the complement system [40,41]. Responsible for this intrinsic resistance of HIV against human complement are membrane proteins derived from the human cells, which are acquired by the virus during the budding process [42]. Among them are RCAs such as CD46 (MCP), CD55 (DAF) or CD59, which downregulate complement activation at several stages of the cascade [43–46]. The efficient incorporation of RCAs into the viral envelope gives rise to the pseudotyped lentiviral vectors with DAF (CD55) to stabilize these vectors in human serum [47,48]. In addition, HIV can bind fH, an RCA in fluid phase, which further promotes the protection of the virus against lysis by the complement system [49–54]. Thus, a substantial amount of intact viral particles remains opsonized in the serum, lymphoid tissue, brain or seminal fluid of infected individuals and may interact with complement receptors expressed on immune cells as discussed below.

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Contribution of complement receptor 1 in HIV pathogenesis

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Enhanced infection in cis has been shown in vitro after cross-linking complement receptor 1 expressed on T-cell subsets and is discussed in several reviews [55–57]. Whether erythrocytes can bind and transfer HIV to T cells (infection in trans) is still a matter of debate [58–62]. A recent publication indicates a role of erythrocytes in mediating the transfer of HIV to T cells by complement-independent mechanisms in vitro[58]. Inasmuch this mode of infection reflects the in-vivo situation remains unclear as HIV is thought to be opsonized in vivo (Fig. 1c) [24,25].

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Contribution of complement receptor 2 in HIV pathogenesis

Complement receptor 2 is involved in several stages of the pathogenesis of HIV. The main aspects are discussed below.

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Trapping of HIV in germinal centers of lymphoid tissues

Follicular dendritic cells (FDCs) retain immune-complexed antigens in their native conformation on their surface for months, thereby playing a crucial role in the maintenance of an appropriate B-cell response by triggering affinity maturation of antibodies and memory B-cell development [63]. Early studies on HIV infection have already demonstrated an association of HIV with the FDC network in the germinal centers of lymphoid tissues [64]. Majority of the studies, except for a few [65,66], did not provide any evidence for an infection of FDCs suggesting a virus pool associated extracellularly to the surface of FDCs [67,68]. HIV bound extracellularly to FDCs represents by far the largest virus reservoir in HIV infection [69]. More importantly, FDC-associated HIV has been demonstrated to trap in an infectious form [25,70,71]. FDC retained virions preserved infectivity for months [72] and were highly infectious for CD4+ T cells even in the presence of neutralizing antibody [72]. HIV infection leads to a degeneration of FDC network evident already in the presymptomatic stage followed by complete destruction of lymphoid tissue architecture. The damage of FDC network is accompanied by a loss of specific immune responses against HIV and other pathogens, thereby contributing to the acquired immune deficiency and opportunistic infections characteristic of the advanced disease. The underlying mechanism for the loss of FDC network is not completely understood. However, these pathological events are not irreversible; treatment of patient even in advanced stage of HIV disease resulted in a slow regeneration of FDC network and functions [73,74].

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Role of complement receptor 2 in the establishment of extracellular reservoir of HIV in lymphoid tissues

The involvement of FDC network in HIV pathogenesis turned attention to mechanisms responsible for the deposition of HIV in lymphoid tissues. FDCs retain native antigens on their surface in form of immune complexes through complement receptors and FcγRs, thereby pointing to a role of complement and antibody in HIV trapping. Due to the intrinsic resistance of HIV to CML, C3-fragments and, after seroconversion, HIV-specific antibodies are deposited and accumulate on the viral surface [24]. As human FDCs express complement receptor 1, complement receptor 2 and complement receptor 3, it was not surprising that HIV opsonized in vitro with normal human serum as source of complement could interact with isolated tonsillar FDCs [75,76]. Studies on the relative contributions of complement receptors to HIV trapping identified complement receptor 2 as the main binding site for HIV in the germinal centers in vivo, as a monoclonal antibody blocking complement receptor 2–C3d interactions was able to detach about 80% of extracellularly trapped HIV from lymphoid tissues of HIV-infected individuals (Fig. 1d) [77]. In contrast, no evidence for the involvement of either complement receptor 1 or complement receptor 3 was detected [77]. Subsequent investigations have demonstrated that HIV trapped in lymphoid tissues through complement receptor 2–C3d interactions preserves infectivity [25]. Mathematical analysis of multivalent interactions between C3d-opsonized HIV and complement receptor 2 on FDCs revealed a long-term attachment of virus on FDCs [78,79].

Due to their complement receptor 2 expression, B-lymphocytes have also been implicated to be involved in HIV trapping in lymphoid tissues. Indeed, B cells were demonstrated to bind C-opsonized HIV immune complexes in complement receptor 2-dependent manner [80–82]. More importantly, B cells isolated from lymph nodes or peripheral blood of HIV-infected individuals carried HIV immune-complexes on their surface through complement receptor 2–complement interactions [83]. B cells bearing C-opsonized HIV on their surface efficiently transmitted the virus to stimulated and unstimulated T cells [24,80–83]. Thus, circulating B cells potentially propagate HIV infection by transporting the virus in the lymphoid tissues, promoting infection of permissive cells and participating in extracellular HIV trapping.

Trapping of HIV in lymphoid tissues through complement receptor 2–C3d interactions requires a processing of C3 fragments on the viral surface. Factor I-mediated processing of C3-fragments on HIV has been shown to target the virus to complement receptor 2-expressing cells [84]. Therefore, factor I in concert with complement receptor 1 expressed on erythrocytes, FDCs and B cells together with factor H in the serum due to their co-factor activity might be important contributors for the generation of infectious HIV reservoirs in lymphoid tissues [85].

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Emerging contribution of complement receptor 3 and complement receptor 4 in HIV infection

In addition to their role in the enhancement of HIV replication, the complement receptor 3 and complement receptor 4 seem to be involved in antigen presentation and the induction of virus-specific CTL responses.

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C-mediated clearance of HIV by complement receptor 3 and complement receptor 4 expressing cells

Opsonization with antibody and complement tags HIV for uptake and destruction by phagocytes, such as dendritic cells, monocytes/macrophages or polymorphonuclear granulocytes [86]. Phagocytic cells internalize immune-complexed viruses via their Fc and complement receptors, which upon engagement trigger uptake and subsequent degradation. In complement receptor-mediated phagocytosis, cell-bound C3-fragments act as opsonins and favor binding to the phagocyte via complement receptors (Fig. 1) [87]. Although not directly linked to complement, Fc–FcγR interactions may reduce the infection of dendritic cells and monocytes/macrophages, as nonneutralizing antibodies were shown to inhibit the infection of these cells in vitro[88–91]. Inasmuch the engagement of complement receptor 3/complement receptor 4 and/or FcγRs contributes to the reduction in viral loads of HIV-infected individuals is not completely elucidated yet. Defects in both, complement and Fc receptor-dependent phagocytosis of macrophages and neutrophils are reported during disease progression [92–96].

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C-mediated enhancement of HIV infection in cis

The presence of iC3b-fragments on the surface of HIV suggests a more pronounced interaction with complement receptor 3 and complement receptor 4 expressing cells like dendritic cells and monocytes/macrophages. The exploitation of these complement receptors on permissive cells might influence infection in cis. Indeed, several studies reported an enhanced HIV infection of complement receptor 3 and complement receptor 4 expressing cells. Increased replication of HIV has been demonstrated in latently infected monocytic cells following stimulation of complement receptor 3 most probably due to the induction of viral transcription by nuclear factor-κB (NF-κB) translocation [97].

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Involvement of complement receptor 3 and complement receptor 4 in HIV infection in trans

Dendritic cells expressing complement receptor 3 and complement receptor 4 transmit HIV to freshly isolated monocytes, monocyte-derived macrophages and also to CD4+ T cells [98,99]. A main mechanism involved in the transmission of nonopsonized HIV to T cells is the interaction of the virus with C-type lectines like DC-SIGN expressed on dendritic cells [100]. In contrast, C-opsonized HIV interacts with dendritic cells in a C-type lectin-independent manner [101]. The transfer of C-opsonized virus from dendritic cells to T cells involves mainly complement receptor 3 and complement receptor 4 [101].

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Role of complement in the induction of HIV-specific CD8+ T-cell response

Increasing evidence reveals the involvement of complement in the induction of specific T-cell responses in viral infections (Fig. 1f). For example, upon infection of mice deficient for C3 (C3−/−) with influenza virus, the priming of CD4 helper cells and virus-specific CTLs was found to be strongly impaired, resulting in delayed clearance of the infection and increased viral titers [102]. Similarly, the induction and expansion of CD8+ T cells during infection with lymphocytic choriomeningitis virus depends on C3 [103]. A further study indicates that complement activation of both classical and alternative pathways is required for the induction of efficient T-cell responses in West Nile virus infection [104]. As virus-specific T-cell responses are thought to be primed by professional APCs like dendritic cells, modulating effects of C3 on T-cell induction might most likely be mediated through complement receptor 3 and complement receptor 4 expressed on dendritic cells. Studies investigating the binding and intracellular trafficking of differentially opsonized HIV in human dendritic cells revealed that the opsonization pattern on the viral surface influences the mode of internalization and the antigen-presenting capacity of dendritic cells [91]. Subsequent studies provided evidence for an enhancing effect of C3-opsonization of retroviral particles increasing the ability of dendritic cells to induce HIV-specific CD8+ T cells in vitro[105•]. Using Friend virus, a mouse model for retroviral infections, the role of C3 in the induction of specific T-cell responses by dendritic cells was further confirmed in vivo as in C3−/− mice, significantly lower frequencies of FV-specific CD8+ T cells are detected, which correlated with the higher percentage of infected cells [105•]. These results indicate that complement serves as natural adjuvant for dendritic cell-induced expansion and differentiation of specific CTLs against retroviruses.

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Contribution of anaphylatoxins in HIV infection

The role of the anaphylatoxins C3a and C5a in retroviral pathogenesis is not completely defined. In general, APCs express C3aR and C5aR, which are downregulated in HIV-infected individuals. This may impair migrations of APCs and, thus, contribute to the decreased inflammatory responses [95]. In addition, infections of monocyte-derived macrophages or dendritic cells are significantly enhanced in the presence of anaphylatoxins [106,107] (Fig. 1).

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Although the complement system contributes to the control of viral replication during all stages of infection and is involved in both, innate and adaptive immune responses, retroviruses have exploited several mechanisms to counteract these immune responses. In the long term, this delicate balance is in favor of the virus mounting a chronic infection in the host.

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The authors are supported by the 6th framework of the EU (DEC-VAC 2005-018685 to H.S.), grants of the Austrian Research Fund FWF (215080 to Z.B.) and FFG (Bridge Project 815463 to H.S.) and the Federal Government of Tyrol (Tiroler Wissenschaftsfonds TWF-2008-1-562 to H.S.). The secretarial support of B. Müllauer and T. Hitzler is gratefully acknowledged.

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Conflicts of interest

There are no conflicts of interest.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* • of special interest

* •• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 448).

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This study shows the involvement of complement in the induction of virus-specific CTLs by dendritic cells.

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complement; cytotoxic T lymphocyte response; resistance to complement-mediated lysis; retrovirus

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