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.
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 .
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 , 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 . 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 . 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) . By this C3-amplification loop, more and more C3b is recruited and covalently attached to the microbial surface . 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 . 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 , 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 . 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].
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 . MBL binds to the virus via high mannose carbohydrates on gp120 and the interaction of MBL with HIV depends on sialylation . 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 . This neutralization mechanism has been described for other viruses too  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 . 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 . 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.
Contribution of complement receptor 1 in HIV pathogenesis
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. 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].
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.
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 . Early studies on HIV infection have already demonstrated an association of HIV with the FDC network in the germinal centers of lymphoid tissues . 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 . More importantly, FDC-associated HIV has been demonstrated to trap in an infectious form [25,70,71]. FDC retained virions preserved infectivity for months  and were highly infectious for CD4+ T cells even in the presence of neutralizing antibody . 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].
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 . 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) . In contrast, no evidence for the involvement of either complement receptor 1 or complement receptor 3 was detected . Subsequent investigations have demonstrated that HIV trapped in lymphoid tissues through complement receptor 2–C3d interactions preserves infectivity . 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 . 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 . 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 .
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.
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 . 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) . 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].
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 .
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 . In contrast, C-opsonized HIV interacts with dendritic cells in a C-type lectin-independent manner . The transfer of C-opsonized virus from dendritic cells to T cells involves mainly complement receptor 3 and complement receptor 4 .
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 . Similarly, the induction and expansion of CD8+ T cells during infection with lymphocytic choriomeningitis virus depends on C3 . 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 . 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 . 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.
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 . In addition, infections of monocyte-derived macrophages or dendritic cells are significantly enhanced in the presence of anaphylatoxins [106,107] (Fig. 1).
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.
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.
Conflicts of interest
There are no conflicts of interest.
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).
1. Speth C, Prodinger W, Würzner R, et al.
Complement. In: Paul WE, editor. Fundamental immunology. 6th ed. Lippincott Williams & Wilkins; 2008. pp. 1047–1078.
2. Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344:1058–1066.
3••. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11:785–797.
This elegant review gives an updated view of the function, structure and dynamics of the complement network.
4. Phillips AE, Toth J, Dodds AW, et al. Analogous interactions in initiating complexes of the classical and lectin pathways of complement. J Immunol 2009; 182:7708–7717.
5. Nauta AJ, Bottazzi B, Mantovani A, et al. Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol 2003; 33:465–473.
6. Roumenina LT, Ruseva MM, Zlatarova A, et al. Interaction of C1q with IgG1, C-reactive protein and pentraxin 3: mutational studies using recombinant globular head modules of human C1q A, B, and C chains. Biochemistry 2006; 45:4093–4104.
7. Litvack ML, Palaniyar N. Review: soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components – implications on exacerbating or resolving inflammation. Innate Immun; 2010, 16:191–200.
8. Janeway CJ, Travers P, Walport M, Schlomchik M, editors. Immunobiology: the immune system in health and disease. 6th ed. New York: Garland Publishing; 2005.
9•. Eisen DP. Mannose-binding lectin deficiency and respiratory tract infection. J Innate Immun 2009; 2:114–122.
This review describes the clinical associations between MBL deficiency and susceptibility to respiratory tract infection.
10. Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis 2003; 37:1496–1505.
11. Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol 2009; 104:115–149.
12. Spitzer D, Mitchell LM, Atkinson JP, Hourcade DE. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. J Immunol 2007; 179:2600–2608.
13. Kondos SC, Hatfaludi T, Voskoboinik I, et al.
The structure and function of mammalian membrane-attack complex/perforin-like proteins. Tissue Antigens 2010; 76:341–351.
14. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298–300.
15. Kim DD, Song WC. Membrane complement regulatory proteins. Clin Immunol 2006; 118 (2–3):127–136.
16•. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol 2009; 9:729–740.
This article provides insights into the mechanisms of complement regulation.
17. Manthey HD, Woodruff TM, Taylor SM, Monk PN. Complement component 5a (C5a). Int J Biochem Cell Biol 2009; 41:2114–2117.
18. Matthews KW, Mueller-Ortiz SL, Wetsel RA. Carboxypeptidase N: a pleiotropic regulator of inflammation. Mol Immunol 2004; 40:785–793.
19. Fraczek LA, Martin BK. Transcriptional control of genes for soluble complement cascade regulatory proteins. Mol Immunol 2010; 48:9–13.
20. Thurman JM, Renner B. Dynamic control of the complement system by modulated expression of regulatory proteins. Lab Invest 2010; 91:4–11.
21. Ebenbichler CF, Thielens NM, Vornhagen R, et al. Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp41. J Exp Med 1991; 174:1417–1424.
22. Spear GT, Jiang HX, Sullivan BL, et al. Direct binding of complement component C1q to human immunodeficiency virus (HIV) and human T lymphotrophic virus-I (HTLV-I) coinfected cells. AIDS Res Hum Retroviruses 1991; 7:579–585.
23. Ji X, Gewurz H, Spear GT. Mannose binding lectin (MBL) and HIV. Mol Immunol 2005; 42:145–152.
24. Dopper S, Wilflingseder D, Prodinger WM, et al. Mechanism(s) promoting HIV-1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co-cultures. Eur J Immunol 2003; 33:2098–2107.
25. Banki Z, Kacani L, Rusert P, et al. Complement dependent trapping of infectious HIV in human lymphoid tissues. Aids 2005; 19:481–486.
26. Scherl M, Posch U, Obermoser G, et al. Targeting human immunodeficiency virus type 1 with antibodies derived from patients with connective tissue disease. Lupus 2006; 15:865–872.
27. Sullivan BL, Takefman DM, Spear GT. Complement can neutralize HIV-1 plasma virus by a C5-independent mechanism. Virology 1998; 248:173–181.
28. Falkensammer B, Rubner B, Hiltgartner A, et al. Role of complement and antibodies in controlling infection with pathogenic simian immunodeficiency virus (SIV) in macaques vaccinated with replication-deficient viral vectors. Retrovirology 2009; 6:60.
29. Nemerow GR, Cooper NR. Isolation of Epstein Barr-virus and studies of its neutralization by human IgG and complement. J Immunol 1981; 127:272–278.
30. Prohaszka Z, Hidvegi T, Ujhelyi E, et al. Interaction of complement and specific antibodies with the external glycoprotein 120 of HIV-1. Immunology 1995; 85:184–189.
31. Gregersen JP, Mehdi S, Baur A, Hilfenhaus J. Antibody- and complement-mediated lysis of HIV-infected cells and inhibition of viral replication. J Med Virol 1990; 30:287–293.
32. Spear GT, Takefman DM, Sullivan BL, et al. Complement activation by human monoclonal antibodies to human immunodeficiency virus. J Virol 1993; 67:53–59.
33. Hildgartner A, Wilflingseder D, Gassner C, et al. Induction of complement-mediated lysis of HIV-1 by a combination of HIV-specific and HLA allotype-specific antibodies. Immunol Lett 2009; 126 (1–2):85–90.
34. Huber M, Fischer M, Misselwitz B, et al. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLoS Med 2006; 3:e441.
35. Freissmuth D, Hiltgartner A, Stahl-Hennig C, et al.
Analysis of humoral immune responses in rhesus macaques vaccinated with attenuated SIVmac239Deltanef and challenged with pathogenic SIVmac251. J Med Primatol 2010; 39:97–111.
36. Aasa-Chapman MM, Holuigue S, Aubin K, et al. Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection. J Virol 2005; 79:2823–2830.
37. Spear GT, Olinger GG, Saifuddin M, Gebel HM. Human antibodies to major histocompatibility complex alloantigens mediate lysis and neutralization of HIV-1 primary isolate virions in the presence of complement. J Acquir Immune Defic Syndr 2001; 26:103–110.
38. Spear GT, Sullivan BL, Landay AL, Lint TF. Neutralization of human immunodeficiency virus type 1 by complement occurs by viral lysis. J Virol 1990; 64:5869–5873.
39. Sullivan BL, Knopoff EJ, Saifuddin M, et al. Susceptibility of HIV-1 plasma virus to complement-mediated lysis. Evidence for a role in clearance of virus in vivo. J Immunol 1996; 157:1791–1798.
40. Banki Z, Soederholm A, Mullauer B, et al. Tracing complement-retroviral interactions from mucosal surfaces to the lymphatic tissue. Front Biosci 2007; 12:2096–2106.
41. Stoiber H, Clivio A, Dierich MP. Role of complement in HIV infection. Annu Rev Immunol 1997; 15:649–674.
42. Frank I, Stoiber H, Godar S, et al. Acquisition of host cell-surface-derived molecules by HIV-1. Aids 1996; 10:1611–1620.
43. Marschang P, Sodroski J, Wurzner R, Dierich MP. Decay-accelerating factor (CD55) protects human immunodeficiency virus type 1 from inactivation by human complement. Eur J Immunol 1995; 25:285–290.
44. Montefiori DC, Cornell RJ, Zhou JY, et al. Complement control proteins, CD46, CD55, and CD59, as common surface constituents of human and simian immunodeficiency viruses and possible targets for vaccine protection. Virology 1994; 205:82–92.
45. Saifuddin M, Hedayati T, Atkinson JP, et al. Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction. J Gen Virol 1997; 78 (Pt 8):1907–1911.
46. Schmitz J, Zimmer JP, Kluxen B, et al. Antibody-dependent complement-mediated cytotoxicity in sera from patients with HIV-1 infection is controlled by CD55 and CD59. J Clin Invest 1995; 96:1520–1526.
47. Guibinga GH, Friedmann T. Preparation of pseudotyped lentiviral vectors resistant to inactivation by serum complement. Cold Spring Harb Protoc 2010.; pdb.prot5420. doi: 10.1101/pdb.prot5420.
48. Cronin J, Zhang XY, Reiser J. Altering the tropism of lentiviral vectors through pseudotyping. Curr Gene Ther 2005; 5:387–398.
49. Pinter C, Siccardi AG, Longhi R, Clivio A. Direct interaction of complement factor H with the C1 domain of HIV type 1 glycoprotein 120. AIDS Res Hum Retroviruses 1995; 11:577–588.
50. Pinter C, Siccardi AG, Lopalco L, et al. HIV glycoprotein 41 and complement factor H interact with each other and share functional as well as antigenic homology. AIDS Res Hum Retroviruses 1995; 11:971–980.
51. Stoiber H, Ebenbichler C, Schneider R, et al. Interaction of several complement proteins with gp120 and gp41, the two envelope glycoproteins of HIV-1. Aids 1995; 9:19–26.
52. Stoiber H, Pinter C, Siccardi AG, et al. Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55). J Exp Med 1996; 183:307–310.
53. Stoiber H, Schneider R, Janatova J, Dierich MP. Human complement proteins C3b, C4b, factor H and properdin react with specific sites in gp120 and gp41, the envelope proteins of HIV-1. Immunobiology 1995; 193:98–113.
54. Stoiber H, Ammann C, Spruth M, et al. Enhancement of complement-mediated lysis by a peptide derived from SCR 13 of complement factor H. Immunobiology 2001; 203:670–686.
55. Dierich MP, Stoiber H, Clivio AA. A ‘complement-ary’ AIDS vaccine. Nat Med 1996; 2:153–155.
56. Willey S, Aasa-Chapman MM. Humoral immunity to HIV-1: neutralisation and antibody effector functions. Trends Microbiol 2008; 16:596–604.
57. Huber M, Olson WC, Trkola A. Antibodies for HIV treatment and prevention: window of opportunity? Curr Top Microbiol Immunol 2008; 317:39–66.
58. Beck Z, Brown BK, Wieczorek L, et al. Human erythrocytes selectively bind and enrich infectious HIV-1 virions. PLoS One 2009; 4:e8297.
59. Fierer DS, Vargas J Jr, Patel N, Clover G. Absence of erythrocyte-associated HIV-1 in vivo. J Infect Dis 2007; 196:587–590.
60. He W, Neil S, Kulkarni H, et al. Duffy antigen receptor for chemokines mediates trans-infection of HIV-1 from red blood cells to target cells and affects HIV-AIDS susceptibility. Cell Host Microbe 2008; 4:52–62.
61. Hess C, Klimkait T, Schlapbach L, et al. Association of a pool of HIV-1 with erythrocytes in vivo: a cohort study. Lancet 2002; 359:2230–2234.
62. Horakova E, Gasser O, Sadallah S, et al. Complement mediates the binding of HIV to erythrocytes. J Immunol 2004; 173:4236–4241.
63. Allen CD, Cyster JG. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin Immunol 2008; 20:14–25.
64. Tenner-Racz K, Racz P, Bofill M, et al. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am J Pathol 1986; 123:9–15.
65. Parmentier HK, van Wichen D, Sie-Go DM, et al. HIV-1 infection and virus production in follicular dendritic cells in lymph nodes. A case report, with analysis of isolated follicular dendritic cells. Am J Pathol 1990; 137:247–251.
66. Spiegel H, Herbst H, Niedobitek G, et al. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol 1992; 140:15–22.
67. Schmitz J, van Lunzen J, Tenner-Racz K, et al. Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia. J Immunol 1994; 153:1352–1359.
68. Tsunoda R, Hashimoto K, Baba M, et al. Follicular dendritic cells in vitro are not susceptible to infection by HIV-1. Aids 1996; 10:595–602.
69. Haase AT, Henry K, Zupancic M, et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 1996; 274:985–989.
70. Heath SL, Tew JG, Tew JG, et al. Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 1995; 377:740–744.
71. Keele BF, Tazi L, Gartner S, et al. Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. J Virol 2008; 82:5548–5561.
72. Smith BA, Gartner S, Liu Y, et al. Persistence of infectious HIV on follicular dendritic cells. J Immunol 2001; 166:690–696.
73. Alos L, Navarrete P, Morente V, et al. Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence. Mod Pathol 2005; 18:127–136.
74. Zhang ZQ, Schuler T, Cavert W, et al. Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection. Proc Natl Acad Sci U S A 1999; 96:5169–5172.
75. Joling P, Bakker LJ, Van Strijp JA, et al. Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. J Immunol 1993; 150:1065–1073.
76. Reynes M, Aubert JP, Cohen JH, et al. Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens. J Immunol 1985; 135:2687–2694.
77. Kacani L, Prodinger WM, Sprinzl GM, et al. Detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2. J Virol 2000; 74:7997–8002.
78. Hlavacek WS, Percus JK, Percus OE, et al. Retention of antigen on follicular dendritic cells and B lymphocytes through complement-mediated multivalent ligand-receptor interactions: theory and application to HIV treatment. Math Biosci 2002; 176:185–202.
79. Hlavacek WS, Wofsy C, Perelson AS. Dissociation of HIV-1 from follicular dendritic cells during HAART: mathematical analysis. Proc Natl Acad Sci U S A 1999; 96:14681–14686.
80. Doepper S, Stoiber H, Kacani L, et al. B cell-mediated infection of stimulated and unstimulated autologous T lymphocytes with HIV-1: role of complement. Immunobiology 2000; 202:293–305.
81. Jakubik JJ, Saifuddin M, Takefman DM, Spear GT. B lymphocytes in lymph nodes and peripheral blood are important for binding immune complexes containing HIV-1. Immunology 1999; 96:612–619.
82. Jakubik JJ, Saifuddin M, Takefman DM, Spear GT. Immune complexes containing human immunodeficiency virus type 1 primary isolates bind to lymphoid tissue B lymphocytes and are infectious for T lymphocytes. J Virol 2000; 74:552–555.
83. Moir S, Malaspina A, Li Y, et al. B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med 2000; 192:637–646.
84. Banki Z, Wilflingseder D, Ammann CG, et al. Factor I-mediated processing of complement fragments on HIV immune complexes targets HIV to CR2-expressing B cells and facilitates B cell-mediated transmission of opsonized HIV to T cells. J Immunol 2006; 177:3469–3476.
85. Rask R, Rasmussen JM, Jepsen HH, Svehag SE. Enhanced binding of immune complexes processed by erythrocyte CR1 (CD 35) receptors to purified CR2 (CD 21) receptors from tonsillar mononuclear cells. APMIS 1989; 97:374–380.
86. Rabinovitch M. Professional and nonprofessional phagocytes: an introduction. Trends Cell Biol 1995; 5:85–87.
87. Brown EJ. Complement receptors and phagocytosis. Curr Opin Immunol 1991; 3:76–82.
88. Chan AW, Langan MC, Leong FW, et al. Partial cross-dependence on ethanol in mice dependent on chlordiazepoxide. Pharmacol Biochem Behav 1990; 35:379–384.
89. Forthal DN, Moog C. Fc receptor-mediated antiviral antibodies. Curr Opin HIV AIDS 2009; 4:388–393.
90. Holl V, Xu K, Peressin M, et al.
Stimulation of HIV-1 replication in immature dendritic cells in contact with primary CD4 T or B lymphocytes. J Virol 2010; 84:4172–4182.
91. Wilflingseder D, Banki Z, Garcia E, et al. IgG opsonization of HIV impedes provirus formation in and infection of dendritic cells and subsequent long-term transfer to T cells. J Immunol 2007; 178:7840–7848.
92. Azzam R, Kedzierska K, Leeansyah E, et al. Impaired complement-mediated phagocytosis by HIV type-1-infected human monocyte-derived macrophages involves a cAMP-dependent mechanism. AIDS Res Hum Retroviruses 2006; 22:619–629.
93. Bender BS, Davidson BL, Kline R, et al. Role of the mononuclear phagocyte system in the immunopathogenesis of human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Rev Infect Dis 1988; 10:1142–1154.
94. Kedzierska K, Azzam R, Ellery P, et al. Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol 2003; 26:247–263.
95. Monari C, Casadevall A, Pietrella D, et al. Neutrophils from patients with advanced human immunodeficiency virus infection have impaired complement receptor function and preserved Fcgamma receptor function. J Infect Dis 1999; 180:1542–1549.
96. Thomas CA, Weinberger OK, Ziegler BL, et al. Human immunodeficiency virus-1 env impairs Fc receptor-mediated phagocytosis via a cyclic adenosine monophosphate-dependent mechanism. Blood 1997; 90:3760–3765.
97. Thieblemont N, Haeffner-Cavaillon N, Haeffner A, et al. Triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) induces nuclear translocation of NF-kappa B (p50/p65) in human monocytes and enhances viral replication in HIV-infected monocytic cells. J Immunol 1995; 155:4861–4867.
98. Arrighi JF, Pion M, Garcia E, et al. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med 2004; 200:1279–1288.
99. Kacani L, Frank I, Spruth M, et al. Dendritic cells transmit human immunodeficiency virus type 1 to monocytes and monocyte-derived macrophages. J Virol 1998; 72:6671–6677.
100. Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000; 100:587–597.
101. Pruenster M, Wilflingseder D, Banki Z, et al. C-type lectin-independent interaction of complement opsonized HIV with monocyte-derived dendritic cells. Eur J Immunol 2005; 35:2691–2698.
102. Kopf M, Abel B, Gallimore A, et al. Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat Med 2002; 8:373–378.
103. Suresh M, Molina H, Salvato MS, et al. Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection. J Immunol 2003; 170:788–794.
104. Mehlhop E, Diamond MS. Protective immune responses against West Nile virus are primed by distinct complement activation pathways. J Exp Med 2006; 203:1371–1381.
105•. Banki Z, Posch W, Ejaz A, et al.
Complement as an endogenous adjuvant for dendritic cell-mediated induction of retrovirus-specific CTLs. PLoS Pathog 2010; 6:e1000891.
This study shows the involvement of complement in the induction of virus-specific CTLs by dendritic cells.
106. Kacani L, Banki Z, Zwirner J, et al. C5a and C5a(desArg) enhance the susceptibility of monocyte-derived macrophages to HIV infection. J Immunol 2001; 166:3410–3415.
107. Soederholm A, Banki Z, Wilflingseder D, et al. HIV-1 induced generation of C5a attracts immature dendritic cells and promotes infection of autologous T cells. Eur J Immunol 2007; 37:2156–2163.