The good and evil of complement activation in HIV-1 infection

Abstract

The complement system, a key component of innate immunity, is a first-line defender against foreign pathogens such as HIV-1. The role of the complement system in HIV-1 pathogenesis appears to be multifaceted. Although the complement system plays critical roles in clearing and neutralizing HIV-1 virions, it also represents a critical factor for the spread and maintenance of the virus in the infected host. In addition, complement regulators such as human CD59 present in the envelope of HIV-1 prevent complement-mediated lysis of HIV-1. Some novel approaches are proposed to combat HIV-1 infection through the enhancement of antibody-dependent complement activity against HIV-1. In this paper, we will review these diverse roles of complement in HIV-1 infection.

Introduction

The complement system, a key component of innate immunity, is a first-line defender against foreign pathogens such as HIV-1. On the other hand, complement activation also enhances HIV-1 infectivity. The role of the complement system in HIV-1 pathogenesis has been debated for many years. For over a decade, it has been proposed that the enhancement of antibody (Ab)-dependent complement-mediated effects on HIV-1 and HIV-1-infected cells may be a novel approach for the treatment and prevention of HIV-1 infection. However, the role of the complement system in HIV-1 infection has been underestimated and has not drawn extensive attention. In this paper, we will review current views of the role of the complement system in HIV-1 infection.

Complement activation and regulation

The complement system, a main effector of innate and acquired immunity, has the capacity to lyse and thereby inactivate pathogenic microorganisms, including enveloped viruses in circulation in infected hosts. The complement system consists of about 30 soluble and membrane-bound proteins and is activated by three distinct pathways either on the pathogen surface or in the plasma.^{1, 2, 3} The classical pathway is triggered by antigen-bound Ab molecules and is initiated by the binding of the Ab's Fc part to the C1 component.⁴ The alternative pathway is a humoral component of the immune system's natural defense against infections and is activated by cleavage of C3 and then C5. The mannose-binding lectin (MBL) pathway is initiated when the plasma MBL protein forms a complex with MBL-associated protease-1 and -2, which then bind to arrays of mannose groups on the surfaces of bacterial cells.⁵ In all three pathways, a C3-convertase cleaves and activates component C3, creating C3a and C3b and causing a cascade of further cleavage and activation events, eventually resulting in formation of the membrane attack complex (MAC), the end product of all three complement activation pathways. The MAC forms a lytic pore in the infected cell's lipid bilayer membrane that allows free passage of solutes and water across the membrane, destroying the membrane's integrity and resulting in the death of foreign pathogens, including viruses, and infected cells.⁶

In order to prevent this devastating complement attack on the autologous cells, a number of plasma and membrane complement regulators have evolved to restrict complement activation at different stages of the three complement activation cascades.^{1, 2} Soluble plasma complement regulators include: (i) C1 inhibitor that regulates C1; (ii) factors H and I that regulate the alternative pathway; (iii) C4-binding protein that catalyzes the cleavage of C4b by factor I; and (iv) S-protein, clusterin and serum lipids that compete with membrane lipids for reaction with nascent C5b67.⁴ Moreover, three membrane proteins that are expressed on the surface of almost all cell types have been shown to inhibit autologous complement activation, thereby protecting self cells from complement-mediated injury.⁴ These regulators include decay-accelerating factor (CD55), membrane cofactor protein (CD46) and membrane inhibitor of reactive lysis (CD59). CD55 inactivates the C3 and C5 convertases by accelerating the decay of these enzymes.^{7, 8, 9} CD46 acts as a cofactor for the cleavage of cell-bound C4b and C3b by the serum protease factor.¹⁰ CD59 restricts MAC formation by preventing C9 incorporation and polymerization, blocking all three pathways of complement activation.¹¹

There is a delicate balance between complement activation and complement regulation. The ability of the complement system to damage ‘self' cells is the result of this delicate balance in autologous cells.¹² This balance can be broken either by increased complement activation, as in diseases in which antibodies activate the classical pathway, or by decreased restriction, as in paroxysmal nocturnal hemoglobinuria in which the absence of glycosyl-phosphatidylinositol-linked proteins, including CD59 in bone marrow precursors, causes complement-mediated hemolytic anemia and thrombosis.¹² In immune diseases associated with vasculitis and accelerated atherosclerosis, such as lupus erythematosus, or in organ transplantation, abnormal complement activation may result from Ab-mediated activation of the classical pathway rather than from decreased protection. Specifically, in the case of HIV-1 infection, the role of complement in HIV-1 pathogenesis appears to be multifaceted.^{13, 14} There exists substantial in vitro and ex vivo evidence indicating that HIV-1 virions not only take advantage of complement activation to enhance HIV-1 infectivity, but also hijack complement regulators to escape human complement-dependent attack, which we review below.

Protective role of complement activation and ab immunity in HIV-1 infection

Complement activation in HIV-1 infection

Extensive evidence demonstrates that activation of the classical pathway by monoclonal and serum-derived HIV-1-specific antibodies occurs upon binding to HIV-1 particles.^{14, 15, 16} Using a novel real-time PCR-based assay strategy that allows reliable and sensitive quantification of viral lysis by complement, Huber et al. documented that complement (sera from HIV-1-infected patients)-mediated lysis activity against the HIV-1 primary virus was higher during chronic disease stages than during the acute phase.¹⁷ They also found that plasma viral load levels during the acute but not the chronic infection phase correlated inversely with the autologous complement lysis activity.¹⁷ These effects were attributed to anti-envelope (Env) Ab-mediated complement-dependent lysis. Together, these results indicate that Ab-mediated complement virion lysis develops rapidly and is effective early in the course of infection.¹⁷ Moreover, the HIV-1 surface proteins gp41 and gp120 further enhance Ab-mediated complement activation by binding C1q or MBL, respectively.^{18, 19, 20, 21, 22, 23, 24, 25} Using serum from an uninfected C1q- or C3-deficient individual as a source of complement does not mediate any anti-HIV-1 activity, which indicates that the classical pathways contribute mainly to the complement activation against HIV-1.²⁶ Several reports demonstrate that complement-dependent virus lysis occurs in vivo^{27, 28} and that the complement can enhance the effect of neutralizing Ab both in vivo and in vitro.^{29, 30} The complement activation is further evidenced by the finding that C3 accumulates on the surface of HIV-1 virions from infected individuals.¹⁴ Also, HIV-1-infected patients develop anti-HIV-1 cytotoxic antibodies specific for HIV-1-infected cells,^{31, 32, 33} and abrogation of the complement regulator function sensitizes the infected cells to complement-dependent attack.^{31, 32} Taken together, these results indicate that complement-mediated virolysis induced by specific antibodies or Env proteins may be an important player in the host immune response to HIV-1 infection. Therefore, the development of anti-HIV-1 antibodies with potent complement activation activity may be an important determinant of vaccine-induced immunity to HIV-1 infection.¹⁷

Ab immunity in HIV-1 infection

While antibodies activate the complement system and mediate complement-dependent lysis of HIV-1 virions and HIV-1-infected cells, they have other important roles in clearing and neutralizing HIV-1 virions and HIV-1-infected cells. Both neutralizing Abs (nAbs) and non-neutralizing Abs (non-nAbs) can be simultaneously elicited during an effective immune response to viral infection. In the case of HIV-1 infection, nAb is an Ab that specifically binds to critical sites of HIV-1 Env to defend a target cell from viral binding, entry and infection, while non-nAb is an Ab that can specifically bind to non-critical sites of HIV-1 proteins, including Env, but that is unable to prevent the virus from binding to its cellular CD4 receptor. Generally, nAbs are critical for generating immunity against virus infection through multiple mechanisms. They may interfere with virion binding to receptors, block uptake or entry into cells, prevent uncoating of the viral genome in endosomes or cause aggregation of virus particles. The majority of nAbs neutralize free virions by preventing receptor engagement, an essential step in the life cycle of all Env viruses, or by interfering with the fusion process.³⁴ Later in the viral life cycle, nAbs that block replication by preventing viral uncoating or budding have been described in several viral diseases.³⁴ The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process.^{35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45}

When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins. These Abs consist of a mixture of nAbs and non-nAbs, which can contribute to antiviral immunity in four ways:³⁴ (i) nAbs directly neutralize free virus particles; (ii) both nAbs and non-nAbs trigger complement-mediated lysis of free virus particles and infected cells via specific Ab-antigen binding events and complement activation; (iii) both nAbs and non-nAbs bind to and coat viruses to mediate opsonization and phagocytosis by macrophages and other cells; and (iv) both nAbs and non-nAbs trigger destruction of viruses by stimulating other immune responses such as Ab-dependent cellular cytotoxicity (ADCC).

Ab responses to HIV-1 are generally vigorous at all stages of viral infection.^{34, 46} Within a few weeks of infection, Abs against the viral Env (gp120 and gp41), core (Gag) and matrix (p17) become detectable in the plasma of HIV-1-positive individuals.^{47, 48, 49, 50, 51, 52} Ab levels mount in response to the gradual increase in viral load and appear to be maintained at high levels throughout the disease.⁵³ Why does such a vigorous and sustained Ab response fail to play its role in the containment of HIV-1 replication and cytotoxicity? It is currently believed that only a fraction of the elicited Abs bear neutralizing activity, which is not sufficient to prevent the initiation of HIV-1 infection by blocking viral attachment to its CD4 receptor.³⁴ However, in HIV-1 infection, almost all individuals develop Abs capable of neutralizing autologous viruses in vitro.⁴⁶ Indeed, Abs with potent neutralizing activity against a broad range of HIV-1 strains across HIV-1 clades have been found in HIV-1-infected individuals.^{54, 55, 56, 57, 58, 59, 60} Among these nAbs, 2G12, 2F5 and 4E10 are three of the most broadly used Abs cloned from HIV-1-infected patients.^{54, 55, 57, 58, 61, 62, 63, 64} 2G12 recognizes a unique mannose-dependent epitope within gp120,^{55, 61, 65, 66, 67} while binding sites of 2F5 and 4E10 lie within a well-defined region of the membrane-proximal external region of gp41.^{54, 57, 58, 60, 68} Passive immunization with a cocktail of these three human monoclonal Abs was effective in animal models, i.e., it conferred protection against intravenous, intravaginal or oral challenge with simian human immunodeficiency virus (a monkey HIV-1 analog) in rhesus macaques.^{69, 70, 71} However, in a clinical trials with this nAb cocktail in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of HAART, only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization, indicating the limits of these nAbs in controlling HIV-1 infection.^{64, 72}

Why does passive immunization with a cocktail of nAbs provide anti-HIV-1 protection in animal models, but not in humans? Did the HIV-1 viruses mutate under the Ab immune pressure in humans? Studies suggest that HIV-1 can permanently escape nAb responses by: (i) masking or shedding putative neutralizing epitopes with extensive glycosylation and rapid rearrangement of the glycan shield, (ii) rapid mutation and recombination of the viral genome, particularly the Env gene, or (iii) displaying monomeric gp120 and gp41 stumps, not the typical wild-type gp120-gp41 trimers on the viral surface, which may not be properly recognized by the induced nAbs.^{39, 45, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83} Therefore, the nAb responses of the host are chasing a rapidly evolving HIV-1 virus. Eventually, these nAbs lose their neutralizing capability and become non-nAbs. However, viral genome sequences amplified directly from the passive immunization participants' plasma and from viral isolates showed no mutations in the core epitopes binding to these nAbs,⁷² suggesting that the virus has the ability to escape the Ab-mediated attack without viral mutation.

Why do vigorous non-nAbs generated in HIV-1-infected patients also fail to play their expected antiviral role by clearing virus particles and infected cells by complement activation, opsonization and phagocytosis and ADCC?^{84, 85, 86, 87} An in vivo study in TgH (KL25) mice showed that non-nAbs binding to the neutralizing antigenic sites on the lymphocytic choriomeningitis virus surface glycoprotein exerted an important biological effect by limiting early virus replication and spread.⁸⁴ In studies of mechanisms of protection against rotavirus infection and disease, nAbs have been found to be protective, but non-nAbs demonstrated important effector properties as well.⁸⁵ Taylor reported on mice inoculated with 25 monoclonal Abs (mAbs) intravenously to test Ab-mediated anti-respiratory syncytial virus (RSV) activity against intranasal challenge with RSV.⁸⁶ Two mAbs (R13-1 and R281-1, both to RSV F protein) gave similar levels of protection against infection, although the neutralization titer of R281-1 was 50 times greater than that of R13-1. In addition, two other mAbs (R18-3 and R402-5, both to RSV GP84) reduced viral titer 10- to 100-fold compared with control mice, yet neither had detectable neutralizing activity.⁸⁶ Similarly, Walsh et al. passively immunized cotton rats with nine mAbs with cross-reactive antigenic sites, thus reducing pulmonary virus titers of both A and B RSV subtypes.⁸⁷ The protection, however, did not correlate with in vitro neutralizing capacity. It therefore appears that mechanisms other than nAbs may also be involved in the resistance of HIV-1 against Ab-mediated protection.

We still face unprecedented challenges in developing an effective vaccine to eliminate HIV-1 infection. Nevertheless, development of a preventative vaccine remains the best strategy to control the HIV-1 epidemic and is a public health priority. More than 35 vaccine candidates have been tested in phase I/II clinical trials, involving more than 10 000 volunteers. Two phase III trials have been completed, involving more than 7500 volunteers.⁸⁸ Multiple vaccine concepts and vaccination strategies have been tested, including DNA vaccines,^{89, 90, 91, 92}, subunit vaccines,^{45, 88} recombinant live vector vaccines^{93, 94} and various prime-boost vaccine combinations.^{95, 96} None showed significant efficacy. These formidable scientific challenges may be related to the high genetic variability of the virus, the lack of immune correlates of protection, limitations of the existing animal models and logistical problems associated with the conduction of multiple clinical trials.^{97, 98, 99} Thus, a safe, globally effective, and affordable HIV-1 vaccine still seems far away.

On the whole, it appears that HIV-1 viruses and infected cells can escape Ab immunity, regardless of nAb-mediated neutralization and nAb/non-nAb-mediated complement attack, opsonization, phagocytosis and ADCC.^{100, 101} Although the underlying mechanisms remain unknown, previous studies have suggested that regulators of complement activation, including hCD59 on the surface of HIV-1 virions and infected cells, provide resistance to Ab-dependent complement-mediated lysis (ADCML), which we will discuss below.

MBL pathway in HIV-1 infection

MBL is present in human serum and plays an important role in innate immunity by binding to carbohydrates on the surfaces of microorganisms, including HIV-1. HIV-1 gp120/gp41 Env protein provides a potential site of attack by the innate immune system through the C-type lectin, MBL.¹⁰² Indeed, a number of studies have demonstrated that MBL binds to HIV-1 Env protein: gp120/gp41, leading to complement activation.^{20, 103, 104} Also, several in vitro experimental results indicate that MBL may affect the clearance of HIV-1 from the blood by binding to the virus and mediating uptake by tissue macrophages,¹⁰⁵ directly neutralizing HIV-1¹⁰³ and enhancing Ab-mediated neutralization.^{105, 106} However, the results obtained from the clinical studies of the relationship between HIV-1 infection and MBL level are contradictory.¹⁰² Although two recent studies indicate that the specific MBL genotype related to low levels of MBL is associated with HIV-1 infection and central nervous system impairment in specific populations,^{107, 108} the role of MBL in HIV-1 infection has not been established and still requires further investigation.

Complement enhances HIV-1 infectivity

Although the complement system and Ab immunity play a critical role in clearing HIV-1 virions, they also represent critical factors for the spread and maintenance of the virus in the infected host. The deposition of complement activation products such as C3 fragment and C5a in HIV-1 virions facilitates HIV-1 interaction with cells such as monocytes/macrophages and dendritic cells expressing complement receptor CR3 and CR4.^{74, 109, 110} Complement-mediated enhancement of HIV infection also occurs in vitro in peripheral blood mononuclear cells.¹¹¹ The fixation of C1q to intact virions results in enhanced HIV-1 infection in the cell cultures,¹¹² which may be related to the binding of C1q to gp41 on intact HIV-1 virions.¹¹³ Complement activation by HIV results in the binding of C3 fragments to the gp160 complex and enhanced infection of C3 receptor-bearing target cells. CR1 and CR2 contribute in an independent and complementary fashion to penetrate opsonized virus into complement receptor-expressing T cells.¹¹⁴ Additionally, the CD4-gp120 and C3d-CR2 interactions may increase the virus adhesion to target cells, a step determined to be the most important in virus entry according to the recent studies by Lund et al.¹¹⁵ Several independent lines of evidence also indicate that the interaction between HIV-1 and CR3 may contribute to viral entry and support intracellular viral spread. This interaction might be due to a gp41-CR3 interaction or the binding of viral adhesion molecules to their counterparts on host cells.¹¹⁶ Furthermore, in vitro experimental evidence suggests that complement activation product C5a, an anaphylatoxin, and C5a_desArg may increase the susceptibility of monocytes and monocyte-derived macrophages to HIV infection through stimulating tumor-necrosis factor-α and IL-6 secretion from these cells.¹¹⁷ Furthermore, C5a induced by HIV-1 and antibodies attract dendritic cells, which in turn promote the productive infection of autologous primary T cells.¹¹⁸ In addition to complement activation enhancing HIV-1 infectivity, HIV-1 strongly induces the synthesis of complement factor 3 in astrocytes and neurons.¹¹⁹ The purified HIV-1 viral proteins Nef and gp41 are biologically active in upregulating C3, whereas Tat, gp120 and gp160 were not able to modulate C3 synthesis. This HIV-induced complement synthesis may also contribute to neurodegeneration in the pathogenesis of AIDS-associated neurological disorders.¹¹⁹

Moreover, the binding of anti-HIV antibodies to complement-opsonized HIV-1 virions facilitates HIV-1 interaction with erythrocytes, as do other types of immune complex when exposed to complement. HIV-1 alone binds to erythrocytes in a complement/CR1-dependent manner. These HIV-1-bound erythrocytes may not only deliver immune-complexed HIV-1 to organs susceptible to infection, but also free HIV. They may play a crucial role in the progression of the primary infection.¹²⁰ Factor I, in concert with CR1 on erythrocytes and factor H in serum, may be an important cofactor for the generation of C3d-opsonized infectious HIV-1 reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals.¹²¹ Clinical evidence indicates that a pool of HIV-1 is associated with erythrocytes even after long-term suppression of viral RNA in plasma, which may play a role in HIV-1 replication or release in these individuals.¹²²

Although B cells are not readily infected by HIV, they are similar to follicular dendritic cells in their capacity to serve as extracellular reservoirs for HIV-1. B cells possess the capability of circulating in peripheral blood and migrating through tissues where they can potentially interact with and pass virus to T cells.¹²³ Treatment of virus with a source of Ab and complement increased immune-complexed HIV binding to B cells by 5.6-fold. Together, the direct interaction between B and T lymphocytes and direct binding of opsonized virus to CR2 on B cells may be critical in the pathogenesis of HIV.^{124, 125, 126}

The complement system plays various roles in the enhancement of HIV-1 infection at different stages. To enhance the efficiency of complement-mediated HIV lysis, Xu et al. propose a new approach—that a new activator of complement, consisting of a target domain (C3-binding region of complement receptor type 2) linked to a complement-activating human IgG1 Fc domain (CR2-Fc), would target and amplify complement deposition onto HIV virions.¹²⁷ This hypothesis still needs to be extensively tested in vitro and in vivo for efficacy and toxicity effects.

Complement regulators on the surface of HIV-1 protect HIV-1 from complement-mediated lysis

As we discussed extensively above, the complement system, a key member of innate immunity, plays a critical role not only in defending against HIV-1 infection, but also in enhancing HIV-1 infection. HIV-1 in circulation escapes complement-mediated lysis and remains highly infective, even though there is strong experimental evidence that both the virus itself and the anti-HIV-1 antibodies in the blood of HIV-1-infected individuals are capable of activating the complement cascades.¹²⁸ The protection of HIV-1 from ADCML is due, at least in part, to the presence of regulators of complement activation such as CD59 and CD55 in the viral Env, which the virus recruits from the host cell in the budding process.^{31, 32, 33} Additionally, binding of the fluid-phase complement regulator factor H to HIV-1 provides the virus with further protection from complement attack.¹²⁹ Many pathogenic enveloped viruses, including HIV-1, cytomegalovirus, herpes virus, Ebola virus and influenza virus, among others, escape ADCML by incorporating host cell regulators of complement activation proteins into their own viral Env.^{31, 130, 131, 132, 133, 134, 135} The presence of complement regulator proteins such as CD59 on the external surface of the viral Env provides resistance to ADCML, which may explain why certain human pathogenic viruses are not neutralized by complement in human fluids even when they induce a strong Ab response. In the specific case of HIV-1 infection, sera from HIV-1-infected patients contain vigorous HIV-1 Env-specific Abs, but fail to complete ADCML to virions and infected cells^{31, 32, 33} due to the presence of hCD59 in the HIV-1 Env or in the membranes of the infected cells.³² Deficiency or inhibition of hCD59 on the surface of either the viral Env or the infected cell membrane sensitizes them to the lytic effects of complement.^{31, 32, 136} For these reasons, a therapeutic inhibitor of complement regulators, including CD59, which would sensitize HIV-1 virions or HIV-infected cells to the lytic effect of complement, has been actively sought by us and others.^{33, 137}

The development of cd59 inhibitors for HIV-1 immune therapy

Because CD59 is expressed in cells of multiple tissues and at especially high levels in erythrocytes and endothelial cells, potential side effects are the main hurdles for the development of clinically useful hCD59 inhibitors. Two candidates developed so far by other groups are not appropriate for inhibiting hCD59 activity: (i) anti-hCD59 Abs: monoclonal Abs directed against hCD59 are useful tools for studying CD59 function in vitro.^{138, 139, 140} However, it is impossible to apply them to HIV-1 therapy, as they bind not only to HIV-1 but also to many other cells that express hCD59, potentially inducing ADCC, complement-dependent cytotoxicity or apoptosis in normal cells. To overcome this problem, Ziller et al. screened a human phage-display library to identify mini-Abs (single-chain variable fragments, or scFv) that specifically blocked hCD59 and hCD55 function.¹⁴¹ They reported that these mini-Abs blocked hCD59 function in mice. Although the mini-Abs failed to activate complement alone, they killed about 25% cells through ADCC.^{142, 143} (ii) Peptides derived from C8 and C9: extensive studies of hCD59 structure, as well as of its interaction with C8 and C9, revealed the region of hCD59 critical for inhibiting MAC formation through preventing binding of C8 and C9.^{144, 145, 146, 147, 148} Small peptides derived from C8 and C9 that bind to this region are effective against hCD59 function at concentrations greater than 300 µmol/l of IC₅₀, limiting their therapeutic usefulness.^{147, 148}

Recently, we reported the development of a recombinant form of the fourth domain of the bacterial toxin intermedilysin (rILYd4), a 114 amino-acid protein that inhibits human CD59 function with high affinity and specificity. In the presence of rILYd4, HIV-1 virions derived from either cell lines or peripheral blood mononuclear cells of HIV-1-infected patients became highly sensitive to complement-mediated lysis activated by either anti-HIV-1 gp120 antibodies or by viral infection-induced antibodies present in the plasma of HIV-1-infected individuals. We also demonstrated that rILYd4 together with serum or plasma from HIV-1-infected patients used as a source of anti-HIV-1 antibodies and complement did not mediate complement-mediated lysis of either erythrocytes or peripheral blood mononuclear cells.¹³⁷ Previously, Terpos et al. documented that patients with HIV-1 infection also have diminished expression of the glycosyl-phosphatidylinositol-anchored cell surface proteins CD55 and CD59 on their erythrocytes and granulocytes.¹⁴⁹ Since the density of hCD59 on the surface of HIV-1-infected cells appears to be reduced, one would expect that primary virions would carry less hCD59. In patients, a lower density of hCD59 in infected than in non-infected cells would enhance the efficacy of rILYd4 in specifically eliminating HIV-1 virions and HIV-1-infected cells. Together, these results indicate that rILYd4 might be a preclinical candidate that deserves further investigation as a potential therapeutic agent against HIV-1 infection/AIDS¹³⁷ or might provide a platform from which to develop an inhibitor of CD59 for the treatment or prevention of HIV-1 infection.

Conclusion

The complement system plays diverse roles in the pathogenesis of HIV-1 infection. It fights against the infection through Ab-mediated complement-dependent lysis of HIV-1 virions and HIV-1-infected cells and neutralizes HIV-1 particles. The complement-mediated lysis of HIV-1 and HIV-1-infected cells is limited by the presence of complement regulators such as CD59 and factor H on the surface of HIV-1 and HIV-1-infected cells. On the other hand, complement also enhances HIV-1 infectivity through complement deposition, facilitating interaction with complement receptor-expressing cells such as monocytes/macrophages and dendritic cells. Complement also facilitates HIV-1 interaction with non-infected cells such as erythrocytes and B cells as the delivery and release source for infecting other cells. Most of these conclusions are based on in vitro and ex vivo studies. Therefore, the in vivo roles of complement in the pathogenesis of HIV-1 infection should be extensively studied. Although several approaches have been proposed for enhancing complement activation of HIV-1 infection for the treatment and prevention of HIV-1 infection, they still require further evaluation and extensive investigation.