Complement enhancement of HIV infection is mediated by complement receptors

Complement enhancement of HIV infection is mediated by complement receptors

Immunopharmacology, 25 (1993) 87-93 Elsevier Science Publishers B.V. 87 I M P H A R 00635 Invited Review Complement enhancement of HIV infection i...

564KB Sizes 0 Downloads 100 Views

Immunopharmacology, 25 (1993) 87-93 Elsevier Science Publishers B.V.

87

I M P H A R 00635

Invited Review

Complement enhancement of HIV infection is mediated by complement receptors Nathalie T h i e b l e m o n t , C a t h e r i n e Delibrias, Elisabeth Fischer, L a u r e n c e Weiss, M i c h e l D. K a z a t c h k i n e a n d Nicole Haeffner-Cavaillon I N S E R M U28, Hdpital Broussais, Paris, France (Accepted 3 November 1992)

Introduction Human immunodeficiency virus (HIV) is tropic and cytopathic for human T lymphocytes bearing the CD4 molecule. In vivo and in vitro findings suggest that HIV tropism is not limited to CD4 positive cells. The identification of the infected target cells and of the mechanisms underlying the viral entry are critical to the understanding of the pathogenesis of this disease, and may facilitate therapeutical approaches. The present review focuses on the enhancing role of complement on infection of CD4 + and CD4 target cells.

Complement activation by HIV Most viruses elicit in man an antiviral humoral immune response. Virus particles coated with immunoglobulin G (IgG) or IgM activate the classical pathway of the complement system through the formation of closely packed IgG clusters and activation of complement component C1. Some viruses also activate complement in the absence of antibodies, the p15E envelope constituant of Moloney leukemia virus has been Correspondence to: M.D. Kazatchkine, I N S E R M U28, Hrpital Broussais, 96 rue Didot, 75014 Paris, France.

identified as a Cl-activating retroviral protein (Bartholomew et al., 1978) whereas Epstein-Barr viruses directly activate the alternative pathway through its envelope glycoprotein gp350 (Mold et al., 1988). The HIV1 efficiently activates complement (Perricone et al., 1987; Senaldi et al., 1990; Tausk et al., 1986), although activation is poorly effective in neutralizing and lysing the virus (Banapour etal., 1986). The molecular mechanisms that are responsible for the resistance of HIV to lysis or inactivation by human complement have not yet been identified. HIV infection is also associated with acquired changes in the membrane expression of complement regulatory molecules, including a decreased expression of CR1 on erythrocytes (Jouvin et al., 1987), a defective expression of DAF(CD55) on leukocytes (Lederman et al., 1989) and of the CD59 membrane inhibitor of complementmediated cytolysis on T lymphocytes (Weiss et al., 1992). The latter alterations could explain the increased susceptibility of lymphocytes of AIDS patients to homologous complementmediated lysis (Lederman et al., 1989). Intact HIV, recombinant gp160, synthetic peptide of gp41 and HIV-infected cells have been shown to activate complement in human serum resulting in the cleavage of C3 (SOlder et al., 1989; Ebenbichler et al., 1991). Complement ac-

88 tivation by HIV occurs through the classical pathway following the binding of C l q to conserved extracellular peptidic sequences of the gp41 envelope protein of HIV-1 and direct activation of the C1 complex. An epitope which contains the major C1 binding and activating sequence is exposed after sCD4 binding to gpl20. This change of the steric configuration of the CD4-gp 120-gp41 complex could facilitate the interaction between gp41 and the C1 complex and could mediate antibody-independent activation of C1 (Ebenbichler et al., 1991). Recent evidence indicates that, upon classical pathway activation in whole serum, mammalian-derived recombinant gpl60 and gpl20 bind C3b/iC3b with a molecular stoichiometry of one to one in the absence of antibodies. Although classical pathway activation of C1 by gp41 and by gpl60 may occur in the absence of antibodies, it was significantly enhanced in serum containing antiHIV antibodies (Thieblemont et al., 1992). As a result of complement activation by viral particles, the infectious agents become opsonized with complement proteins including Clq, C4b and C3b. These proteins promote viral clearance but may also, in some cases prevent or enhance viral attachment to complement receptors on cell surfaces.

Complement-mediated penetration of HIV Complement alone or in association with antiHIV antibodies was shown to enhance infection of various cell targets with opsonized HIV in vitro (Robinson et al., 1988; Tremblay et al., 1990; Boyer et al., 1991; Thieblemont et al., 1992). The ability of HIV to cleave C3 in whole human serum results in the effective binding of C3b/iC3b onto the envelope glycoprotein complex and provides a basis for C3-mediated facilitation of infection with HIV of both CD4-positive and CD4-negative target cells, including T lymphocytes and T cell lines (Robinson et al., 1988; June etal., 1991; Boyer etal., 1991), B cell lines (Tremblay et al., 1990; Gras et al., 1991), mono-

cytes (Thieblemont et al., 1992) monocytic cell lines (Reisinger et al., 1990), and glial cells (Thieblemont et al., 1992).

Complement-mediated enhancement of infection of monocyte/macrophages Instead of destroying HIV in infected individuals, mononuclear phagocytes may serve as a reservoir and a means of transportation of the virus through the human body. Depending on their state of maturation, cells of the monocytic lineage express various amounts of immunoglobulin Fc receptors gamma: RI(CD64), Fc gamma RII(CD32), Fc gamma RIII(CD16), and complement receptors: CR1(CD35) and CR3(CD1 lb/CD18). CR1 is a polymorphic glycoprotein of 160-250 kDa which serves as the receptor for C3b and C4b. CR3 is a heterodimer belonging to the Leu CAM integrin family including the L F A - I ( C D l l a / C D 1 8 ) and p1509 5 ( C D l l c / C D 1 8 ) molecules. The monocytes also express the CD4 molecule at low density on the membrane. In vitro infection of monocytes/macrophages with HIV is enhanced by complement in the presence of antibodies and in the absence of antibodies (Reisinger etal., 1990; Thieblemont et al., 1992). Binding and uptake of purified fluorescein-labeled HTLV-IIIB by the monocytes has been shown to be increased following opsonization of the virus with complement or with antibodies and complement (Bakker et al., 1992). Infection with low amounts of HIV-1 of the promonocytic U937 cells is facilitated by complement without anti-HIV IgG. Infection of U937 cells was reduced in the presence of antibodies directed against the CD4 molecule, or the CR3 receptor, and was abrogated with a combination of the two antibodies (Reisinger, 1990). We have recently demonstrated that opsonization of HIV with complement results in earlier and enhanced infection of cells of the monocytic lineage (THP1, Mono Mac6) with HIV-1 and HIV-2. The enhancing effect was lost if opsonization was performed in the presence of EDTA or with C2 deficient serum. The enhancing effect of complement was

89 totally suppressed by blocking CRl(CD35) or CR3(CDllb/CD18) receptors with anti-CR1 and anti-CR3 F(ab')2 fragments, while blocking the LFA-1 molecule with anti-LFA F(ab')2 fragments had no effect. It may be anticipated that deposition of higher amounts of C3 fragments on the viral envelope in the presence of anti-HIV antibodies and coopsonization of the virus would further enhance the infection of cells of the monocytic lineage. Stimulation of the C3b/C4b receptor (CR1) in serum-free cultured normal human monocytes results in the induction of production of cellassociated I L - l e and fl and in the extracellular release of biologically active IL-lfl (Bacle et al., 1990) and stimulation of CR3 induces the intracellular accumulation of both IL-1 (Couturier et al., 1990). Transcription of the IL-lfl genes as well as HIV replication are dependent on translocation of nuclear factors such as NF-kappaB or AP-1. We have recently demonstrated that stimulation of the CD35 receptor induces a higher viral replication in different monocytic cell lines and a higher translocation of the nuclear transcriptional factor NF-kappaB (Thieblemont et al., manuscript in preparation). Therefore, it can be suggested that during opportunist infections, the benefit of complement activation for efficient killing of bacteria may be counterbalanced by the triggering of complement receptors CR1 and CR3 on monocytes, since the stimulation of CR1 induces translocation of nuclear proteins and contributes to induction of IL-1 gene concomitently to the reactivation of the latent proviruses.

Complement-mediated enhancement of infection of T lymphocytes Approximately 15 ~o of peripheral blood CD4 + and CD8 + T cells express CR1 (Wilson et al., 1983; Rodgaard et al., 1991) and 50~o express CR2 at an approximately 10-fold lower density than B cells (Fischer et al., 1991). CR1 + T lymphocytes also express Fc gamma receptors. CR2 is a 145 kDa glycoprotein that functions as a receptor for C3dg/C3d and iC3b (Cooper

et al., 1988) and as the receptor for EBV on B lymphocytes (Fingeroth et al., 1984; Nemerow et al., 1985). On the human T cell line HPB-ALL, CR2 and CR1 are co-internalized when crosslinked with anti-receptor antibodies; CR2 is capable of signal transduction (Delibrias et al., 1992). The first evidence for the role of complement in enhancing HIV infection o f T cells came from the observation by Robinson that sera from more than 80~o of HIV antibody-positive individuals increased infectious virus release from cells of the MT2 T cell line upon infection with HIV-1 in vitro. Enhancement of CD4 + CR2 + infection by seropositive serum required complement, antiHIV antibodies and the CD4 molecule (Robinson et al., 1988, 1989). We have subsequently found that complement alone was capable of enhancing infection of MT2 cells in the presence of suboptimal amounts of HIV-1 (Boyer et al., 1991). Productive viral infection of MT2 cells with low inputs of HIV occurred through the interaction of opsonized virus with CR2, since infection was blocked by cross-linked mAb against CR2 (Boyer et al., 1991). Complement alone also enhances infection of PHA-stimulated seronegative peripheral blood leukocytes cocultured with cells from HIV-infected individuals (Boyer et al., 1991). Little is known at present on the role of CR1 in facilitating the infection of T cells with complement-opsonized HIV. Preliminary experiments indicate that blocking of CR1 partially decreased CD4-dependent infection of the CD4 + CD8 + CR1 + CR2 + HPB-ALL T cell line with complement-opsonized HIV. CR1 on T cells could either function as a receptor alone mediating viral entry into the cells or as a cofactor for the cleavage of C3b into iC3b and C3dg to allow the interaction of opsonized virus with CR2.

Complement-mediated enhancement of infection of B cells Lymphoblastoid B cell lines express CR2 and, some of the cell lines also express CR1. The

90 expression of CR2 is upregulated by EBV in EBV-transformed B cell lines (Cohen etal., 1987). All normal mature B lymphocytes express CR1 and CR2 (Tedder et al., 1983, 1984). Triggering of CR1 on pre-activated B cells enhances their differentiation into antibody-secreting cells (Daha et al., 1984; Weiss et al., 1987), whereas triggering of CR2 induces B cell proliferation (Bohnsack et al., 1988; Hatzfeld et al., 1988). Early studies have shown that EBV-transformed human B cells lines are susceptible to HIV infection in vitro (Montagnier et al., 1984; Salahuddin et al., 1987). Depending on the cell line and on the strain of HIV, infection of EBV + B cells has resulted in cell lysis or in persistent non-productive or productive infection (Dahl etal., 1987, 1990; Tremblay et al., 1988; De Rossi et al., 1990). HIV has also been shown to infect EBV-Burkitt lymphoma B cell lines, indicating that susceptibility to HIV infection is not strictly dependent on the presence of the EBV genome (Monroe et al., 1988). An enhancing role of complement on infection ofEBV + B cells was first shown in an experimental system wherein CD4 + B lymphoblastoid cell line was used as the target for infection in the presence of complement and anti-HIV antibodies (Tremblay et al., 1990). A recent report indicated that antibody and complement-dependent enhancement of infection of the EBV + IC-1 B cell line was mediated by CR2 and blocked by anti-CD4 antibodies (Gras et al., 1991). Opsonization with complement would enhance infection by increasing the number of viral particles attaching to CR2bearing cells and by subsequently facilitating the entry of the virus through CD4 on cells expressing low amounts of the molecule. CR2 may mediate on its own the productive infection of the Raji B lymphoblastoid cell line with complement-opsonized H1V (Boyer et al., 1992). Infection of the cells occurred independently of antibodies and of CD4 molecule since HIV-seronegative serum was used for infection and since the cells lack the expression of CD4 surface antigen and of CD4 transcript.

CD4-independent productive HIV infection of human cells The CD4 molecule mediates the high affinity binding of the gpl20 envelope glycoprotein of HIV to target cells expressing CD4 (Mizukami et al., 1988; Sattentau et al., 1986). Recent studies have shown that a number of C D 4 - cells are susceptible to HIV infection in vivo and in vitro, indicating that alternative pathways to CD4 exist for viral penetration into target cells. HIV infection of human neural cells and primary fetal dorsal root ganglia glial cells involved an entry pathway distinct from that of lymphoid cells. The medulloblastoma and glioblastoma cells had no detectable CD4 on their surfaces and nor detectable transcription of the CD4 gene using either RNA blot hybridization or nuclease protection assays but were infectable by various isolates of HIV (Harouse etal., 1989). The infection of human fibroblastoid cells (Tateno et al., 1989), clonal and purified polyclonal populations of natural killer cells (Chehimi etal., 1991), hepatoma cells (Cao et al., 1990), transformed trophoblast-derived cells (Zachar et al., 1991) and Raji B lymphoblastoid cell line (Boyer et al., 1992) which expressed neither surface CD4 nor CD4 m R N A is not blocked by anti-CD4 monoclonal antibodies. Furthermore, HIV-1 infection in hepatoma and neuronal cell lines could not be blocked soluble CD4 (Li et al., 1990). Similar results were obtained using human follicular dendritic cells (Stahmer etal., 1991), brain and muscle cells (Clapham et al., 1990) that could be infected with HIV-1. All these cells were infected in the presence of soluble CD4 or anti-CD4 antibody Leu-3a. Monocytes/macrophages, whether freshly isolated or two months old, are susceptible to HIV infection in spite of the fact that CD4 + molecule are not detectable on macrophages after 15 days of culture (Valentin et al., 1990). We have observed that CD4 + THP1 promonocytic cells and the monocytic CD4 Mono Mac6 and glial U251-MG cell lines which lack expression of CD4 m R N A and of the CD4 antigen are similarly susceptible to HIV-1 and HIV-2 infection in the presence of serum (Thie-

91

blemont et al., 1992). Complement-mediated infection of mononuclear phagocytic cells by HIV may occur independently of CD4, indicating that the interaction of opsonized virus with complement receptors may be sufficient to mediate penetration of HIV into monocytes. As in the case of other infectious microorganisms, complement activation may contribute to the pathogenesis of HIV infection by opsonizing the virus and facilitating entry of viral particles. Therefore in addition to attachment of HIV-1 to Fc-receptor via antibodies, gangliosides and LFA-1 molecule, C3 complement receptors may contribute, alone or in association with CD4, to infection of various cells with opsonized HIV.

References Bacle F, Haeffner-Cavaillon N, Laude M, Couturier C, Kazatchkine MD. Induction of interleukin-1 release through stimulation of the C3b/C4b complement receptor type 1 (CR1, CD35) on human monocytes. J Immunol 1990; 144: 147-152. Bakker LJ, Nottet HSLM, De Vos NM, De Graaf L, Van Strijp JAG, Visser MR, Verhoef J. Antibodies and complement enhance binding and uptake of HIV-1 by human monocytes. AIDS 1992; 6: 35-41. Banapour B, Sernatinger J, Levy JA. The AIDS-associated retrovirus is not sensitive to lysis or inactivation by human serum. Virology 1986; 152: 268-271. Bartholomew RM, Esser AF, Milller-Eberhard HJ. Lysis of oncornaviruses by human serum. Isolation of viral complement (C1) receptor and identification as pl5E. J Exp Med 1978; 147: 844-853. Boyer V, Desgranges C, Trabaud M-A, Fischer E, Kazatchkine MD. Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion. J Exp Med 1991; 173: 1151-1158. Boyer V, Delibrias C, Noraz N, Fischer E, Kazatchkine MD, Desgranges C. Complement receptor type 2 mediates infection of the hmnan CD4-negative Raji B cell line with opsonized HIV. Scand J Immunol 1992; in press. Bohnsack JF, Cooper NR. CR2 ligands modulate human B cell activation. J Immunol 1988; 141: 2569-2576. Cao Y, Friedman-Kien AE, Huang Y, Li XL, Mirabile M, Moudgil T, Zucker-Franklin D, Ho DD. CD4-independent, productive human immunodeficiency virus type 1 infection of hepatoma cell lines in vitro. J Virol 1990; 64: 2553-2559.

Chehimi J, Bandyopadhyay S, Prakash K, Perussia B, Hassan NF, Kawashima H, Campbell D, Kornbluth J, Starr SE. In vitro infection of natural killer cells with different human immunodeficiency virus type 1 isolates. J Virol 1991; 65: 1812-1822. Clapham PR, Weber JN, Whitby D, McIntosh K, Dalgleish AG, Maddon PJ, Deen KC, Sweet RW, Weiss RA. Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature (London) 1989; 337: 368-370. Cohen JHM, Fischer E, Kazatchkine MD, Lenoir GM, Lefevre-Delvincourt C, Revillard J-P. Expression of CR1 and CR2 complement receptors following Epstein-Barr virus infection of Burkitt's lymphoma cell lines. Scand J Immunol 1987; 25: 587-598. Cooper NR, Moore MD, Nemerow GR. Immunobiology of CR2, the B lymphocyte receptor for Epstein-Barr virus and the C3d complement fragment. Annu Rev Immunol 1988; 6: 85-113. Couturier C, Haeffner-Cavaillon N, Weiss L, Kazatchkine MD. Induction of cell-associated interleukin 1 through stimulation of the adhesion-promoting proteins LFA-1 (CD1 la/CD18) and CR3 (CD1 lb/CD18) of human monocytes. Eur J Immunol 1990; 20: 999-1005. Daha MR, Bloem AC, Ballieux RE. Immunoglobulin production by human peripheral lymphocytes induced by anti-C3 receptor antibodies. J Immunol 1984; 132: 1197-1201. Dahl K, Martin K, Miller G. Differences among human immunodeficiency virus strains in their capacities to induce cytolysis or persistent infection of a lymphoblastoid cell line immortalized by Epstein-Barr virus. J Virol 1987; 61: 1620-1628. Dahl KE, Burrage T, Jones F, Miller G. Persistent non productive infection of Epstein-Barr virus transformed human B lymphocytes by human immunodeficiency virus type 1. J Virol 1990; 64: 1771-1783. Delibrias C, Fischer E, Bismuth G, Kazatchkine MD. Expression, molecular association and functions of CR1 and CR2 on the human T cell line HPB-ALL. J Immunol 1992; in press. De Rossi A, Roncella S, Calabro ML, D'Andrea E, Pasti M, Panozzo M, Mammano F, Ferrarini M, Chieco-Bianchi L. Infection of Epstein-Barr virus-transformed lymphoblastoid B cells by the human immunodeficiency virus: evidence for a persistent and productive infection leading to B cell phenotypic changes. Eur J Immunol 1990; 20: 2041-2049. Ebenbichler CF, Thielens NM, Vornhagen R, Marschang P, Arlaud GJ, Dierich MP. 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. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. Epstein-Barr virus receptor of human B

92 lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci USA 1984; 81: 4510-4514. Fischer E, Delibrias C, Kazatchkine MD. Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphoctes. J Immunol 1991; 146: 865-869. Gras GS, Dormont D. Antibody-dependent and antibodyindependent complement-mediated enhancement of human immunodeficiency virus type 1 infection in a human, Epstein-Barr virus-transformed B-lymphocytic cell line. J Virol 1991; 65: 541-545. Harouse JM, Kunsch C, Hartle HT, Laughlin MA, Hoxie JA, Wigdahl B, Gonzalez-Scarano F. CD4-independent infection of human neural cells by human immunodeficiency virus type 1. J Virol 1989; 63: 2527-2533. Hatzfeld A, Fischer E, Levesque JP, Perrin R, Hatzfeld J, Kazatchkine MD. Binding of C3 and C3dg to the CR2 complement receptor induces growth of an Epstein-Barr virus-positive human B cell line. J Immunol 1988; 140: 170-175. Jouvin M-H, Rozenbaum W, Russo R, Kazatchkine MD. Decreased expression of the C3b/C4b complement receptor (CR1) in AIDS and AIDS-related syndromes correlates with clinical subpopulations of patients with HIV infection. AIDS 1987; 1: 89-94. June RA, Schade SZ, Bankowski MJ, Kuhns M, McNamara A, Lint TF, Landay AL, Spear GT. Complement and antibody mediate enhancement of HIV infection by increasing virus binding and provirus formation. AIDS 1991; 5: 269-274. Lederman MM, Purvis SF, Walter EI, Carey JT, Medof ME. Heightened complement sensitivity of acquired immunodeficiency syndrome lymphocytes related to diminished expression of decay-accelerating factor. Proc Natl Acad Sci USA 1989; 86: 4205-4209. Li XL, Moudgil T, Vinters HV, Ho DD. CD4-independent, productive infection of a neuronal cell line by human immunodeficiency virus type 1. J Virol 1990; 64: 1383-1387. Mizukami T, Fuerst TR, Berger EA, Moss B. Binding region for human immunodeficiency virus (HIV) and epitopes for HIV-blocking monoclonal antibodies of the CD4 molecule defined by site-directed mutagenesis. Proc Natl Acad Sci USA 1988; 85: 9273-9277. Montagnier L, Gruest J, Chamaret S, Dauguet C, Axler C, Guetard D, Nuggeyre MT, Barre-Sinouszsi F, Chermann JC, Brunet JB, Klatzmann JC, Gluckman JC. Adaptation of lymphadenopathy-associated virus (LAV) to replication in EBV-transformed B lymphoblastoid cell lines. Science 1984; 225: 63-66. Monroe JE, Calender A, Mulder C. Epstein-Barr viruspositive and -negative B-cell lines can be infected with human immunodeficiency virus types 1 and 2. J Virol 1988; 2: 3497-3500. Mold C, Bradt BM, Nemerow GR, Cooper NR. Activation of the alternative complement pathway by EBV and the

viral envelope glycoprotein, gp350. J Immunol 1988; 140: 3867-3874. Nemerow GR, Wolfert R, McNaughton ME, Cooper NR. Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2). J Vir 1985; 55: 347-351. Perricone R, Fontana L, De Carolis C, Carini C, Sirianni MC, Aiuti F. Evidence for activation of complement in patients with AIDS related complex (ARC) and/or lymphoadenopathy syndrome (LAS). Clin Exp Immunol 1987; 70: 500-507. Reisinger EC, Vogetseder W, Berzow D, K0fler D, Bitterlich G, Lehr HA, Wachter H, Dierich MP. Complementmediated enhancement of HIV-1 infection of the monoblastoid cell line U937. AIDS 1990; 4: 961-965. Robinson WE, Montefiori DC, Mitchell WM. Antibodydependent enhancement of human immunodeficiency virus type 1 infection. Lancet 1988; i: 790-794. Robinson WE, Montefiori DC, Gillespie DH, Mitchell WM. Complement-mediated, antibody-dependent enhancement of HIV-I infection in vitro is characterized by increased protein and RNA syntheses and infectious virus release. J Acq Immune Def Synd 1989; 2: 33-42. Rodgaard A, Christensen LD, Thomsen BS, Wiik A, Bendixen G. Complement receptor type 1 (CR1,CD35) expression on peripheral T lymphocytes: Both CD4- and CD8positive cells express CR1. Complement and Inflamm 1991; 8: 303-309. Salahuddin SZ, Ablashi DV, Hunter EA, Gonda MA, Sturzenegger S, Markham PD, Gallo RC. HTEV-III infection of EBV-genome-positive B-lymphoid cells with or without detectable T4 antigens. Int J Cancer 1987; 39: 198-202. Sattentau QJ, Dalgleish AG, Weiss RA, Beverley PCL. Epitopes of the CD4 antigen in HIV infection. Science 1986; 234: 1120-1123. Senaldi G, Peakman M, McManus T, Davies ET, Tee DEH, Vergani D. Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity. J Infect Dis 1990; 162: 1227-1232. SOlder BM, Schulz TF, Hengster P, LOwer J, Larcher C, Bitterlich G, Kurth R, Wachter H, Dierich MP. HIV and HIV-infected cells differentially activate the human complement system independent of antibody. Immunol Lett 1989; 22: 135-145. Stahmer I, Zimmer JP, Ernst M, Fenner T, Finnern R, Schmitz H, Flad H-D, Gerdes J. Isolation of normal human follicular dendritic cells and CD4-independent invitro infection by human immunodeficiency virus (HIV-1). Eur J Immunol 1991; 21: 1873-1878. Tateno M, Gonzalez-Scarano F, Levy JA. Human immunodeficiency virus can infect CD4-negative human fibroblastoid cells. Proc Natl Acad Sci USA 1989; 86: 4287-4290.

93 Tausk FA, McCutchan JA, Spechko P, Schreiber RD, Gigli I. Altered erythrocyte C3b receptor expression immune complexes, and complement activation in homosexual men in varying risk groups for acquired immune deficiency syndrome. J Clin Invest 1986; 78: 977-982. Tedder TF, Fearon DT, Gartland GL, Cooper MD. Expression of C3b receptors on human B cells and myelomonocytic cells but not natural killer cells. J Immunol 1983; 130: 1668-1673. Tedder TF, Clement LT, Cooper MD. Expression of C3d receptors during human B cell differentiation: immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol 1984; 133: 678-683. Thieblemont N, Haeffner-Cavaillon N, L'Age-Stehr J, Ziegler-Heitbrock HWL, Kazatchkine MD. CRl(CD35) and CR3(CDllb/CD18) mediate infection of human monocytes and monocytic cell lines with complementopsonized HIV independentlyof CD4. J Exp Med 1992; in press. Thieblemont N, Haeffner-Cavaillon N, Weiss L, Maillet F, Kazatchkine MD. Complement activation by the gp160 glycoprotein of HIV-1. AIDS Res Hum Retroviruses 1992; in press. Tremblay M, Meloche S, Sekaly R-P, Wainberg MA. Corn-

plement receptor 2 mediates enhancement of human immunodeficiency virus type 1 infection in EpsteinBarr virus-carrying B cells. J Exp Med 1990; 171: 1791-1796. Valentin A, Matsuda S, Asj0 B. Characterisation of the in vitro maturation of monocytes and the susceptibility to HIV infection. AIDS Res Hum Retroviruses 1990; 6: 977-979. Weiss L, Delfraissy JF, Vasquez A, Wallon C, Galanaud P, Kazatchkine MD. Monoclonal antibodies to the human C3b/C4b receptor (CR1) enhance specific B cell differentiation. J Immunol 1987; 138: 2988-2993. Weiss L, Okada N, Haeffner-Cavaillon N, Hattori T, Faucher C, Kazatchkine MD, Okada H. Decreased expression of the membrane inhibitor of complementmediated cytolysis CD59 on T-lymphocytes of HIVinfected patients. AIDS 1992; 6: 379-385. Wilson JG, Tedder TF, Fearon DT. Characterization of human T lymphocytes that express the C3b receptor. J Immunol 1983; 113: 684-689. Zachar V, Spire B, Hirsch I, Chermann J-C, Ebbesen P. Human transformed trophoblast-derived cells lacking CD4 receptor exhibit restricted permissiveness for human immunodeficiency virus type 1. J Virol 1991; 65: 2102-2107.