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. 1991 Dec 1;174(6):1417–1424. doi: 10.1084/jem.174.6.1417

Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp41

PMCID: PMC2119058  PMID: 1744579

Abstract

Human immunodeficiency virus type 1 (HIV-1), in contrast to animal retroviruses such as murine leukemia virus, is not lysed by human complement. Nevertheless, HIV-1 activates complement via the classical pathway independent of antibody, and C3b deposition facilitates infection of complement receptor-bearing cells. Using gel exclusion chromatography on Sephacryl S-1000, purified virions were found to bind 125I-labeled C1q, but not 125I-labeled dimeric proenzyme C1s. Virions activated the C1 complex, reconstituted from C1q, proenzyme C1r, and 125I-labeled proenzyme C1s, to an extent comparable with that obtained with immunoglobulin G-ovalbumin immune complexes. To determine the activating viral component, recombinant viral proteins were used: in the solid phase, soluble gp41 (sgp41) (the outer membrane part of gp41, residues 539-684 of gp160) bound C1q, but not dimeric proenzyme C1s, while gp120 was ineffective. In the fluid phase, sgp41 activated the C1 complex in a dose- and time-dependent manner, more efficiently than aggregated Ig, but less efficiently than immune complexes. To localize the C1 activating site(s) in gp41, synthetic peptides (15-residue oligomers spanning amino acids 531-695 of gp160) were used. Peptides covering positions 591-605 and 601-620 and, to a lesser extent, positions 561-575, had both the ability to bind C1q and to induce C3 deposition. These data provide the first experimental evidence of a direct interaction between the C1 complex and HIV-1, and indicate that C1 binding and activation are mediated by specific sites in gp41.

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Selected References

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  1. Arlaud G. J., Sim R. B., Duplaa A. M., Colomb M. G. Differential elution of Clq, Clr and Cls from human Cl bound to immune aggregates. Use in the rapid purification of Cl subcomponents. Mol Immunol. 1979 Jul;16(7):445–450. doi: 10.1016/0161-5890(79)90069-5. [DOI] [PubMed] [Google Scholar]
  2. Arlaud G. J., Villiers C. L., Chesne S., Colomb M. G. Purified proenzyme C1r. Some characteristics of its activation and subsequent proteolytic cleavage. Biochim Biophys Acta. 1980 Nov 6;616(1):116–129. doi: 10.1016/0005-2744(80)90269-7. [DOI] [PubMed] [Google Scholar]
  3. Banapour B., Sernatinger J., Levy J. A. The AIDS-associated retrovirus is not sensitive to lysis or inactivation by human serum. Virology. 1986 Jul 15;152(1):268–271. doi: 10.1016/0042-6822(86)90392-2. [DOI] [PubMed] [Google Scholar]
  4. Bartholomew R. M., Esser A. F. Mechanism of antibody-independent activation of the first component of complement (Cl) on retrovirus membranes. Biochemistry. 1980 Jun 24;19(13):2847–2853. doi: 10.1021/bi00554a005. [DOI] [PubMed] [Google Scholar]
  5. Bartholomew R. M., Esser A. F., Müller-Eberhard H. J. Lysis of oncornaviruses by human serum. Isolation of the viral complement (C1) receptor and identification as p15E. J Exp Med. 1978 Mar 1;147(3):844–853. doi: 10.1084/jem.147.3.844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyer V., Desgranges C., Trabaud M. A., Fischer E., Kazatchkine M. D. 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 May 1;173(5):1151–1158. doi: 10.1084/jem.173.5.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cole J. L., Housley G. A., Jr, Dykman T. R., MacDermott R. P., Atkinson J. P. Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Proc Natl Acad Sci U S A. 1985 Feb;82(3):859–863. doi: 10.1073/pnas.82.3.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cooper N. R., Jensen F. C., Welsh R. M., Jr, Oldstone M. B. Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway. J Exp Med. 1976 Oct 1;144(4):970–984. doi: 10.1084/jem.144.4.970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooper N. R., Morrison D. C. Binding and activation of the first component of human complement by the lipid A region of lipopolysaccharides. J Immunol. 1978 Jun;120(6):1862–1868. [PubMed] [Google Scholar]
  10. Davis D., Chaudhri B., Stephens D. M., Carne C. A., Willers C., Lachmann P. J. The immunodominance of epitopes within the transmembrane protein (gp41) of human immunodeficiency virus type 1 may be determined by the host's previous exposure to similar epitopes on unrelated antigens. J Gen Virol. 1990 Sep;71(Pt 9):1975–1983. doi: 10.1099/0022-1317-71-9-1975. [DOI] [PubMed] [Google Scholar]
  11. Dierich M. P., Ebenbichler C. F., Hallfeldt P. H., Prodinger W. M., Fuchs D., Wachter H. Interaction of complement with HIV-1 and Candida albicans: molecular mechanisms and biological implications. Mol Immunol. 1990 Dec;27(12):1349–1353. doi: 10.1016/0161-5890(90)90042-x. [DOI] [PubMed] [Google Scholar]
  12. Duncan A. R., Winter G. The binding site for C1q on IgG. Nature. 1988 Apr 21;332(6166):738–740. doi: 10.1038/332738a0. [DOI] [PubMed] [Google Scholar]
  13. Freed E. O., Myers D. J., Risser R. Characterization of the fusion domain of the human immunodeficiency virus type 1 envelope glycoprotein gp41. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4650–4654. doi: 10.1073/pnas.87.12.4650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Friedman H. M., Cohen G. H., Eisenberg R. J., Seidel C. A., Cines D. B. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells. Nature. 1984 Jun 14;309(5969):633–635. doi: 10.1038/309633a0. [DOI] [PubMed] [Google Scholar]
  15. Gnann J. W., Jr, Nelson J. A., Oldstone M. B. Fine mapping of an immunodominant domain in the transmembrane glycoprotein of human immunodeficiency virus. J Virol. 1987 Aug;61(8):2639–2641. doi: 10.1128/jvi.61.8.2639-2641.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gras G. S., Dormont D. Antibody-dependent and antibody-independent complement-mediated enhancement of human immunodeficiency virus type 1 infection in a human, Epstein-Barr virus-transformed B-lymphocytic cell line. J Virol. 1991 Jan;65(1):541–545. doi: 10.1128/jvi.65.1.541-545.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Homsy J., Meyer M., Tateno M., Clarkson S., Levy J. A. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science. 1989 Jun 16;244(4910):1357–1360. doi: 10.1126/science.2786647. [DOI] [PubMed] [Google Scholar]
  18. Hoshino H., Tanaka H., Miwa M., Okada H. Human T-cell leukaemia virus is not lysed by human serum. 1984 Jul 26-Aug 1Nature. 310(5975):324–325. doi: 10.1038/310324a0. [DOI] [PubMed] [Google Scholar]
  19. Hosoi S., Borsos T., Dunlop N., Nara P. L. Heat-labile, complement-like factor(s) of animal sera prevent(s) HIV-1 infectivity in vitro. J Acquir Immune Defic Syndr. 1990;3(4):366–371. [PubMed] [Google Scholar]
  20. Jouault T., Chapuis F., Olivier R., Parravicini C., Bahraoui E., Gluckman J. C. HIV infection of monocytic cells: rôle of antibody-mediated virus binding to Fc-gamma receptors. AIDS. 1989 Mar;3(3):125–133. [PubMed] [Google Scholar]
  21. June R. A., Schade S. Z., Bankowski M. J., Kuhns M., McNamara A., Lint T. F., Landay A. L., Spear G. T. Complement and antibody mediate enhancement of HIV infection by increasing virus binding and provirus formation. AIDS. 1991 Mar;5(3):269–274. doi: 10.1097/00002030-199103000-00004. [DOI] [PubMed] [Google Scholar]
  22. Klasse P. J., Pipkorn R., Blomberg J. Presence of antibodies to a putatively immunosuppressive part of human immunodeficiency virus (HIV) envelope glycoprotein gp41 is strongly associated with health among HIV-positive subjects. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5225–5229. doi: 10.1073/pnas.85.14.5225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kotwal G. J., Moss B. Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins. Nature. 1988 Sep 8;335(6186):176–178. doi: 10.1038/335176a0. [DOI] [PubMed] [Google Scholar]
  24. Kowalski M., Potz J., Basiripour L., Dorfman T., Goh W. C., Terwilliger E., Dayton A., Rosen C., Haseltine W., Sodroski J. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science. 1987 Sep 11;237(4820):1351–1355. doi: 10.1126/science.3629244. [DOI] [PubMed] [Google Scholar]
  25. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  26. McKeating J. A., Griffiths P. D., Weiss R. A. HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature. 1990 Feb 15;343(6259):659–661. doi: 10.1038/343659a0. [DOI] [PubMed] [Google Scholar]
  27. McKeating J. A., McKnight A., Moore J. P. Differential loss of envelope glycoprotein gp120 from virions of human immunodeficiency virus type 1 isolates: effects on infectivity and neutralization. J Virol. 1991 Feb;65(2):852–860. doi: 10.1128/jvi.65.2.852-860.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Modrow S., Hahn B. H., Shaw G. M., Gallo R. C., Wong-Staal F., Wolf H. Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions. J Virol. 1987 Feb;61(2):570–578. doi: 10.1128/jvi.61.2.570-578.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mold C., Bradt B. M., Nemerow G. R., Cooper N. R. Activation of the alternative complement pathway by EBV and the viral envelope glycoprotein, gp350. J Immunol. 1988 Jun 1;140(11):3867–3874. [PubMed] [Google Scholar]
  30. Mold C., Bradt B. M., Nemerow G. R., Cooper N. R. Epstein-Barr virus regulates activation and processing of the third component of complement. J Exp Med. 1988 Sep 1;168(3):949–969. doi: 10.1084/jem.168.3.949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Montefiori D. C., Murphey-Corb M., Desrosiers R. C., Daniel M. D. Complement-mediated, infection-enhancing antibodies in plasma from vaccinated macaques before and after inoculation with live simian immunodeficiency virus. J Virol. 1990 Oct;64(10):5223–5225. doi: 10.1128/jvi.64.10.5223-5225.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Montefiori D. C., Robinson W. E., Jr, Hirsch V. M., Modliszewski A., Mitchell W. M., Johnson P. R. Antibody-dependent enhancement of simian immunodeficiency virus (SIV) infection in vitro by plasma from SIV-infected rhesus macaques. J Virol. 1990 Jan;64(1):113–119. doi: 10.1128/jvi.64.1.113-119.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Moore J. P., McKeating J. A., Norton W. A., Sattentau Q. J. Direct measurement of soluble CD4 binding to human immunodeficiency virus type 1 virions: gp120 dissociation and its implications for virus-cell binding and fusion reactions and their neutralization by soluble CD4. J Virol. 1991 Mar;65(3):1133–1140. doi: 10.1128/jvi.65.3.1133-1140.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Moore J. P., McKeating J. A., Weiss R. A., Sattentau Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science. 1990 Nov 23;250(4984):1139–1142. doi: 10.1126/science.2251501. [DOI] [PubMed] [Google Scholar]
  35. Nicholson-Weller A., Burge J., Fearon D. T., Weller P. F., Austen K. F. Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. J Immunol. 1982 Jul;129(1):184–189. [PubMed] [Google Scholar]
  36. Penefsky H. S. Reversible binding of Pi by beef heart mitochondrial adenosine triphosphatase. J Biol Chem. 1977 May 10;252(9):2891–2899. [PubMed] [Google Scholar]
  37. Pinter A., Honnen W. J., Tilley S. A., Bona C., Zaghouani H., Gorny M. K., Zolla-Pazner S. Oligomeric structure of gp41, the transmembrane protein of human immunodeficiency virus type 1. J Virol. 1989 Jun;63(6):2674–2679. doi: 10.1128/jvi.63.6.2674-2679.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ratner L., Haseltine W., Patarca R., Livak K. J., Starcich B., Josephs S. F., Doran E. R., Rafalski J. A., Whitehorn E. A., Baumeister K. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24;313(6000):277–284. doi: 10.1038/313277a0. [DOI] [PubMed] [Google Scholar]
  39. Reisinger E. C., Vogetseder W., Berzow D., Köfler D., Bitterlich G., Lehr H. A., Wachter H., Dierich M. P. Complement-mediated enhancement of HIV-1 infection of the monoblastoid cell line U937. AIDS. 1990 Oct;4(10):961–965. doi: 10.1097/00002030-199010000-00003. [DOI] [PubMed] [Google Scholar]
  40. Robinson W. E., Jr, Kawamura T., Gorny M. K., Lake D., Xu J. Y., Matsumoto Y., Sugano T., Masuho Y., Mitchell W. M., Hersh E. Human monoclonal antibodies to the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 enhance HIV-1 infection in vitro. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3185–3189. doi: 10.1073/pnas.87.8.3185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Robinson W. E., Jr, Kawamura T., Lake D., Masuho Y., Mitchell W. M., Hersh E. M. Antibodies to the primary immunodominant domain of human immunodeficiency virus type 1 (HIV-1) glycoprotein gp41 enhance HIV-1 infection in vitro. J Virol. 1990 Nov;64(11):5301–5305. doi: 10.1128/jvi.64.11.5301-5305.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Robinson W. E., Jr, Montefiori D. C., Mitchell W. M. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet. 1988 Apr 9;1(8589):790–794. doi: 10.1016/s0140-6736(88)91657-1. [DOI] [PubMed] [Google Scholar]
  43. Robinson W. E., Jr, Montefiori D. C., Mitchell W. M. Complement-mediated antibody-dependent enhancement of HIV-1 infection requires CD4 and complement receptors. Virology. 1990 Apr;175(2):600–604. doi: 10.1016/0042-6822(90)90449-2. [DOI] [PubMed] [Google Scholar]
  44. Sattentau Q. J., Moore J. P. Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J Exp Med. 1991 Aug 1;174(2):407–415. doi: 10.1084/jem.174.2.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schawaller M., Smith G. E., Skehel J. J., Wiley D. C. Studies with crosslinking reagents on the oligomeric structure of the env glycoprotein of HIV. Virology. 1989 Sep;172(1):367–369. doi: 10.1016/0042-6822(89)90142-6. [DOI] [PubMed] [Google Scholar]
  46. Soelder B. M., Reisinger E. C., Koefler D., Bitterlich G., Wachter H., Dierich M. P. Complement receptors: another port of entry for HIV. Lancet. 1989 Jul 29;2(8657):271–272. doi: 10.1016/s0140-6736(89)90452-2. [DOI] [PubMed] [Google Scholar]
  47. Sölder B. M., Schulz T. F., Hengster P., Löwer J., Larcher C., Bitterlich G., Kurth R., Wachter H., Dierich M. P. HIV and HIV-infected cells differentially activate the human complement system independent of antibody. Immunol Lett. 1989 Aug;22(2):135–145. doi: 10.1016/0165-2478(89)90180-6. [DOI] [PubMed] [Google Scholar]
  48. Takeda A., Tuazon C. U., Ennis F. A. Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry. Science. 1988 Oct 28;242(4878):580–583. doi: 10.1126/science.2972065. [DOI] [PubMed] [Google Scholar]
  49. Tenner A. J., Lesavre P. H., Cooper N. R. Purification and radiolabeling of human C1q. J Immunol. 1981 Aug;127(2):648–653. [PubMed] [Google Scholar]
  50. Thielens N. M., Aude C. A., Lacroix M. B., Gagnon J., Arlaud G. J. Ca2+ binding properties and Ca2(+)-dependent interactions of the isolated NH2-terminal alpha fragments of human complement proteases C1-r and C1-s. J Biol Chem. 1990 Aug 25;265(24):14469–14475. [PubMed] [Google Scholar]
  51. Tremblay M., Meloche S., Sekaly R. P., Wainberg M. A. Complement receptor 2 mediates enhancement of human immunodeficiency virus 1 infection in Epstein-Barr virus-carrying B cells. J Exp Med. 1990 May 1;171(5):1791–1796. doi: 10.1084/jem.171.5.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tóth F. D., Szabó B., Ujhelyi E., Pálóczi K., Horváth A., Füst G., Kiss J., Bánhegyi D., Hollán S. R. Neutralizing and complement-dependent enhancing antibodies in different stages of HIV infection. AIDS. 1991 Mar;5(3):263–268. doi: 10.1097/00002030-199103000-00003. [DOI] [PubMed] [Google Scholar]
  53. Welsh R. M., Jr, Cooper N. R., Jensen F. C., Oldstone M. B. Human serum lyses RNA tumour viruses. Nature. 1975 Oct 16;257(5527):612–614. doi: 10.1038/257612a0. [DOI] [PubMed] [Google Scholar]
  54. Welsh R. M., Jr, Jensen F. C., Cooper N. R., Oldstone M. B. Inactivation of lysis of oncornaviruses by human serum. Virology. 1976 Oct 15;74(2):432–440. doi: 10.1016/0042-6822(76)90349-4. [DOI] [PubMed] [Google Scholar]
  55. Wright J. K., Tschopp J., Jaton J. C., Engel J. Dimeric, trimeric and tetrameric complexes of immunoglobulin G fix complement. Biochem J. 1980 Jun 1;187(3):775–780. doi: 10.1042/bj1870775. [DOI] [PMC free article] [PubMed] [Google Scholar]

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