1887

Abstract

Increasing interest has been devoted to the role that monocyte–macrophages play in the pathogenesis of AIDS. The hypothesis of an involvement in AIDS pathogenesis of human/simian immunodeficiency virus (HIV/SIV) Nef also is currently under evaluation by many investigators. The original basis of this hypothesis came from evidence that monkeys infected with a -deleted SIV strain failed to develop simian AIDS. Here, we show that treatment of human monocyte-derived macrophages (MDM) with recombinant HIV-1 Nef protein (rNef) induces a strong inhibition of the replication of either macrophage (M-) or dual-tropic HIV-1 strains. Through cytofluorimetric analyses, we detected internalization of FITC-conjugated rNef in MDM as early as 6 h after treatment. Confocal microscope observations demonstrated that the intracellular distribution of internalized rNef was identical to that of endogenously produced Nef. Down-regulation of the CD4 HIV receptor detected upon rNef treatment of MDM suggested that the rNef-induced HIV inhibition occurred at the virus entry step. This deduction was strengthened by the observation that CD4-independent infection was totally insensitive to rNef treatment. The specificity of all observed effects was demonstrated by immunodepletion of rNef. Finally, we showed that the resistance to HIV replication induced by rNef treatment in MDM favours the spread of T-tropic over M-tropic HIV strains in doubly infected CD4 lymphocyte–MDM co-cultures. We propose that extracellular Nef contributes to AIDS pathogenesis by inducing resistance to M-tropic HIV replication in MDM, thereby facilitating the switching from M- to T-tropic HIV prevalence that correlates frequently with AIDS progression.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-12-2905
2000-12-01
2019-10-23
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/12/0812905a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-12-2905&mimeType=html&fmt=ahah

References

  1. Ablashi, D. V., Salahuddin, S. Z., Josephs, S. F., Imam, F., Lusso, P., Gallo, R. C., Hung, C., Lemp, J. & Markham, P. D. ( 1987; ). HBLV (or HHV-6) in human cell lines. Nature 329, 207.
    [Google Scholar]
  2. Adachi, A., Gendelman, H. E., Koenig, S., Folks, T., Willey, R., Rabson, A. & Martin, M. A. ( 1986; ). Production of acquired immunodeficiency syndrome associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. Journal of Virology 59, 284-291.
    [Google Scholar]
  3. Aiken, C. & Trono, D. ( 1995; ). Nef stimulates human immunodeficiency virus type 1 proviral DNA synthesis. Journal of Virology 69, 5048-5056.
    [Google Scholar]
  4. Aiken, C., Konner, J., Landau, N. R., Lenburg, E. & Trono, D. ( 1994; ). Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane proximal CD4 cytoplasmic domain. Cell 75, 853-864.
    [Google Scholar]
  5. Alkhatib, G., Combadiere, C., Broder, C. C., Feng, Y., Kennedy, P. E., Murphy, P. M. & Berger, E. A. ( 1996; ). CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955-1958.[CrossRef]
    [Google Scholar]
  6. Allan, J. S., Coligan, J. E., Lee, T., McLane, M. F., Kanki, P. J., Groopman, J. E. & Essex, M. ( 1985; ). A new HTLV-III/LAV encoded antigen detected by antibodies from AIDS patients. Science 230, 810-813.[CrossRef]
    [Google Scholar]
  7. Ameisen, J. C., Guy, B., Chamaret, S., Loche, M., Mouton, Y., Neyrinck, J. L., Khalife, J., Leprevost, C., Beaucaire, G., Boutillon, G., Gras-Masse, H., Maniez, M., Kieny, M. P., Laustriat, D., Berthier, A., Mach, B., Montaigner, L., Lecocq, J. P. & Capron, A. ( 1989; ). Antibodies to the Nef protein and to Nef peptides in HIV-1 infected seronegative individuals. AIDS Research and Human Retroviruses 5, 279-291.[CrossRef]
    [Google Scholar]
  8. Anderson, S. J., Lenburg, M., Landau, N. R. & Garcia, J. V. ( 1994; ). The cytoplasmic domain of CD4 is sufficient for its down-regulation from the cell surface by human immunodeficiency virus type 1 Nef. Journal of Virology 68, 3092-3101.
    [Google Scholar]
  9. Bahraoui, E., Yagello, M., Billaud, J. N., Sabatier, J. M., Guy, B., Muchmore, E., Girard, M. & Gluckman, J. C. ( 1990; ). Immunogenicity of the human immunodeficiency virus (HIV) recombinant nef gene product. Mapping of T-cell and B-cell epitopes in immunized chimpanzees. AIDS Research and Human Retroviruses 6, 1087-1098.[CrossRef]
    [Google Scholar]
  10. Baiocchi, M., Olivetta, E., Chelucci, C., Santarcangelo, A. C., Bona, R., d’Aloja, P., Testa, U., Komatsu, N., Verani, P. & Federico, M. ( 1997; ). Human immunodeficiency virus (HIV)-resistant CD4+ UT-7 megakaryocytic human cell line becomes highly HIV-1 and HIV-2 susceptible upon CXCR4 transfection: induction of cell differentiation by HIV-1 infection. Blood 89, 2670-2678.
    [Google Scholar]
  11. Bandres, J. C., Shaw, A. S. & Ratner, L. ( 1995; ). HIV-1 Nef protein downregulation of CD4 surface expression: relevance of the Lck binding domain of CD4. Virology 207, 338-341.[CrossRef]
    [Google Scholar]
  12. Brambilla, A., Turchetto, L., Gatti, A., Bovolenta, C., Veglia, F., Santagostino, E., Gringeri, A., Clementi, M., Poli, G., Bagnarelli, P. & Vicenzi, E. ( 1999; ). Defective nef alleles in a cohort of hemophiliacs with progressing and nonprogressing HIV-infection. Virology 259, 349-368.[CrossRef]
    [Google Scholar]
  13. Chelucci, C., Casella, I., Federico, M., Testa, U., Macioce, G., Pelosi, E., Guerriero, R., Mariani, G., Giampaolo, A., Hassan, H. J. & Peschle, C. ( 1999; ). Lineage-specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: correlation with susceptibility to T- and M-tropic HIV and chemokine-mediated HIV resistance. Blood 94, 1590-1600.
    [Google Scholar]
  14. Cheng-Mayer, C., Seto, D., Tateno, M. & Levy, J. A. ( 1988; ). Biologic features of HIV-1 that correlate with virulence in the host. Science 240, 80-82.[CrossRef]
    [Google Scholar]
  15. Choe, H., Farzan, M., Sun, Y., Sullivan, N., Rollins, B., Ponath, P. D., Wu, L., Mackay, C. R., La Rosa, G., Newman, W., Gerard, N., Gerard, C. & Sodroski, J. ( 1996; ). The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135-1148.[CrossRef]
    [Google Scholar]
  16. Chowers, M. Y., Spina, C. A., Kwoh, N. J., Fitch, D., Richman, D. & Guatelli, J. C. ( 1994; ). Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. Journal of Virology 68, 2906-2914.
    [Google Scholar]
  17. Cocchi, F., De Vico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C. & Lusso, P. ( 1995; ). Identification of RANTES, MIP-1α and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811-1815.[CrossRef]
    [Google Scholar]
  18. d’Aloja, P., Olivetta, E., Bona, R., Nappi, F., Pedacchia, D., Pugliese, K., Ferrari, G., Verani, P. & Federico, M. ( 1998; ). Gag, vif and nef genes contribute to the homologous viral interference induced by a nonproducer human immunodeficiency virus type 1 (HIV-1) variant: identification of novel HIV-1 inhibiting viral protein mutants. Journal of Virology 72, 4308-4319.
    [Google Scholar]
  19. Deacon, N. J., Tsykin, A., Solomon, A., Smith, K, Ludford-Menting, M., Hooker, D. J., McPhee, D. A., Greenway, A. L., Ellett, A. & Chattefield, C. ( 1995; ). Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270, 988-991.[CrossRef]
    [Google Scholar]
  20. Deng, H., Liu, R., Ellmeir, W., Choe, S., Unutmaz, D., Burkhart, M., Di Marzio, P., Marmon, S., Sutton, R. E., Hill, C. M., Davis, C. B., Peiper, S. C., Shall, T. J., Littman, D. R. & Landau, N. R. ( 1996; ). Identification of a major coreceptor for primary isolates of HIV-1. Nature 381, 661-666.[CrossRef]
    [Google Scholar]
  21. Dolei, A., Biolchini, A., Serra, C., Curreli, S., Gomes, E. & Dianzani, F. ( 1998; ). Increased replication of T-cell-tropic HIV strains and CXC-chemokine receptor-4 induction in T cells treated with macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES β-chemokines. AIDS 12, 183-190.[CrossRef]
    [Google Scholar]
  22. Dragic, T., Litwin, V., Allaway, G. P., Martin, S. R., Huang, Y., Nagashima, K. A., Cayanan, C., Maddon, P. J., Koup, R. A., Moore, J. P. & Paxton, W. A. ( 1996; ). HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667-673.[CrossRef]
    [Google Scholar]
  23. Fauci, A. S. ( 1996; ). Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529-534.[CrossRef]
    [Google Scholar]
  24. Federico, M., Taddeo, B., Carlini, F., Nappi, F., Verani, P. & Rossi, G. B. ( 1993; ). A recombinant retrovirus carrying a nonproducer human immunodeficiency virus (HIV) type 1 variant induces resistance to superinfecting HIV. Journal of General Virology 74, 2099-2110.[CrossRef]
    [Google Scholar]
  25. Feng, Y., Broden, C. C., Kennedy, P. E. & Berger, E. A. ( 1996; ). HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane G protein coupled receptor. Science 272, 872-877.[CrossRef]
    [Google Scholar]
  26. Fujii, Y., Otake, K., Tashiro, M. & Adachi, A. ( 1996; ). A soluble Nef antigen of HIV-1 is cytotoxic for human CD4+ T cells. FEBS Letters 393, 93-96.[CrossRef]
    [Google Scholar]
  27. Garcia, J. V. & Miller, A. D. ( 1991; ). Serine phosphorylation-independent downregulation of cell-surface CD4 by Nef. Nature 350, 508-511.[CrossRef]
    [Google Scholar]
  28. Gartner, S., Markovits, P., Markovitz, D. M., Kaplan, M. H., Gallo, R. C. & Popovic, P. ( 1986; ). The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215-219.[CrossRef]
    [Google Scholar]
  29. Greenberg, M. E., Iafrate, A. J. & Skowronski, J. ( 1998a; ). The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO Journal 17, 2777-2789.[CrossRef]
    [Google Scholar]
  30. Greenberg, M. E., Bronson, S., Lock, M., Neumann, M., Pavlakis, G. N. & Skowronski, J. ( 1998b; ). Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. EMBO Journal 16, 6964-6976.
    [Google Scholar]
  31. Greenway, A. L., McPhee, D. A., Grgacic, E., Hewish, D., Lucantoni, A., Macreadie, I. & Azad, A. ( 1994; ). Nef 27, but not the Nef 25 isoform of human immunodeficiency virus-type 1 pNL4-3 down-regulates surface CD4 and IL-2R expression in peripheral blood mononuclear cells and transformed T cells. Virology 198, 245-256.[CrossRef]
    [Google Scholar]
  32. Hanna, Z., Denis, G. K, Rebai, N., Guimond, N., Jothy, N. & Jolicoeur, N. ( 1998; ). Nef harbors a major determinant of pathogenicity for AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95, 163-175.[CrossRef]
    [Google Scholar]
  33. Hirsch, V. M., Sharkey, M. E., Brown, C. R., Brichacek, B., Goldstein, S., Wakefield, J., Byrum, R., Elkins, W. R., Hahn, B. H., Lifson, J. D. & Stevenson, M. ( 1998; ). Vpx is required for dissemination and pathogenesis of SIVsm PBj: evidence of macrophage-dependent viral amplification. Nature Medicine 4, 1401-1408.[CrossRef]
    [Google Scholar]
  34. Huang, Y., Zhang, L. & Ho, D. D. ( 1995; ). Characterization of the nef sequences in long-term survivors of human immunodeficiency virus type 1 infection. Journal of Virology 69, 93-100.
    [Google Scholar]
  35. Kestler, H. W., Ringler, D. J., Mori, K., Panicali, D. L., Sehgal, P. K., Daniel, M. D. & Desrosiers, R. C. ( 1991; ). Importance of the nef gene for the maintenance of high virus loads and for development of AIDS. Cell 65, 651-662.[CrossRef]
    [Google Scholar]
  36. Kinter, A., Catanzaro, A., Monaco, J., Ruiz, M., Justment, J., Moir, S., Arthos, J., Oliva, A., Ehler, L., Mizell, S., Jackson, R., Ostrowski, M., Hoxie, J., Offord, R. & Fauci, A. S. ( 1998; ). CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4+ T cells: role of signal transduction. Proceedings of the National Academy of Sciences, USA 95, 11880-11885.[CrossRef]
    [Google Scholar]
  37. Kirchoff, F., Greenough, T. C., Brettler, D. B., Sullivan, J. L. & Desrosiers, R. C. ( 1995; ). Absence of intact nef sequence in a long-term survivor with nonprogressive HIV-1 infection. New England Journal of Medicine 332, 228-232.[CrossRef]
    [Google Scholar]
  38. Koenig, S., Gendelman, H. E., Orenstein, J. M., Dal Canto, M. C., Pezeshkpour, G. H., Yungbluth, M., Janotta, F., Akasamit, A., Martin, M. A. & Fauci, A. S. ( 1986; ). Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233, 1089-1093.[CrossRef]
    [Google Scholar]
  39. Michael, N. L., Chang, G., d’Arcy, L. A., Tseng, C. J., Birx, D. L. & Sheppard, H. W. ( 1995; ). Functional characterization of human immunodeficiency virus type 1 nef genes in patients with divergent rates of disease progression. Journal of Virology 69, 6758-6769.
    [Google Scholar]
  40. Miller, M., Warmerdam, M. T., Gaston, I., Greene, W. C. & Feinberg, M. B. ( 1994; ). The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages. Journal of Experimental Medicine 179, 101-113.[CrossRef]
    [Google Scholar]
  41. Oberlin, E., Amara, A., Bachelerie, F., Bessia, C., Virelizier, J. L., Arenzana Seisdedos, F., Schwartz, O., Heard, J. M., Clark-Lewis, I., Leler, D., Loetscher, M., Baggiolini, M. & Moser, D. ( 1996; ). The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833-835.[CrossRef]
    [Google Scholar]
  42. Okada, H., Takei, R. & Tashiro, M. ( 1997; ). HIV-1 Nef protein-induced apoptotic cytolysis of a broad spectrum of uninfected human blood cells independently of CD95 (Fas). FEBS Letters 414, 603-606.[CrossRef]
    [Google Scholar]
  43. Piguet, V., Gu, F., Foti, M., Demaurex, N., Gruenberg, J., Carpentier, J. L. & Trono, D. ( 1999; ). Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of β-COP in endosomes. Cell 97, 63-73.[CrossRef]
    [Google Scholar]
  44. Rhee, S. S. & Marsh, J. W. ( 1994; ). Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4. Journal of Virology 68, 5156-5163.
    [Google Scholar]
  45. Schellekens, P. T., Tersmette, M., Roos, M. T., Keet, R. P., de Wolf, F., Coutinho, R. A. & Miedema, F. ( 1992; ). Biphasic rate of CD4+ cell count decline during progression to AIDS correlates with HIV-1 phenotype. AIDS 6, 665-669.[CrossRef]
    [Google Scholar]
  46. Schuitemaker, H., Koot, M., Koostra, N. A., Dercksen, M. W., de Goede, R. E., Steenwijk, R. P., Lange, J. M., Schattenkerk, J. K., Miedema, F. & Tersmette, M. ( 1992; ). Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytropic to T-cell-tropic virus population. Journal of Virology 66, 1354-1360.
    [Google Scholar]
  47. Schwartz, O., Maréchal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. ( 1996; ). Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Medicine 2, 338-342.[CrossRef]
    [Google Scholar]
  48. Spina, C. A., Kwoh, T. J., Chowers, M. Y., Guatelli, J. C. & Richman, D. D. ( 1994; ). The importance of Nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes. Journal of Experimental Medicine 179, 115-123.[CrossRef]
    [Google Scholar]
  49. Swingler, S., Mann, A., Jacquè, J. M., Brichaek, B., Sasseville, V. G., Williams, K., Lackner, A. A., Janoff, E. N., Wang, R., Fisher, D. & Stevenson, M. ( 1999; ). HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nature Medicine 5, 997-1003.[CrossRef]
    [Google Scholar]
  50. Tersmette, M., Lange, J. M., de Goede, R. E., de Wolf, E., Coutinho, R. A., Huisman, J. G., Goudsmith, J. & Miedema, F. ( 1989; ). Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet i, 983-985.
    [Google Scholar]
  51. Torres, B. A. & Johnson, H. M. ( 1994; ). Identification of an HIV-1 Nef peptide that binds to HLA class II antigens. Biochemical and Biophysical Research Communications 200, 1059-1065.[CrossRef]
    [Google Scholar]
  52. Tosini, F., Venanzi, S., Boschi, A. & Battaglia, P. A. ( 1998; ). The Uvp1 gene on the R46 plasmid encodes a resolvase that catalyzes site-specific resolution involving the 5′-conserved segment of the adjacent integron In 1. Molecular and General Genetics 258, 404-411.[CrossRef]
    [Google Scholar]
  53. Wigler, M., Sweet, R., Sim, G. K., Wold, B., Pellicer, A., Lacy, E., Maniatis, T., Silverstein, S. & Axel, R. ( 1979; ). Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell 16, 758-777.
    [Google Scholar]
  54. Yi, Y., Rana, S., Turner, J. D., Gaddis, N. & Collman, R. G. ( 1998; ). CXCR-4 is expressed by primary macrophages and supports CCR5-independent infection by dual-tropic but not T-tropic isolates of human immunodeficiency virus type 1. Journal of Virology 72, 772-777.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-81-12-2905
Loading
/content/journal/jgv/10.1099/0022-1317-81-12-2905
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error