Effects of HIV-1 and HIV-1 Envelope Glycoproteins on Signaling Pathways in Human T Lymphocytes

  • Sudhir Gupta


HIV-1 infection is unique with regard to immune responses, in which there is evidence for immune paradox, i. e., both immune activation and immune suppression. Immune stimulation is evident by elevated levels of various cytokines and hyperimmunoglobulinemia, whereas immune suppression is associated with quantitative and qualitative deficiency of T cells, especially of CD4+ T cells (reviewed in Fauci, 1988). It appears that HIV-1 or its envelope glycoproteins (gp160, gp120) can induce these paradoxical changes by various mechanisms, including blocking CD4-major histocompatibility complex (MHC) class II interaction and by altering signal transduction pathway. In this chapter, I will review the role of HIV-1 and its glycoproteins in activation and downregulation of signaling pathways in human T cells.


Human Immunodeficiency Virus Human Immunodeficiency Virus Type Tyrosine Phosphorylation Protein Tyrosine Kinase Envelope Glycoprotein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Banda, N. K., Bernier, J., Kurahara, D. K., Kurrle, R., Haigwood, N., Sekaly, R.-P, and Finkel, T. H., 1992, Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis, J. Exp. hied. 176:1099–1106.CrossRefGoogle Scholar
  2. Cayota, A. E., Vuiller, R., Siliciano, J., and Dighiero, G., 1994, Defective protein tyrosine phosphorylation and altered levels of p59fyn and p56lck in CD4 T cells from HIV-1-infected patients, Int. Immunol 6:611–621.PubMedCrossRefGoogle Scholar
  3. Cefai, D., Debre, P., Kaczorek, M., Idziorek, T., Autran, B., and Bismuth, G., 1990, Human immunodeficiency virus 1 glycoprotein gp120 and gp160 specifically inhibit the CD3/T cell antigen receptor phosphoinositol pathway, J. Clin. Invest. 86:2117–2124.PubMedCrossRefGoogle Scholar
  4. Cefai, D., Ferrer, M., Serpente, N., Idziorek, T., Dautry-Varsat, A., Debre, P., and Bismuth, G., 1992, Internalization of HIV glycoprotein gp120 is associated with down-modulation of membrane CD4 p56lck, J. Immunol. 149:285–294.PubMedGoogle Scholar
  5. Chirmule, N., Kalyanaraman, V., Oyaizu, N., and Pahwa, S., 1988, Inhibitory influences of envelope glycoproteins of HIV-1 on normal immune responses, J. AIDS 1:425–430.Google Scholar
  6. Chirmule, N., Kalyanaraman, V. S., Oyaizu, N., Slade, H. B., and Pahwa, S., 1990, Inhibition of functional properties of tetanus antigen-specific T-cell clones by envelope glycoprotein 120 of human immunodeficiency virus, Blood 75:152–159.PubMedGoogle Scholar
  7. Chirmule, N., Kalyanaraman, V. S., and Pahwa, S., 1994, Signal transduced through the CD4 molecule on T lymphocytes activate NF-kB, Biochem. Biophys. Res. Commun. 203:498–505.PubMedCrossRefGoogle Scholar
  8. Chirmule, N., Goonewardena, H., Pahwa, S., Pasieka, R., Kalyanaraman, V. S., and Pahwa, S., 1995, HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells, J. Biol. Chem. 270:19364–19369.PubMedCrossRefGoogle Scholar
  9. Cohen, D. I., Tani, Y., Tian, H., Boone, E., Samelson, L. E., and Lane, H. C., 1992, Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1, Science 256:542–545.PubMedCrossRefGoogle Scholar
  10. Corado, J., Mazerolles, F., LeDeist, F., Barbat, C., Kaczorek, M., and Fischer, A., 1991, Inhibition of CD4+ T cell activation and adhesion by peptides derived from the gp160, J. Immunol. 147:475–482.PubMedGoogle Scholar
  11. Diamond, D. C., Sleckman, B. P., Gregory, T., Lasky, L. A., Greenstein, J. L., and Burakoff, S. J., 1988, Inhibition of CD(+) T cell function by the HIV envelope protein gp120, J. Immunol 141:3715–3717.PubMedGoogle Scholar
  12. Fauci, A. S., 1988, The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis, Science 239:617–623.PubMedCrossRefGoogle Scholar
  13. Fields, A. P., Bednarik, D. P., Hess, A., and May, W. S., 1988, Human immunodeficiency virus induces phosphorylation of its cell surface receptor, Nature 333:278–280.PubMedCrossRefGoogle Scholar
  14. Gaulton, G. N., Brass, L. F., Kozbor, D., Pletcher, C. H., and Hoxie, J. A., 1992, Inhibition of T cell antigen receptor-dependent phosphorylation of CD4 in human immunodeficiency virus type 1 infected cells, J. Biol. Chem. 267:4102–4109.PubMedGoogle Scholar
  15. Goldman, F., Jensen, W. A., Johnson, G. L., Heasley, L., and Cambier, J. C., 1994, gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation, J. Immunol. 153:2905–2917.PubMedGoogle Scholar
  16. Gupta, S., 1993, Signal transduction defect in the acquired immunodeficiency syndrome and AIDS-related complex, Thymus 22:83–90.PubMedGoogle Scholar
  17. Gupta, S., and Vayuvegula, B., 1987, Human immunodeficiency virus-associated changes in signal transduction, J. Clin. Immunol. 7:486–489.PubMedCrossRefGoogle Scholar
  18. Gupta, S., Aggarwal, S., Kim, C., and Gollapudi, S., 1994, Human immunodeficiency virus-1 gp120 induces changes in protein kinase C isozymes—A preliminary report, Int. J. Immunopharmacol. 16:197–204.PubMedCrossRefGoogle Scholar
  19. Hivroz, C., Mazerolles, F., Soula, M., Fagard, R., Graton, S., Meloche, S., Sekaly, R.-R, and Fischer, A., 1993, Human immunodeficiency virus gp120 and derived peptides activate protein tyrosine kinase p56lck in human CD4 T lymphocytes, Eur. J. Immunol. 23:600–607.PubMedCrossRefGoogle Scholar
  20. Horak, I. D., Popovic, M., Horak, E. M., Lucas, P. J., Gress, R. E., June, C. H., and Bolen, J. B., 1990, No T-cell tyrosine protein kinase signalling or calcium mobilization after CD4 association with HIV-1 or HIV-1 gp120, Nature 348:557–560.PubMedCrossRefGoogle Scholar
  21. Houlgatte, R., Scarmato, P., Marhomy, S. E., Martin, M., Ostankovitch, M., Lafosse, S., Vervisch, A., Auffray, C., and Tonneau, D. P., 1994, MHC class II antigens and the HIV envelope glycoprotein gp120 bind to the same face of CD4, J. Immunol. 152:4475–4488.PubMedGoogle Scholar
  22. Hoxie, J. A., Rackowski, J. L., Haggarty, B. S., and Gaulton, G. N., 1988, T4 endocytosis and phosphorylation induced by phorbol esters but not not by mitogen or HIV infection, J. Immunol. 140:786–795.PubMedGoogle Scholar
  23. Jabado, N., LeDeist, F., Fischer, A., and Hivroz, C., 1994, Interaction of HIV gp120 and anti-CD4 antibodies with CD4 molecule on human CD4+ T cells inhibits the binding activity of NFAT, NF-kB and AP-1, three nuclear factors regulating interleukin-2 gene enhancer activity, Eur. J. Immunol. 24:2646–2652.PubMedCrossRefGoogle Scholar
  24. June, C. H., Bluestone, J. A., Nadler, L. M., and Thompson, C. B., 1994, The B7 and CD28 receptor families, Immunol. Today 15:321–331.PubMedCrossRefGoogle Scholar
  25. Juszczak, R. J., Turchin, J., Truneh, A., Culp, J., and Kassis, S., 1991, Effect of human immunodeficiency virus gp120 glycoprotein on the association of the protein tyrosine kinase p56lck with the CD4 on human T lymphocytes, J. Biol. Chem. 266:11176–11183.PubMedGoogle Scholar
  26. Kaufmann, R., Laroche, D., Buchner, K., Hucho, F., Rudd, C., Lindschau, P., Ludwig, A., Hoer, E., Oberdisse, E., Kopp, J., Körner, I. J., and Repke, H., 1992, The HIV-1 surface protein gp120 has no effect on transmembrane signal transduction, J. AIDS 15:760–770.Google Scholar
  27. Kornfeld, H., Cruickshank, W. W., Pyle, S., Berman, J. S., and Center, D. M., 1988, Lymphocyte activation by HIV-1 envelope glycoprotein, Nature 335:445–454.PubMedCrossRefGoogle Scholar
  28. Linette, G. P., Hartzman, R. J., Ledbetter, J. A., and June, C. H., 1988, HIV-1 infected T cells show a selective signaling defect after perturbation of CD3/antigen receptor, Science 241:573–576.PubMedCrossRefGoogle Scholar
  29. Weiss, A., and Littman, D. R., 1994, Signal transduction by lymphocyte antigen receptors, Cell 76:263–274.PubMedCrossRefGoogle Scholar
  30. Mann, D., Lasane, F., Popovic, M., Arthur, L. O., Robe, G. W., Blattner, W. A., and Newman, M. J., 1987, HTLV III large envelope glycoprotein (gp120) suppresses PHA-induced lymphocyte blastogenesis, J. Immunol. 138:2640–2644.PubMedGoogle Scholar
  31. Mittler, R. S., and Hoffman, M. K., 1988, Synergism between HIV gp120 and gp120-specific antibody in blocking human T cell activation, Science 245:1380–1382.CrossRefGoogle Scholar
  32. Neudorf, S. M. L., Jones, M. M., McCarthy, B. M., Harmony, J. A. K., and Choi, E. M., 1990, The CD4 molecule transmits biochemical information important in the regulation of T lymphocyte activity. Cell Immunol. 125:301–314.PubMedCrossRefGoogle Scholar
  33. Nye, K. E., and Pinching, A. J., 1990, HIV infection of H9 lymphoblastoid cells chronically activates the inositol polyphosphate pathway, AIDS 4:41–45.PubMedCrossRefGoogle Scholar
  34. Nye, K. E., Riley, G. A., and Pinching, A. J., 1992, The defect seen in the PI hydrolysis pathway in HIV infected lymphocytes and lymphoblastoid cells is due to inhibition of the 1,4,5 triphosphate, 1,3,4,5 tetrakisphosphate and 5-phosphomonoesterase, Clin. Exp. Immunol. 89:89–93.PubMedCrossRefGoogle Scholar
  35. Orloff, G. M., Kennedy, M. S., Dawson, C., and McDougal, J. S., 1991, HIV-1 binding to CD4 T cells does not induce a Ca++ influx or lead to activation of protein kinases, AIDS Res. Hum. Retrovir. 7:587–593.PubMedCrossRefGoogle Scholar
  36. Oyaizu, N., Chirmule, N., Kalyanaraman, V S., Hall, W. W., Good, R. A., and Pahwa, S., 1990, Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA, Proc. Natl. Acad. Sci. USA 87:2379–2383.PubMedCrossRefGoogle Scholar
  37. Prasad, K. V. S., Kapeller, R., Janssen, O., Duke-Cohan, J. S., Cantley, L. C., and Rudd, C. E., 1993, Phosphatidylinositol (PI) 3-kinase binding to the CD4-p56lck complex: The p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase, Mol. Cell. Biol. 13:7708–7717.PubMedGoogle Scholar
  38. Rudd, C. E., Janssen, O., Cai, Y.-C., de Silva, A. J., Raab, M., and Prasad, K. V. S., 1994, Two step TCRζ/CD3-CD4 and CD28 signaling in T cells: SH2/SH3 domains, protein-tyrosine and lipid kinases, Immunol. Today 15:225–234.PubMedCrossRefGoogle Scholar
  39. Ryu, S. E., Kwong, P. D., Truneh, A., Porter, T. G., Arthos, J., Rosenberg, M., Dai, X., Xuong, N. H., Axel, R., Sweet, R. W., and Hendrickson, W. A., 1990, Crystal structure of an HIV-binding recombinant fragment of human CD4, Nature 348:419–426.PubMedCrossRefGoogle Scholar
  40. Selvey, L. A., Morse, H. C., III, June, C. H., and Hodes, R. J., 1995, Analysis of antigen receptor signaling in B cells from mice with retrovirus-induced acquired immunodeficiency syndrome, J. Immunol. 154:171–179.PubMedGoogle Scholar
  41. Shalaby, M. R., Krowka, J. R., Gregory, T. J., Hirabayashi, S. E., McCabe, S. M., Kaufman, D. S., Stites, D. P., and Ammann, A. J., 1987, The effects of human immunodeficiency virus recombinant envelope glycoprotein on immune cell functions in vitro, Cell Immunol. 110:140–148.PubMedCrossRefGoogle Scholar
  42. Shin, J., Doyle, C., Yang, Z., Kappes, D., Strominger, J. L., 1990, Structural features of the cytoplasmic region of CD4 required for internalization, EMBO J. 9:425–434.PubMedGoogle Scholar
  43. Soula, M., Fagard, R., and Fischer, S., 1992, Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity, Int. Immunol. 4:295–299.PubMedCrossRefGoogle Scholar
  44. Wang, J., Yan, Y., Garrett, T. R J., Liu, J., Rogers, D. W., Garlick, R. L., Tarr, G. E., Husain, Y., Reinherz, E. L., and Harrison, S. C., 1990, Atomic structure of a fragment of human CD4 containing two immunoglobulin-like-domains, Nature 348:411–418.PubMedCrossRefGoogle Scholar
  45. Weinhold, K. J., Lyerly, H. K., Stanley, H. D., Austin, A. A., Matthews, T. J., and Bolognesi, D. P., 1989, HIV-1 gp120-mediated immune suppression and lymphocyte destruction in the absence of viral infection, J. Immunol 142:3091–3097.PubMedGoogle Scholar
  46. Yoshida, H., Kaga, K., Moroi, Y., Kimura, G., and Momoto, K., 1992, The effect of p56lck, a lymphocyte-specific protein tyrosine kinase on syncytium formation by HIV envelope glycoprotein, Int. Immunol. 4:233–242.PubMedCrossRefGoogle Scholar
  47. Zauli, G., Furlini, G., Vitale, M., Re, M. C., Gibellini, D., Zamai, L., and Visani, G., 1994, CD4 engagement by HIV-1 in TF-1 hematopoietic progenitor cells increases protein kinase C activity and reduces intracellular Ca++ levels, Microbiologica 17:85–92.PubMedGoogle Scholar
  48. Zorn, N. E., Weill, C. L., and Russell, D. H., 1990, The HIV protein GP120 activates nuclear protein kinase C in nuclei from lymphocytes and brain. Biochem. Biophys. Res. Commun. 166:1133–1139.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Sudhir Gupta
    • 1
  1. 1.Division of Basic and Clinical ImmunologyUniversity of CaliforniaIrvineUSA

Personalised recommendations