Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1988 Dec 1;168(6):1953–1969. doi: 10.1084/jem.168.6.1953

Loss of CD4 membrane expression and CD4 mRNA during acute human immunodeficiency virus replication

PMCID: PMC2189155  PMID: 3264318

Abstract

Using mAbs and genomic probe to the CD4 molecule, the HIV receptor, we demonstrated that HIV replication induces the disappearance of its functional receptor from the cell surface by two distinct mechanisms. First, after being expressed onto the cell surface, HIV envelope gp110 will complex CD4, efficiently masking the CD4 epitope used by the virus to bind its receptor. This phenomenon occurs on the surface of each infected cell and is not due to the release of soluble gp110; infection with recombinant HIV/vaccinia viruses expressing a mutated HIV env gene designed to prevent gp110 release from the cell surface induces a similar gp/CD4 complexes formation. Second, virus replication induces a dramatic and rapid loss of CD4 mRNA transcripts, preventing new CD4 molecules from being synthesized. These two mechanisms of receptor modulation could have been developed to avoid reinfection of cells replicating the virus as well as to produce more infectious particles. These results suggest that the classical virus interference documented for other retroviruses might not only be due to receptor/envelope interaction, but might also depend on receptor gene expression.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alizon M., Sonigo P., Barré-Sinoussi F., Chermann J. C., Tiollais P., Montagnier L., Wain-Hobson S. Molecular cloning of lymphadenopathy-associated virus. Nature. 1984 Dec 20;312(5996):757–760. doi: 10.1038/312757a0. [DOI] [PubMed] [Google Scholar]
  2. Anilionis A., Wunner W. H., Curtis P. J. Structure of the glycoprotein gene in rabies virus. Nature. 1981 Nov 19;294(5838):275–278. doi: 10.1038/294275a0. [DOI] [PubMed] [Google Scholar]
  3. Asjö B., Ivhed I., Gidlund M., Fuerstenberg S., Fenyö E. M., Nilsson K., Wigzell H. Susceptibility to infection by the human immunodeficiency virus (HIV) correlates with T4 expression in a parental monocytoid cell line and its subclones. Virology. 1987 Apr;157(2):359–365. doi: 10.1016/0042-6822(87)90278-9. [DOI] [PubMed] [Google Scholar]
  4. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  5. Chakrabarti S., Robert-Guroff M., Wong-Staal F., Gallo R. C., Moss B. Expression of the HTLV-III envelope gene by a recombinant vaccinia virus. Nature. 1986 Apr 10;320(6062):535–537. doi: 10.1038/320535a0. [DOI] [PubMed] [Google Scholar]
  6. Clapham P. R., Weiss R. A., Dalgleish A. G., Exley M., Whitby D., Hogg N. Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: receptor modulation and differentiation induced by phorbol ester. Virology. 1987 May;158(1):44–51. doi: 10.1016/0042-6822(87)90236-4. [DOI] [PubMed] [Google Scholar]
  7. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  8. Guy B., Kieny M. P., Riviere Y., Le Peuch C., Dott K., Girard M., Montagnier L., Lecocq J. P. HIV F/3' orf encodes a phosphorylated GTP-binding protein resembling an oncogene product. Nature. 1987 Nov 19;330(6145):266–269. doi: 10.1038/330266a0. [DOI] [PubMed] [Google Scholar]
  9. Hoxie J. A., Alpers J. D., Rackowski J. L., Huebner K., Haggarty B. S., Cedarbaum A. J., Reed J. C. Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV. Science. 1986 Nov 28;234(4780):1123–1127. doi: 10.1126/science.3095925. [DOI] [PubMed] [Google Scholar]
  10. Hu S. L., Kosowski S. G., Dalrymple J. M. Expression of AIDS virus envelope gene in recombinant vaccinia viruses. Nature. 1986 Apr 10;320(6062):537–540. doi: 10.1038/320537a0. [DOI] [PubMed] [Google Scholar]
  11. Jones N., Leiden J., Dialynas D., Fraser J., Clabby M., Kishimoto T., Strominger J. L., Andrews D., Lane W., Woody J. Partial primary structure of the alpha and beta chains of human tumor T-cell receptors. Science. 1985 Jan 18;227(4684):311–314. doi: 10.1126/science.3871253. [DOI] [PubMed] [Google Scholar]
  12. Kieny M. P., Lathe R., Rivière Y., Dott K., Schmitt D., Girard M., Montagnier L., Lecocq J. Improved antigenicity of the HIV env protein by cleavage site removal. Protein Eng. 1988 Sep;2(3):219–225. doi: 10.1093/protein/2.3.219. [DOI] [PubMed] [Google Scholar]
  13. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  14. Lasky L. A., Nakamura G., Smith D. H., Fennie C., Shimasaki C., Patzer E., Berman P., Gregory T., Capon D. J. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell. 1987 Sep 11;50(6):975–985. doi: 10.1016/0092-8674(87)90524-1. [DOI] [PubMed] [Google Scholar]
  15. Lifson J. D., Feinberg M. B., Reyes G. R., Rabin L., Banapour B., Chakrabarti S., Moss B., Wong-Staal F., Steimer K. S., Engleman E. G. Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature. 1986 Oct 23;323(6090):725–728. doi: 10.1038/323725a0. [DOI] [PubMed] [Google Scholar]
  16. Littman D. R. The structure of the CD4 and CD8 genes. Annu Rev Immunol. 1987;5:561–584. doi: 10.1146/annurev.iy.05.040187.003021. [DOI] [PubMed] [Google Scholar]
  17. Lyerly H. K., Matthews T. J., Langlois A. J., Bolognesi D. P., Weinhold K. J. Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4601–4605. doi: 10.1073/pnas.84.13.4601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maddon P. J., Littman D. R., Godfrey M., Maddon D. E., Chess L., Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell. 1985 Aug;42(1):93–104. doi: 10.1016/s0092-8674(85)80105-7. [DOI] [PubMed] [Google Scholar]
  19. Mann D. L., Lasane F., Popovic M., Arthur L. O., Robey W. G., Blattner W. A., Newman M. J. HTLV-III large envelope protein (gp120) suppresses PHA-induced lymphocyte blastogenesis. J Immunol. 1987 Apr 15;138(8):2640–2644. [PubMed] [Google Scholar]
  20. McDougal J. S., Cort S. P., Kennedy M. S., Cabridilla C. D., Feorino P. M., Francis D. P., Hicks D., Kalyanaraman V. S., Martin L. S. Immunoassay for the detection and quantitation of infectious human retrovirus, lymphadenopathy-associated virus (LAV). J Immunol Methods. 1985 Jan 21;76(1):171–183. doi: 10.1016/0022-1759(85)90489-2. [DOI] [PubMed] [Google Scholar]
  21. McDougal J. S., Kennedy M. S., Sligh J. M., Cort S. P., Mawle A., Nicholson J. K. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science. 1986 Jan 24;231(4736):382–385. doi: 10.1126/science.3001934. [DOI] [PubMed] [Google Scholar]
  22. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  23. Montagnier L., Clavel F., Krust B., Chamaret S., Rey F., Barré-Sinoussi F., Chermann J. C. Identification and antigenicity of the major envelope glycoprotein of lymphadenopathy-associated virus. Virology. 1985 Jul 15;144(1):283–289. doi: 10.1016/0042-6822(85)90326-5. [DOI] [PubMed] [Google Scholar]
  24. Morimoto C., Letvin N. L., Boyd A. W., Hagan M., Brown H. M., Kornacki M. M., Schlossman S. F. The isolation and characterization of the human helper inducer T cell subset. J Immunol. 1985 Jun;134(6):3762–3769. [PubMed] [Google Scholar]
  25. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  26. Nicholson J. K., Cross G. D., Callaway C. S., McDougal J. S. In vitro infection of human monocytes with human T lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). J Immunol. 1986 Jul 1;137(1):323–329. [PubMed] [Google Scholar]
  27. Palese P., Tobita K., Ueda M., Compans R. W. Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology. 1974 Oct;61(2):397–410. doi: 10.1016/0042-6822(74)90276-1. [DOI] [PubMed] [Google Scholar]
  28. Peterson A., Seed B. Genetic analysis of monoclonal antibody and HIV binding sites on the human lymphocyte antigen CD4. Cell. 1988 Jul 1;54(1):65–72. doi: 10.1016/0092-8674(88)90180-8. [DOI] [PubMed] [Google Scholar]
  29. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Raulet D. H., Garman R. D., Saito H., Tonegawa S. Developmental regulation of T-cell receptor gene expression. Nature. 1985 Mar 7;314(6006):103–107. doi: 10.1038/314103a0. [DOI] [PubMed] [Google Scholar]
  31. Sattentau Q. J., Clapham P. R., Weiss R. A., Beverley P. C., Montagnier L., Alhalabi M. F., Gluckmann J. C., Klatzmann D. The human and simian immunodeficiency viruses HIV-1, HIV-2 and SIV interact with similar epitopes on their cellular receptor, the CD4 molecule. AIDS. 1988 Apr;2(2):101–105. doi: 10.1097/00002030-198804000-00005. [DOI] [PubMed] [Google Scholar]
  32. Sattentau Q. J., Dalgleish A. G., Weiss R. A., Beverley P. C. Epitopes of the CD4 antigen and HIV infection. Science. 1986 Nov 28;234(4780):1120–1123. doi: 10.1126/science.2430333. [DOI] [PubMed] [Google Scholar]
  33. Saunders A. M., Chang C. H. A new immune monitoring system for the determination of lymphoid cell subsets. Ann N Y Acad Sci. 1986;468:128–143. doi: 10.1111/j.1749-6632.1986.tb42035.x. [DOI] [PubMed] [Google Scholar]
  34. Schneider J., Kaaden O., Copeland T. D., Oroszlan S., Hunsmann G. Shedding and interspecies type sero-reactivity of the envelope glycopolypeptide gp120 of the human immunodeficiency virus. J Gen Virol. 1986 Nov;67(Pt 11):2533–2538. doi: 10.1099/0022-1317-67-11-2533. [DOI] [PubMed] [Google Scholar]
  35. Smith G. L., Mackett M., Moss B. Infectious vaccinia virus recombinants that express hepatitis B virus surface antigen. Nature. 1983 Apr 7;302(5908):490–495. doi: 10.1038/302490a0. [DOI] [PubMed] [Google Scholar]
  36. Sodroski J., Goh W. C., Rosen C., Campbell K., Haseltine W. A. Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. 1986 Jul 31-Aug 6Nature. 322(6078):470–474. doi: 10.1038/322470a0. [DOI] [PubMed] [Google Scholar]
  37. Stevenson M., Meier C., Mann A. M., Chapman N., Wasiak A. Envelope glycoprotein of HIV induces interference and cytolysis resistance in CD4+ cells: mechanism for persistence in AIDS. Cell. 1988 May 6;53(3):483–496. doi: 10.1016/0092-8674(88)90168-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stevenson M., Zhang X. H., Volsky D. J. Downregulation of cell surface molecules during noncytopathic infection of T cells with human immunodeficiency virus. J Virol. 1987 Dec;61(12):3741–3748. doi: 10.1128/jvi.61.12.3741-3748.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Thomas E. K., Weber J. N., McClure J., Clapham P. R., Singhal M. C., Shriver M. K., Weiss R. A. Neutralizing monoclonal antibodies to the AIDS virus. AIDS. 1988 Feb;2(1):25–29. doi: 10.1097/00002030-198802000-00004. [DOI] [PubMed] [Google Scholar]
  40. Toyonaga B., Yoshikai Y., Vadasz V., Chin B., Mak T. W. Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8624–8628. doi: 10.1073/pnas.82.24.8624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Veronese F. D., DeVico A. L., Copeland T. D., Oroszlan S., Gallo R. C., Sarngadharan M. G. Characterization of gp41 as the transmembrane protein coded by the HTLV-III/LAV envelope gene. Science. 1985 Sep 27;229(4720):1402–1405. doi: 10.1126/science.2994223. [DOI] [PubMed] [Google Scholar]
  42. Wain-Hobson S., Sonigo P., Danos O., Cole S., Alizon M. Nucleotide sequence of the AIDS virus, LAV. Cell. 1985 Jan;40(1):9–17. doi: 10.1016/0092-8674(85)90303-4. [DOI] [PubMed] [Google Scholar]
  43. Weis W., Brown J. H., Cusack S., Paulson J. C., Skehel J. J., Wiley D. C. Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature. 1988 Jun 2;333(6172):426–431. doi: 10.1038/333426a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES