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Role of CD4 in the Penetration of Cells by HIV

  • J. S. McDougal
  • P. J. Maddon
  • G. Orloff
  • P. R. Clapham
  • A. G. Dalgleish
  • S. Jamal
  • R. A. Weiss
  • R. A. Axel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 300)

Abstract

Enveloped viruses penetrate host cells by two distinct. mechanisms: by direct fusion between viral and cell membrane or by receptor-mediated endocytosis. Though not mutually exclusive, it is likely that viruses use one pathway or the other, that one predominates, or even that both occur but only one results in successful infection in the sense that productive infection ensues. Stein et al.1 and McClure et al.2 have shown convincingly that the low pH environment of the endosome is not necessary for infection by HIV. This does not mean that endocytosis does not occur; it may be that HIV is endocytosed but the low pH environment is not required for access of viral material to the cytoplasm. Electron microscopic studies have not been particularly helpful, and one can find examples supporting either mechanism1,3. Favoring the direct fusion mechanism is the observation that HIV-infected cells fuse with uninfected CD4 cells at neutral pH. The membrane fusion or syncytia phenomenon requires interaction between CD4 and viral envelope glycoprotein gpl20 and its mechanism is likely analagous to infection by cell-free virus. However, the endocytosis mechanism has a certain natural appeal in that the CD4 molecule, the receptor for HIV, has been shown to be internalized in endosomes as a result of T cell activation by mitogen, antigen, or phorbol ester. This occurs as a consequence of protein kinase C (PKC) activation and is associated with phosphorylation of the cytoplasmic segment of CD44-7. Bedinger et al.8 and Maddon et al.7 have made CD4 constructs lacking the cytoplasmic segment of CD4 that are incapable of PKC-induced internalization. Cells expressing these mutant CD4 molecules can be readily infected with HIV 7,8. However, ligand binding may induce internalization of a receptor independent of mechanisms involving PKC-activated phosphorylation of the cytoplasmic segment of the receptor. The EGF receptor is a case in point. Mutations in the cytoplasmic segment of the EGF receptor rendering it unresponsive to PKC induced internalization do not affect ligand-induced internalization9.

Keywords

Phorbol Ester Infectivity Titer Penetration Event Natural Appeal Cyclic Nucleotide Dependent Protein Kinase 
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.

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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • J. S. McDougal
    • 1
    • 2
    • 3
    • 4
  • P. J. Maddon
    • 1
    • 2
    • 3
    • 4
  • G. Orloff
    • 1
    • 2
    • 3
    • 4
  • P. R. Clapham
    • 1
    • 2
    • 3
    • 4
  • A. G. Dalgleish
    • 1
    • 2
    • 3
    • 4
  • S. Jamal
    • 1
    • 2
    • 3
    • 4
  • R. A. Weiss
    • 1
    • 2
    • 3
    • 4
  • R. A. Axel
    • 1
    • 2
    • 3
    • 4
  1. 1.Immunology Branch, Division of Host Factors, Center for Infectious Diseases, Centers for Disease Control, Public Health ServiceU.S. Department of Health and Human ServicesAtlantaUSA
  2. 2.Department of Biochemistry and Molecular Biophysics and the Howard Hughes Medical Institute, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Chester Beatty LaboratoriesInstitute of Cancer ResearchLondonEngland
  4. 4.Clinical Research CentreNorthwick Park Hospital HarrowEngland

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