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Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.

Publication ,  Journal Article
Schnittman, SM; Denning, SM; Greenhouse, JJ; Justement, JS; Baseler, M; Kurtzberg, J; Haynes, BF; Fauci, AS
Published in: Proc Natl Acad Sci U S A
October 1990

Individuals infected by the human immunodeficiency virus type 1 (HIV-1) demonstrate progressive depletion and qualitative dysfunction of the helper T4 (CD4+) cell population. Mechanisms proposed for attrition of CD4+ T cells include direct cytopathicity of these mature cells following infection as well as infection of early T-lymphocyte progenitors. The latter mechanism could lead to failure to regenerate mature functioning CD4+ T cells. The present study determines the susceptibility of thymocytes at various stages of maturity to infection with HIV-1. Various normal thymocyte populations were inoculated with HIV-1, including unfractionated (UF), CD3- CD4- CD8- ["triple negative" (TN)], CD4+ CD8+ ["double positive" (DP)] thymocytes, and thymocyte populations obtained by limited dilution cloning. Cultures were studied for the presence of HIV-1 DNA by polymerase chain reaction in addition to examination for reverse transcriptase activity. We determined that transformed T-cell and thymocyte cell lines completely lacking CD4 were not susceptible to infection by HIV-1, whereas all of the following lines were: UF thymocytes (70-90% CD4hi+); DP thymocytes (99% CD4hi+); TN thymocytes (0% CD4hi+); and TCR alpha beta +, TCR gamma delta +, or CD16+ CD3- (natural killer) thymocyte clones expressing variable levels of CD4 and representing the progeny of TN thymocytes. [TCR alpha beta + and TCR gamma delta + refer to the chains of the T-cell antigen receptor (TCR), and CD4hi refers to a strong rightward shift (greater than 30 linear channels) of the CD4 curve on flow cytometric analysis compared with control.] Monoclonal antibodies (mAbs) to CD4 (T4a epitope) but not to CD3 (T3) were capable of blocking infection of mature and immature CD4hi+ thymocytes. Moreover, anti-CD4(T4a) mAbs also inhibited infection of CD4hi- TN thymocytes, indicating that these T-cell precursors--despite their apparent "triple negativity" (CD3- CD4hi- CD8-)--expressed sufficient CD4 molecules to become infected. Cell sorter analysis with a panel of CD4 mAbs demonstrated a mean shift of the mean fluorescence channel (MFC) with CD4 mAbs on TN thymocytes of 6 +/- 4 MFC units. Thus, intrathymic T-cell precursors and their progeny representing many stages of T-cell ontogeny are susceptible to infection by HIV-1, including early TN thymocytes, which express very low levels of CD4. Infection of multiple stages and multiple subsets of the T-cell lineage in man, mediated via the CD4 molecule, may explain the inability of the T-cell pool to regenerate in the setting of progressive HIV infection.

Duke Scholars

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 1990

Volume

87

Issue

19

Start / End Page

7727 / 7731

Location

United States

Related Subject Headings

  • Thymus Gland
  • T-Lymphocytes
  • Receptors, Antigen, T-Cell
  • Phenotype
  • Lymphocyte Depletion
  • Humans
  • HIV-1
  • HIV Seropositivity
  • Flow Cytometry
  • Clone Cells
 

Citation

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Schnittman, S. M., Denning, S. M., Greenhouse, J. J., Justement, J. S., Baseler, M., Kurtzberg, J., … Fauci, A. S. (1990). Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion. Proc Natl Acad Sci U S A, 87(19), 7727–7731. https://doi.org/10.1073/pnas.87.19.7727
Schnittman, S. M., S. M. Denning, J. J. Greenhouse, J. S. Justement, M. Baseler, J. Kurtzberg, B. F. Haynes, and A. S. Fauci. “Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.Proc Natl Acad Sci U S A 87, no. 19 (October 1990): 7727–31. https://doi.org/10.1073/pnas.87.19.7727.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 1990

Volume

87

Issue

19

Start / End Page

7727 / 7731

Location

United States

Related Subject Headings

  • Thymus Gland
  • T-Lymphocytes
  • Receptors, Antigen, T-Cell
  • Phenotype
  • Lymphocyte Depletion
  • Humans
  • HIV-1
  • HIV Seropositivity
  • Flow Cytometry
  • Clone Cells