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| Content Provider | PubMed Central |
|---|---|
| Author | Schnittman, S. M. Denning, S. M. Greenhouse, J. J. Justement, J. S. Baseler, M. Kurtzberg, J. Haynes, B. F. Fauci, A. S. |
| Abstract | 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. |
| Starting Page | 7727 |
| File Format | |
| ISSN | 10916490 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 19 |
| Volume Number | 87 |
| Language | English |
| Publisher Date | 1990-10-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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