Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2.
The role of Bcl-2, Bax, and Bcl-x in the apoptosis of T lymphocytes in HIV-infected individuals was investigated. A strong correlation between Bcl-2 downregulation and spontaneous apoptosis has been reported by various groups in short-term cultures of CD8+ but not of CD4+ T lymphocytes. We describe a similar correlation in CD4+ T cells and provide an explanation why Bcl-2 downregulation in these cells has not been detected so far. In apoptotic cells not only Bcl-2, but also the CD4 surface receptors, are downregulated, preventing the detection of these cells in flow cytometric analysis. In contrast to Bcl-2, no correlation is detectable between Bax or Bcl-x expression and apoptosis. T lymphocytes of HIV-infected, but not of control, individuals display ex vivo a heterogeneous Bcl-2 expression pattern with a low and a high Bcl-2-expressing lymphocyte fraction. The proportion of low Bcl-2-expressing T cells correlates with a higher viral load in these individuals. Antiretroviral therapy significantly reduces the proportion of low Bcl-2-expressing lymphocytes, which is associated with a decrease in apoptosis. Bcl-2 downregulation and spontaneous apoptosis of T lymphocytes from HIV-infected individuals can be partially prevented by the exogeneous addition of IL-2, but not of IL-12, IL-4, or antibodies that prevent the CD95/CD95 ligand pathway of apoptosis.
Regamey
N
N
Basel Center for HIV Research, Switzerland.
Harr
T
T
Battegay
M
M
Erb
P
P
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D015704:CD4 Antigens; D017320:HIV Protease Inhibitors; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018894:Reverse Transcriptase Inhibitors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; D018664:Interleukin-12; D015847:Interleukin-4