Suppression of the human immunodeficiency virus long terminal repeat by CD8+ T cells is dependent on the NFAT-1 element.
CD8+ T lymphocytes of HIV-1 infected individuals produce a soluble factor that efficiently suppresses HIV-1 replication at the transcriptional level. We show here that the response of the HIV-1 long terminal repeat (LTR) to mitogenic or Tat-mediated activation is sensitive to the suppressive action of a Herpesvirus saimiri (HVS)-transformed CD8+ T cell clone from an HIV-infected individual and supernatants from CD8+ T cells of HIV-1-infected asymptomatic subjects (CD4+ > 350/microliters). Mutagenesis of NF kappa B or Sp-1 elements within the LTR resulted in no change in the ability of CD8+ T cell supernatants to inhibit Tat- or mitogen-mediated LTR transcription. However, the response to HIV-1 Tat by a LTR in which the interleukin (IL)-2 homology NFAT-1 region was mutated resulted in almost complete elimination of suppression by CD8+ T cells. This was not observed when the NFAT-1 mutant LTR was activated by mitogen. We have previously shown that gene expression directed by the HIV-1 NF kappa B elements is inhibited by CD8+ cell-derived supernatants (Copeland et al., AIDS Res Hum Retroviruses, 1995;11:1321-1326). Taken together, these observations suggest that mitogenic activation, mediated primarily through the NF kappa B enhancer, is susceptible to CD8-mediated inhibition, however, inhibition of Tat-mediated activation may rely upon a different pathway that is NFAT-1 dependent.
Copeland
K F
KF
Department of Pathology, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
McKay
P J
PJ
Rosenthal
K L
KL
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015756:Genes, tat; D015658:HIV Infections / Q000276:immunology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors