HIV-1 ASSOCIATED DOWN-MODULATION OF CD4 GENE-EXPRESSION IS DIFFERENTIALLY RESTRICTED IN LYMPHOCYTIC AND MONOCYTIC CELL-LINES

We previously demonstrated that chronic infection of a monocytic cell line (U-937) with human immunodeficiency virus type 1 (HIV-1) was not accompanied by down-modulation of CD4 transcription, unlike the situat ion with CD4(+) T lymphocyte lines. To better understand the refractor iness of monocytes to alterations in levels of CD4 mRNA, we treated HI V-IIIB chronically infected U-937 cells with phorbol myristate acetate (PMA), a known stimulus of HIV gene expression. Although PMA caused a significant increase in HIV mRNA levels that was sustained over 7 day s, no effect on CD4 transcript levels was noted. Clonal derivatives of HIV-IIIB-infected U-937 cells, which produced a variety of infectious and defective particles, were likewise not affected in ability to pro duce CD4 mRNA. To rule out the possibility that U-937 cells select out HIV-1 variants unable to modulate CD4 mRNB levels, we passaged infect ious virus from a U-937 clonal derivative (UHC1) onto different monocy tic and T lymphocytic cell lines. In monocytic cell lines (U-937, PLB- 985, THP-1), we observed an avirulent infection that did not affect CD 4 mRNA levels, whereas UHC1 infection of each of two T lymphocytic cel l lines (CEM-T4, Jurkat) caused both cytopathic replication and reduct ions in CD4 mRNA levels. In one case (Jurkat), variants expressing low CD4 mRNA may have emerged, because the outgrowth no longer expressed viral products. In the other case (CEM-T4), high expression of viral g enes was accompanied by CD4 mRNA downmodulation, suggesting either tha t low-CD4-expressing variants were selected that maintained viral gene expression or that CD4 gene expression was repressed by viral product s.