TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MECHANISMS ARE INVOLVED IN THE ABSENCE OF CD4 SURFACE EXPRESSION IN 2 HIV-1 CHRONICALLY INFECTED T-CELL LINES

In vivo infection of human T cell lymphocytes by HIV-1 is mediated by the specific binding of the HIV-1 envelope glycoprotein gp120 to the T cell CD4 receptor. One of the post-infection events observed in vivo is the progressive loss of CD4+ T cells. One possible mechanism is the production of infected T cells which are lacking in surface expressio n of the CD4 receptor protein. We have analysed this possibility utili zing the two HIV-1 chronically-infected CD4- cell lines, 8E5 and ACH-2 , both of which are derived from a CD4+ parental strain (A3.01) after HIV-1 infection. In each cell (8E5 and ACH-2) the loss of CD4 surface expression was found to occur by different mechanisms. In ACH-2 cells, neither CD4 protein nor the 3 kb CD4 RNA transcript could be detected . However, treatment of ACH-2 cells with cycloheximide elicited produc tion of the 3 kb transcript suggesting the possibility for a repressor protein(s) to act at the level of transcription and/or stability of t he 3 kb mRNA. In contrast, in 8E5 cells the level of the 3 kb CD4 RNA was comparable with that found in the CD4+ A3.01 parental strain. Anal ysis of the 8E5 strain revealed the presence of a CD4-gp160 bimolecula r protein complex sequestered internally in the rough endoplasmic reti culum (RER). Finally, the protein tyrosine kinase p56lck, normally ass ociated with the cellular membrane, appeared to be linked to the RER a nd bound to the CD4-gp160 proteins. Hence in these two chronically inf ected T cells (ACH-2 and 8E5), derived from the same parental cell lin e, the lack of CD4 surface expression due either to limitations in CD4 mRNA accumulation or to impairment of CD4 protein trafficking emphasi zes the diversity and complexity of the retrovirus-host relationship.