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Down‐modulation of TCR/CD3 surface complexes after HIV‐1 infection is associated with differential expression of the viral regulatory genes

We have investigated the mechanism(s) involved in progressive abrogation of CD3‐γ gene expression after HIV‐1 or HIV‐2 infection. A comparison of intracellular virus expression with T cell receptor surface density, revealed both high and low levels of viral p24 antigen in the TCR/CD3hi, TCR/CD3lo, and TCR/CD3– cells. Furthermore, in non‐productively infected cells expressing the multiply spliced, virally encoded tat, rev, and nef regulatory gene transcripts, the same progressive loss of surface TCR/CD3 complexes was observed. We treated HIV‐1‐infected cells with antisense (AS) phosphorothioate oligodeoxynucleotides (P‐OdN) targeted to the viral regulatory genes. All of the HIV‐1 sequence‐specific AS‐P‐OdN′s inhibited intracellular p24 antigen expression in a time‐ and dose‐dependent manner; although, blocking p24 expression alone was not sufficient to modulate TCR/CD3 surface density. Only Tat‐AS and Nef‐AS were able to delay TCR/CD3 down‐modulation on receptor‐positive cells or drive receptor up‐regulation on receptor‐negative cells. In contrast, Rev‐AS accelerated TCR/CD3 loss on receptor‐positive cells. RT‐PCR revealed that Tat‐AS and Nef‐AS reduce the level of tat, nef, and rev transcripts, while Rev‐AS increases the level of tat and nef transcripts in infected cells. Thus, when intracellular conditions favor expression of tat and/or nef in the absence of rev, CD3‐γ gene transcripts and TCR/CD3 surface density are down‐modulated.