Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators

Gene expression profiling was used to explore the role of Nef in HIV. Nef i nduces a transcriptional program in T cells that is 97% identical to that o f anti-CD3 T cell activation. This program is inhibited in the presence of cyclosporin. A requirement for TCR zeta and ZAP-70 is demonstrated for form ation of the complete profile. Among eight factors particular to the anti-C DS activation profile are IL16 and YY1, negative regulators of HIV transcri ption. In contrast, Nef exclusively upregulates factors positively regulati ng HIV, including Tat-SF1, U1 SNRNP, and IRF-2. New genes associated with N ef include CDK9, the induction of which enhances Tat function. Thus, Nef ac ts as a master switch early in the viral life cycle, forcing an environment conducive to dynamic viral production.