Fig. 1. Proviral latency is the result of multiple restrictions on HIV expression. (A) Proviral latency is maintained, in part, by the action of several transcription factors that recruit HDACs and other complexes to the HIV-1 long-terminal repeat (LTR) promoter, which results in histone modifications within chromatin at the HIV promoter that limit the ability of RNA polymerase to initiate transcription. (B) Key cellular factors that are required for robust HIV transcription, such as NF-B or the P-TEFb-cyclin complex, are sequestered in resting CD4+ T cells by cellular regulatory complexes [inhibitor of nuclear factor B (IB) and HEXIM-7SK RNA, respectively). Release and mobilization of these factors is required for proviral expression. (C) When histone acetyltransferases (HATs) supercede the effect of HDACs, coactivators such as NF-B can recruit RNA polymerase (RNA Pol) complexes. Production of Tat allows the recruitment of P-TEFb, mediating an explosive increase in transcription and the escape of provirus from latency. (D) The initial wave of Tat production may be further restricted by inefficient export of multiple spliced HIV mRNAs, relieved upon cellular activation by enhanced expression of PTB. (E) Cellular miRNAs that bind HIV mRNAs may also restrict translation of early expressed HIV mRNAs and so reduce Tat production. CDK, cyclin-dependent kinase; CTD, C-terminal repeat domain; and CycT1, cyclin T1.