As discussed in Sections 714 and 716, activation of T cells by antigen induces activation and nuclear translocation of NFAT and NFκB; activation of effectormemory T cells by cytokines can also activate NFκB in the absence of antigen (Section 1112). Thus, in addition to antigendependent activation of HIV provirus transcription by NFAT and NFκB, provirus might be activated independently of Tcell receptor stimulation in memory CD4 T cells via NFκB alone, as it is in infected macrophages and dendritic cells. Binding of NFAT and NFκB initiates transcription of viral RNA by binding to promoters in the proviral LTR. The viral transcript is spliced in various ways to produce mRNAs for translation of viral proteins (see Fig. 13.26).
At least two of the viral proteins—Tat and Rev—serve to enhance production of the viral genome (see Fig. 13.30). Tat binds to a transcriptional activation region (TAR) in the 5ʹ LTR. This recruits cellular cyclin T1 and its partner, cyclindependent kinase 9 (CDK9), to form a complex that phosphorylates RNA polymerase and enhances its ability to generate fulllength transcripts of the viral genome. In this way, Tat provides a positive feedback circuit for amplification of productive viral replication. Rev is important for shuttling unspliced viral RNA transcripts out of the nucleus by binding to a specific viral RNA sequence, the Rev response element (RRE). Eukaryotic cells have mechanisms to prevent the export from the cell nucleus of incompletely spliced mRNA transcripts. This could pose a problem for the retrovirus, which is dependent on export of unspliced mRNA species that encode the full complement of viral proteins, as well as the viral RNA genome. While export of a fully spliced mRNA transcript that encodes Tat and Rev occurs early after viral infection by means of the normal host cellular mechanisms of mRNA export, the export of later, unspliced viral transcripts requires Rev to prevent their destruction by the host cell.