The regulation of nuclear export by Rev has several important consequences for HIV growth and pathogenesis. In addition to ensuring the nuclear export of specific unspliced RNAs, it divides the viral infection into an early phase (in which Rev is translated from a fully spliced RNA and all of the intron-containing viral RNAs are retained in the nucleus and degraded) and a late phase (in which unspliced RNAs are exported due to Rev function). This timing helps the virus replicate by providing the gene products in roughly the order in which they are needed (Figure 7–63). Regulation by Rev and by Tat, the HIV protein that counteracts premature transcription termination (see p. 414), allows the virus to achieve latency, a condition in which the HIV genome has become integrated into the host-cell genome but the production of viral proteins has temporarily ceased.
Figure 7–62 The compact genome of HIV, the human AIDS virus. the positions of the nine hiv genes are shown in green. the red double line indicates a DnA copy of the viral genome that has become integrated into the host DnA (gray). note that the coding regions of many genes overlap, and that those of Tat and Rev are split by introns. the blue line at the bottom of the figure represents the pre-mrnA transcript of the viral DnA and shows the locations of all the possible splice sites (arrows). there are many alternative ways of splicing the viral transcript; for example, the Env mrnAs retain the intron that has been spliced out of the Tat and Rev mrnAs. the rev response element (rre) is indicated by a blue ball and stick. it is a 234-nucleotide-long stretch of rnA that folds into a defined structure; rev recognizes a particular hairpin within this larger structure.
the Gag gene codes for a protein that is cleaved into several smaller proteins that form the viral capsid. the Pol gene codes for a protein that is cleaved to produce reverse transcriptase (which transcribes rnA into DnA), as well as the integrase involved in integrating the viral genome (as double-stranded DnA) into the host genome. the Env gene codes for the envelope proteins (see figure 5–62). tat, rev, vif, vpr, vpu, and nef are small proteins with a variety of functions. for example, rev regulates nuclear export (see figure 7–63) and tat regulates the elongation of transcription across the integrated viral genome (see p. 414).
Figure 7–63 Regulation of nuclear export by the HIV Rev protein. (A) early in hiv infection, only the fully spliced rnAs (which contain the coding sequences for rev, tat, and nef) are exported from the nucleus and translated. (B) Once sufficient rev protein has accumulated and been transported into the nucleus, unspliced viral rnAs can be exported from the nucleus. Many of these rnAs are translated into protein, and the full-length transcripts are packaged into new viral particles.
If, after its initial entry into a host cell, conditions become unfavorable for viral transcription and replication, Rev and Tat are made at levels too low to promote transcription and export of unspliced RNA. This situation stalls the viral growth cycle until conditions improve, whereupon Rev and Tat levels increase, and the virus enters the replication cycle.
Some mrnAs Are localized to Specific regions of the Cytosol