When a ribosome translates the HIV-1 frameshift region, it encounters the frameshift stimulatory signal and makes a pause, its decoding center covering the slippery sequence (39) (40) (41) . During the pause, the ribosome can shift or not the reading frame, and, after the pause, the ribosome unfolds the frameshift stimulatory signal and translation continues. If the upstream ribosome reaches the frameshift region before the signal has refolded, the probability that the frameshift occurs is extremely weak. The spacing between ribosomes translating the HIV-1 frameshift region, which is determined by the rate of translation initiation [basal rate estimated to about one initiation event every 6.5 s (42)], could thus affect the frameshift efficiency. Therefore, if we assume an average elongation speed of five amino acids per second per ribosome, corresponding to a displacement of 15 nt per second on the mRNA (42) , the minimal distance between the decoding centers of two ribosomes translating a mRNA would be of about 100 nt. A ribosome covers about 32 nt on the mRNA and heel-printing studies showed that the first base of the P-site codon is at a distance of 12 nt from the 5 0 edge of the ribosome and of 20 nt from the 3 0 edge (43) . From these calculations, there would be about 70 exposed nt between two elongating ribosomes. Thus, the HIV-1 frameshift region, including the 43-nt frameshift stimulatory signal, would be exposed after the passage of the first ribosome. The signal would then re-form, which takes only a few microseconds (44), before the upstream ribosome reaches the region of the mRNA containing the sequence of this signal. However, the pause made by the first ribosome when encountering the signal decreases the distance with the following ribosome, which has continued to progress during the pause of the first ribosome. This second ribosome could reach the region corresponding to the stimulatory signal before this signal could refold, being still partially covered by the first ribosome. A pause of about three seconds for the first ribosome is sufficient to prevent the refolding of the stimulatory signal. The second ribosome would thus avoid frameshifting and the spacing between this ribosome and the third ribosome would not be altered. As a consequence, the third ribosome would encounter the stimulatory signal and pause, and frameshifting would be possible. This analysis shows that the signal affects every other ribosome under basal conditions. According to this model, an increase in the rate of translation initiation would decrease the frameshift efficiency, since ribosomes would be closer to each other and a smaller proportion of ribosomes would encounter the folded frameshift stimulatory signal. Conversely, a decrease in translation initiation would increase the frameshift efficiency since ribosomes would be further apart and it is very likely that each ribosome would encounter the folded signal. Interestingly, Lopinski et al. (38) , when studying the effect of a reduced translation initiation rate with the L-A virus in yeast cells, observed that the frameshift efficiency doubled, independently of the severity of the initiation defect. Their interpretation was that every other ribosome encounters the signal under basal conditions and that, with a reduced initiation rate, every ribosome encounters this signal. Our analysis fully supports this interpretation. Figure 6 . Changes in the rate of translation initiation influence the frameshift efficiency by modifying the spacing between elongating ribosomes. This model shows elongating ribosomes that reach the frameshift region and explains how the rate of translation initiation, which determines the spacing between these ribosomes, affects the frameshift efficiency (see the text). Note that a ribosome must encounter a folded frameshift stimulatory signal to make a frameshift, but this encounter does not ensure that frameshifting will occur.