Abstract
We have analyzed a SIV deletion mutant that was compromised both in viral replication and RNA packaging. Serial passage of this variant in two different T-cell lines resulted in compensatory reversion and the generation of independent groups of point mutations within each cell line. Within each group, single point mutations were shown to contribute to increased viral infectivity and the rescue of wild-type replication kinetics. The complete recovery of viral fitness ultimately correlated with the restoration of viral RNA packaging. Consistent with the latter finding was the rescue of Pr55 Gag processing, also restoring proper virus core morphology in mature virions. These seemingly independently arising groups of compensatory mutations were functionally interchangeable in regard to the recovery of wild type replication in rhesus PBMCs. These findings indicate that viral reversion that overcomes a genetic bottleneck is not limited to a single pathway, and illustrates the remarkable adaptability of lentiviruses.
Highlights
The packaging of full-length viral genomic RNA into primate lentiviruses is regulated by a multipartite cisacting signal located within the 5' untranslated region (UTR) or RNA-leader
The A423G point mutation plays an important role in the restoration of viral RNA packaging The SD2 variant (Δnt +398 to +418, Fig. 1) has been shown to package diminished levels of viral RNA in comparison with wild type SIVmac239[6,7]
To further investigate the mechanism(s) involved, seven different SD2 derivates were analyzed that contained all possible combinations of the three point mutations that had been identified in cell lines [7]
Summary
The packaging of full-length viral genomic RNA (vRNA) into primate lentiviruses is regulated by a multipartite cisacting signal located within the 5' untranslated region (UTR) or RNA-leader. In the leader of human immunodeficiency virus type-1 (HIV-1), the packaging signal or Psi (Ψ) is distributed across multiple RNA domains that include stem loop-1 (SL1), SL3 and SL4 [1,2,3]. Comparative packaging studies of simian immunodeficiency virus (SIV) by our group and of human immunodeficiency virus type-2 (HIV-2) by others, have assigned a primary role in packaging to SL1, as compared to all other regions within the SIV and HIV-2 genomes [6,7,8,9,10]. The relationships among the packaging events of different lentiviruses have been extensively studied [16]
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