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Rev-Rev Response Element Activity Selection Bias at the HIV Transmission Bottleneck.

ABSTRACT: HIV is not efficiently transmitted between hosts, and selection of viral variants occurs during the process of sexual transmission. The factors that confer selective advantage at the transmission bottleneck remain incompletely understood. We explored whether differences in the Rev-Rev Response Element (RRE) regulatory axis of HIV affect transmission fitness, since functional variation in the Rev-RRE axis in different viral isolates has been shown to affect replication kinetics and relative expression of many HIV proteins. Single genome HIV sequences were identified from nine linked subject pairs near the time of female-to-male transmission. Using a rapid flow-cytometric assay, we found that the functional Rev-RRE activity varied significantly between isolates. Moreover, it was generally lower in recipients' viruses compared to the corresponding donor viruses. In six of nine transmission events, recipient virus Rev-RRE activity clustered at the extreme low end of the range of donor virus activity. Rev-RRE pair activity was an unpredictable product of component Rev and RRE activity variation. These data indicate selection pressure on the Rev-RRE axis during female-to-male sexual transmission. Variation in the activity of the Rev-RRE axis may permit viral adaptation to different fitness landscapes and could play an important role in HIV pathogenesis.

SUBMITTER: Jackson PEH

PROVIDER: S-EPMC10104022 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Rev-Rev Response Element Activity Selection Bias at the HIV Transmission Bottleneck.

Jackson Patrick E H PEH Holsey Jordan J Turse Lauren L Marie-Louise Hammarskjold H Rekosh David D

bioRxiv : the preprint server for biology 20230405

HIV is not efficiently transmitted between hosts, and selection of viral variants occurs during the process of sexual transmission. The factors that confer selective advantage at the transmission bottleneck remain incompletely understood. We explored whether differences in the Rev-Rev Response Element (RRE) regulatory axis of HIV affect transmission fitness, since functional variation in the Rev-RRE axis in different viral isolates has been shown to affect replication kinetics and relative expre ...[more]

PMID: 37066242

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Project description:The HIV-1 Rev response element (RRE) is a 351-base element in unspliced and partially spliced viral RNA; binding of the RRE by the viral Rev protein induces nuclear export of RRE-containing RNAs, as required for virus replication. It contains one long, imperfect double helix (domain I), one branched domain (domain II) containing a high-affinity Rev-binding site, and two or three additional domains. We previously reported that the RRE assumes an "A" shape in solution and suggested that the location of the Rev binding sites in domains I and II, opposite each other on the two legs of the A, is optimal for Rev binding and explains Rev's specificity for RRE-containing RNAs. Using small-angle X-ray scattering (SAXS) and a quantitative functional assay, we have now analyzed a panel of RRE mutants. All the results support the essential role of the A shape for RRE function. Moreover, they suggest that the distal portion of domain I and the three crowning domains all contribute to the maintenance of the A shape. Domains I and II are necessary and sufficient for substantial RRE function, provided they are joined by a flexible linker that allows the two domains to face each other.IMPORTANCE Retroviral replication requires that some of the viral RNAs transcribed in the cell nucleus be exported to the cytoplasm without being spliced. To achieve this, HIV-1 encodes a protein, Rev, which binds to a complex, highly structured element within viral RNA, the Rev response element (RRE), and escorts RRE-containing RNAs from the nucleus. We previously reported that the RRE is "A" shaped and suggested that this architecture, with the 2 legs opposite one another, can explain the specificity of Rev for the RRE. We have analyzed the functional contributions of individual RRE domains and now report that several domains contribute, with some redundancy, to maintenance of the overall RRE shape. The data strongly support the hypothesis that the opposed placement of the 2 legs is essential for RRE function.

Dataset Information

Rev-Rev Response Element Activity Selection Bias at the HIV Transmission Bottleneck.

Publications

Rev-Rev Response Element Activity Selection Bias at the HIV Transmission Bottleneck.

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