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Sequence and Functional Variation in the HIV-1 Rev Regulatory Axis - PubMed

Sequence and Functional Variation in the HIV-1 Rev Regulatory Axis

Patrick E H Jackson et al. Curr HIV Res. 2020.

Abstract

Background: To complete its replication cycle, HIV-1 requires the nucleocytoplasmic export of intron-containing viral mRNAs. This process is ordinarily restricted by the cell, but HIV overcomes the block by means of a viral protein, Rev, and an RNA secondary structure found in all unspliced and incompletely spliced viral mRNAs called the Rev Response Element (RRE). In vivo activity of the Rev-RRE axis requires Rev binding to the RRE, oligomerization of Rev to form a competent ribonucleoprotein complex, and recruitment of cellular factors including Crm1 and RanGTP in order to export the targeted transcript. Sequence variability is observed among primary isolates in both Rev and the RRE, and the activity of both can be modulated through relatively small sequence changes. Primary isolates show differences in Rev-RRE activity and a few studies have found a correlation between lower Rev-RRE activity and slower progression of clinical disease. Lower Rev-RRE activity has also been associated with the evasion of cytotoxic T lymphocyte mediated killing.

Conclusion: The HIV-1 Rev-RRE regulatory axis is an understudied mechanism by which viral adaptation to diverse immune milieus may take place. There is evidence that this adaptation plays a role in HIV pathogenesis, particularly in immune evasion and latency, but further studies with larger sample sizes are warranted.

Keywords: HIV Rev; HIV Rev Response Element; HIV latency; HIV sequence variation; RNA splicing; post-transcriptional gene regulation..

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflicts of interest. P. E. H. J. was supported by grant K08AI136671 from the National Institutes of Health. Salary support for G.D. and D.R. was provided by the Myles H. Thaler Research Fund and Professorship at the University of Virginia. Salary support for M.-L. H. was provided by the Charles H. Ross Jr. Professorship at the University of Virginia. Research on HIV Rev in the laboratories of D.R. and M-L. H. was supported by grants CA206275 and AI134208 from the National Institutes of Health.

Figures

Figure 1.
Figure 1.

Schematic representation of Rev domain organization. Numbers correspond to amino acid position. N-term = N-terminal region, OD = oligomerization domain, L = linker, ARM = arginine rich motif, NES = nuclear export signal, C-term = C-terminal region. Adapted from [55] and used under a Creative Commons Attribution 4.0 International License (

http://creativecommons.org/licenses/by/4.0/

).

Figure 2.
Figure 2.

Two secondary structures of the “long” 351-nt NL4–3 RRE. A. The five stem-loop RRE structure. B. The four stem-loop structure. The region corresponding to the “short” 234-nt RRE and the primary and secondary Rev binding sites are indicated on both structures. Figure is modified from [63], originally published in Nucleic Acids Research from Oxford University Press.

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