RNA Structure and packaging signals in the 5′ leader region of the human immunodeficiency virus Type 1 genome
Open accessAbstract
The leader region of the human immunodeficiency virus type 1 (HIV-1) genome has a highly folded structure, comprising at least two RNA stem-loops [the transactivation response (TAR) and poly(A) hairpins] near its 5′ end and four others (SL1 to SL4) downstream. Each of these stem-loops contributes to the function of the HIV-1 packaging signal, which efficiently targets genomic RNA into nascent virions. The central 140-base region of the leader, which includes the U5 and primer binding site (PBS) sequences, is also believed to adopt a complex structure, but the nature of this structure and its possible role in RNA packaging have not been extensively explored. Here we report a mutational analysis identifying at least three separate loci within the U5-PBS region which, when mutated, impair both HIV-1 packaging specificity and infectivity in a single-round proviral assay. In common with those of all previously described packaging signals in the leader, the function of one of these loci appeared to depend on secondary structure rather than on sequence alone. By contrast, the activity of the other two loci did not correlate with any predicted conformations. Moreover, unlike SL1 to SL4, the TAR, poly(A), and U5-PBS hairpins were not bound with high affinity by the nucleocapsid portion of the HIV-1 Gag protein in vitro, implying that they contribute to packaging through a mechanism distinct from that of SL1 to SL4. Our findings confirm the existence and importance of secondary structure around the PBS and demonstrate that functional packaging signals are distributed across the entire HIV-1 leader.
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Retroviral genome packaging is tightly coordinated with virus assembly, driven primarily by the Gag precursor polyprotein, which recognizes structural motifs within the 5′ UTR and adjacent gag sequences, collectively referred to as the packaging signal (Psi, Ψ).
“This process is tightly coordinated with virus assembly, driven primarily by the Gag precursor polyprotein, which recognizes structural motifs within the 5′ UTR and adjacent gag sequences, collectively referred to as the packaging signal (Psi, Ψ; Fig. 12)”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Clever et al. 2002
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Clever, J., Sassetti, C., & Parslow, T. G. (1995) · Journal of Virology · doi:10.1128/jvi.69.4.2101-2109.1995 · Cited by 307 · see citing works
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“These interactions are mediated by the nucleocapsid (NC) domain of Gag, which includes a pair of zinc fingers flanked by several basic amino acid residues (1, 19, 21, 37, 40) and which binds specifically to HIV-1 RNA sequences in vitro (3, 6, 8, 9, 16, 18, 20, 28, 38).”
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How retroviruses select their genomes
D'Souza, V., & Summers, M. F. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1210 · Cited by 339 · see citing works
Lever, A. M. L. (2007) · Advances in Pharmacology · doi:10.1016/s1054-3589(07)55001-5 · Cited by 103 · see citing works
Small-angle X-ray scattering-derived structure of the HIV-1 5′ UTR reveals 3D tRNA mimicry
Jones, C. P., Cantara, W. A., Olson, E. D., & Musier-Forsyth, K. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1319658111 · Cited by 71 · see citing works
Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
Jehad, M. A., Ali, L. M., Pillai, V. N., Prabhu, S. G., Mustafa, F., & Rizvi, T. A. (2026) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf066 · Cited by 5 · see citing works
Pillai, V. N., Ali, L. M., Prabhu, S. G., Krishnan, A., Tariq, S., Mustafa, F., & Rizvi, T. A. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e12892 · Cited by 4 · see citing works
- Authors
- Clever, J. L., Miranda, & Parslow, T. G.
- Affiliations
- University of California, San Francisco (US)
- Departments of Pathology and of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143-0511
- Corresponding author
- Parslow, Tristram G.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2002-12
- Volume
- 76
- Issue
- 23
- Pages
- 12381-12387
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC136901
- OpenAlex
- W2114156985
- Cited by
- 127
- References
- 4
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 13
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI37036, R01AI040317, AI-40317)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1, RNA secondary structure, RNA packaging signal, U5 region, primer binding site, stem-loop structure, viral infectivity, mutation analysis
- MeSH terms
- Base Sequence, Cell Line, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Recombinant Fusion Proteins, RNA, Viral, HIV-1, Genome, Viral, 5' Untranslated Regions
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