Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy
Open accessAbstract
Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not "silent," but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.
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A multitude of studies showed that defective HIV-1 genomes inside cells may still produce individual viral transcripts or proteins, which could be mistaken as indicators of a functional reservoir of infectious virus.
“Conversely, a multitude of studies showed that defective HIV-1 genomes inside cells may still produce individual viral transcripts or proteins, 33-35,55 which could be mistaken as indicators of a functional reservoir of infectious virus.”
From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [34]
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Defective HIV-1 proviruses produce viral proteins
Imamichi, H., Smith, M., Adelsberger, J. W., Izumi, T., Scrimieri, F., Sherman, B. T., Rehm, C. A., Imamichi, T., Pau, A., Catalfamo, M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917876117 · Cited by 251 · see citing works
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- Authors
- Imamichi, H., Dewar, R. L., Adelsberger, J. W., Rehm, C. A., O’Doherty, U., Paxinos, E. E., Fauci, A. S., & Lane, H. C.
- Affiliations
- National Institutes of Health (US)
- Leidos Biomedical Research Inc. (United States) (US)
- University of Pennsylvania (US)
- Pacific Biosciences (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-07-18
- Volume
- 113
- Issue
- 31
- Pages
- 8783-8788
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4978246
- OpenAlex
- W2480104137
- Cited by
- 344
- References
- 4
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 33 · 2023: 32 · 2022: 34 · 2021: 39 · 2020: 54 · 2019: 37 · 2018: 37 · 2017: 31 · 2016: 4
- FWCI
- 25.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (NIAID Intramural)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID Intramural)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- defective proviruses, fusion protein, HIV-1 pathogenesis, highly active antiretroviral therapy, immune activation, single genome amplification, pol, Env, Rev, NEF
- MeSH terms
- DNA, Viral, Humans, Leukocytes, Mononuclear, Proviruses, RNA, Viral, Viral Proteins, HIV-1, HIV Infections, Gene Expression Regulation, Viral, Anti-Retroviral Agents
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