Cited by 253HIV Research and TreatmentT-cell and Retrovirus StudiesHIV/AIDS drug development and treatment

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Defective HIV-1 proviruses produce viral proteins

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Imamichi, Hiromi, Smith, Mindy, Adelsberger, Joseph W., Izumi, Taisuke, Scrimieri, Francesca, Sherman, Brad T., Rehm, Catherine A., Imamichi, Tomozumi, Pau, Alice, Catalfamo, Marta, Fauci, Anthony S., Lane, H. Clifford·2020·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1917876117PMC PMC7035625

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Abstract

HIV-1 proviruses persist in the CD4 + T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as “defective” by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant “graveyard” of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4 + T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4 + T cells and T cell–cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

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Authors: Imamichi, H., Smith, M., Adelsberger, J. W., Izumi, T., Scrimieri, F., Sherman, B. T., Rehm, C. A., Imamichi, T., Pau, A., Catalfamo, M., Fauci, A. S., & Lane, H. C.
Affiliations: National Institutes of Health (US)
Frederick National Laboratory for Cancer Research (US)
Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC 20057
Corresponding author: Fauci, Anthony S.
Lane, H. Clifford
ORCID: Imamichi, Hiromi
Izumi, Taisuke
Sherman, Brad T.
Rehm, Catherine A.
Imamichi, Tomozumi
Pau, Alice
Fauci, Anthony S.
Lane, H. Clifford
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2020-02-06
Volume: 117
Issue: 7
Pages: 3704-3710
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1917876117
PMC: PMC7035625
OpenAlex: W3005267901
Cited by: 251
References: 46
Citations by year: 2026: 38 · 2025: 41 · 2024: 40 · 2023: 41 · 2022: 33 · 2021: 38 · 2020: 19
FWCI: 17.40
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases (N/A)
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: HIV-1 Gag protein, HIV-1 Nef, CD4+ T cells, highly active antiretroviral therapy, viral persistence, open reading frames, virus-like particles, innate immunity, persistent immune activation, HIV-1 eradication
MeSH terms: Humans, Leukocytes, Mononuclear, Male, Middle Aged, Proviruses, Viral Proteins, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections

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Defective HIV-1 proviruses produce viral proteins

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