Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication

Tekeste, Shewit S.; Wilkinson, Thomas A.; Weiner, Ethan M.; Xu, Xiaowen; Miller, Jennifer T.; Le Grice, Stuart F. J.; Clubb, Robert T.; Chow, Samson A.

doi:10.1128/jvi.01471-15

Cited by 51HIV Research and TreatmentHIV/AIDS drug development and treatmentVirus-based gene therapy research

Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication

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Tekeste, Shewit S., Wilkinson, Thomas A., Weiner, Ethan M., Xu, Xiaowen, Miller, Jennifer T., Le Grice, Stuart F. J., Clubb, Robert T., Chow, Samson A.·2015·Journal of Virology

DOI 10.1128/jvi.01471-15PMC PMC4645309

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Abstract

Human immunodeficiency virus type 1 (HIV-1) replication requires reverse transcription of its RNA genome into a double-stranded cDNA copy, which is then integrated into the host cell chromosome. The essential steps of reverse transcription and integration are catalyzed by the viral enzymes reverse transcriptase (RT) and integrase (IN), respectively. In vitro , HIV-1 RT can bind with IN, and the C-terminal domain (CTD) of IN is necessary and sufficient for this binding. To better define the RT-IN interaction, we performed nuclear magnetic resonance (NMR) spectroscopy experiments to map a binding surface on the IN CTD in the presence of RT prebound to a duplex DNA construct that mimics the primer-binding site in the HIV-1 genome. To determine the biological significance of the RT-IN interaction during viral replication, we used the NMR chemical shift mapping information as a guide to introduce single amino acid substitutions of nine different residues on the putative RT-binding surface in the IN CTD. We found that six viral clones bearing such IN substitutions (R231E, W243E, G247E, A248E, V250E, and I251E) were noninfectious. Further analyses of the replication-defective IN mutants indicated that the block in replication took place specifically during early reverse transcription. The recombinant INs purified from these mutants, though retaining enzymatic activities, had diminished ability to bind RT in a cosedimentation assay. The results indicate that the RT-IN interaction is functionally relevant during the reverse transcription step of the HIV-1 life cycle. IMPORTANCE To establish a productive infection, human immunodeficiency virus type 1 (HIV-1) needs to reverse transcribe its RNA genome to create a double-stranded DNA copy and then integrate this viral DNA genome into the chromosome of the host cell. These two essential steps are catalyzed by the HIV-1 enzymes reverse transcriptase (RT) and integrase (IN), respectively. We have shown previously that IN physically interacts with RT, but the importance of this interaction during HIV-1 replication has not been fully characterized. In this study, we have established the biological significance of the HIV-1 RT-IN interaction during the viral life cycle by demonstrating that altering the RT-binding surface on IN disrupts both reverse transcription and viral replication. These findings contribute to our understanding of the RT-IN binding mechanism, as well as indicate that the RT-IN interaction can be exploited as a new antiviral drug target.

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NMR identified integrase CTD residues responsible for the integrase-RT interaction, and viruses with mutations at these positions have pronounced reverse transcription defects.
“Studies using nuclear magnetic resonance identified amino acid residues within the IN CTD responsible for the interaction, and viruses carrying mutations at these IN positions displayed pronounced defects in reverse transcription138.”
From Structure and function of retroviral integrase (2022) · cites this paper as [138]
Integrase may organize RNA within infectious particles, consistent with a proposed cofactor function during reverse transcription.
“These data suggest that IN may have a role in organising RNA within infectious particles, which is not inconsistent with the proposed co-factor function during reverse transcription138.”
From Structure and function of retroviral integrase (2022) · cites this paper as [138]

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Characterizing Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Integrase Interaction
Tekeste, S. S. (2014) · eScholarship (California Digital Library)
Self-citation
Specific HIV‐1 integrase‐reverse transcriptase interactions as a mechanism for promoting reverse transcription
Chow, S. A., Wilkinson, T. A., Zhang, M., Januszyk, K., Phillips, M. L., Grice, S. F. J. L., & Clubb, R. (2009) · The FASEB Journal · doi:10.1096/fasebj.23.1_supplement.501.1
Self-citation
Identifying and Characterizing a Functional HIV-1 Reverse Transcriptase-binding Site on Integrase
Wilkinson, T. A., Januszyk, K., Phillips, M. L., Tekeste, S. S., Zhang, M., Miller, J. T., Grice, S. F. J. L., Clubb, R., & Chow, S. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806241200 · Cited by 66 · see citing works
Self-citation
Interaction between Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Integrase Proteins
Hehl, E. A., Joshi, P., Kalpana, G. V., & Prasad, V. R. (2004) · Journal of Virology · doi:10.1128/jvi.78.10.5056-5067.2004 · Cited by 117 · see citing works
Requirement for Integrase during Reverse Transcription of Human Immunodeficiency Virus Type 1 and the Effect of Cysteine Mutations of Integrase on Its Interactions with Reverse Transcriptase
Zhu, K., Dobard, C., & Chow, S. A. (2004) · Journal of Virology · doi:10.1128/jvi.78.10.5045-5055.2004 · Cited by 171 · see citing works
Self-citation

Authors: Tekeste, S. S., Wilkinson, T. A., Weiner, E. M., Xu, X., Miller, J. T., Le Grice, S. F. J., Clubb, R. T., & Chow, S. A.
Affiliations: University of California, Los Angeles (US)
Frederick National Laboratory for Cancer Research (US)
Basic Research Laboratory, National Cancer Institute, Frederick, Maryland, USA
ORCID: Wilkinson, Thomas A.
Xu, Xiaowen
Clubb, Robert T.
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2015-12
Volume: 89
Issue: 23
Pages: 12058-12069
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.01471-15
PMC: PMC4645309
OpenAlex: W2220328959
Cited by: 51
References: 78
Citations by year: 2026: 4 · 2025: 12 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 1
FWCI: 2.53
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institutes of Health (1s10od016336-01a1)
National Institute of General Medical Sciences (T32GM008652, R01GM101416, NIH T32GM008652, GM101416)
National Institute of Allergy and Infectious Diseases (P30AI028697, R01AI052217)
Topics: Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords: HIV-1, reverse transcriptase, integrase, reverse transcription, protein-protein interaction, primer binding site, viral replication, integrase mutants, antiviral drug targets, HIV-1 life cycle, single amino acid substitution
MeSH terms: Escherichia coli, Protein Binding, Virus Replication, Blotting, Western, HIV-1, DNA Primers, HIV Integrase, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Substitution, Reverse Transcription, HIV Reverse Transcriptase, Real-Time Polymerase Chain Reaction

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Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication

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