{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:36:58Z","timestamp":1792089418455,"version":"4.4.0"},"reference-count":140,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rega Virology and Chemotherapy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The enzyme reverse transcriptase (RT) plays a central role in the life cycle of human immunodeficiency virus (HIV), and RT has been an important drug target. Elucidations of the RT structures trapping and detailing the enzyme at various functional and conformational states by X-ray crystallography have been instrumental for understanding RT activities, inhibition, and drug resistance. The structures have contributed to anti-HIV drug development. Currently, two classes of RT inhibitors are in clinical use. These are nucleoside\/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, the error-prone viral replication generates variants that frequently develop resistance to the available drugs, thus warranting a continued effort to seek more effective treatment options. RT also provides multiple additional potential druggable sites. Recently, the use of single-particle cryogenic electron microscopy (cryo-EM) enabled obtaining structures of NNRTI-inhibited HIV-1 RT\/dsRNA initiation and RT\/dsDNA elongation complexes that were unsuccessful by X-ray crystallography. The cryo-EM platform for the structural study of RT has been established to aid drug design. In this article, we review the roles of structural biology in understanding and targeting HIV RT in the past three decades and the recent structural insights of RT, using cryo-EM.<\/jats:p>","DOI":"10.3390\/v14051027","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T23:08:36Z","timestamp":1652396916000},"page":"1027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9998-020X","authenticated-orcid":false,"given":"Abhimanyu K.","family":"Singh","sequence":"first","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"},{"name":"Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8897-324X","authenticated-orcid":false,"given":"Kalyan","family":"Das","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"},{"name":"Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/2261211a0","article-title":"RNA-dependent DNA polymerase in virions of Rous sarcoma virus","volume":"226","author":"Temin","year":"1970","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1038\/2261209a0","article-title":"RNA-dependent DNA polymerase in virions of RNA tumour viruses","volume":"226","author":"Baltimore","year":"1970","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/227561a0","article-title":"Central dogma of molecular biology","volume":"227","author":"Crick","year":"1970","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/228424a0","article-title":"A DNA-depenent DNA polymerase and a DNA endonuclease in virions of Rous sarcoma virus","volume":"228","author":"Mizutani","year":"1970","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0092-8674(79)90357-X","article-title":"A detailed model of reverse transcription and tests of crucial aspects","volume":"18","author":"Gilboa","year":"1979","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1073\/pnas.86.10.3539","article-title":"Ribonuclease H activities associated with viral reverse transcriptases are endonucleases","volume":"86","author":"Krug","year":"1989","journal-title":"Proc. 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