{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:27:13Z","timestamp":1773289633456,"version":"3.50.1"},"reference-count":91,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI150457, R56 AI145498, and R21AI154963"],"award-info":[{"award-number":["R01AI150457, R56 AI145498, and R21AI154963"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Prosetta Biosciences","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The concerning increase in HIV-1 resistance argues for prioritizing the development of host-targeting antiviral drugs because such drugs can offer high genetic barriers to the selection of drug-resistant viral variants. Targeting host proteins could also yield drugs that act on viral life cycle events that have proven elusive to inhibition, such as intracellular events of HIV-1 immature capsid assembly. Here, we review small molecule inhibitors identified primarily through HIV-1 self-assembly screens and describe how all act either narrowly post-entry or broadly on early and late events of the HIV-1 life cycle. We propose that a different screening approach could identify compounds that specifically inhibit HIV-1 Gag assembly, as was observed when a potent rabies virus inhibitor was identified using a host-catalyzed rabies assembly screen. As an example of this possibility, we discuss an antiretroviral small molecule recently identified using a screen that recapitulates the host-catalyzed HIV-1 capsid assembly pathway. This chemotype potently blocks HIV-1 replication in T cells by specifically inhibiting immature HIV-1 capsid assembly but fails to select for resistant viral variants over 37 passages, suggesting a host protein target. Development of such small molecules could yield novel host-targeting antiretroviral drugs and provide insight into chronic diseases resulting from dysregulation of host machinery targeted by these drugs.<\/jats:p>","DOI":"10.3390\/v13030451","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T20:51:42Z","timestamp":1615409502000},"page":"451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs\u2014First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor"],"prefix":"10.3390","volume":"13","author":[{"given":"Jaisri R.","family":"Lingappa","sequence":"first","affiliation":[{"name":"Department of Global Health, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishwanath R.","family":"Lingappa","sequence":"additional","affiliation":[{"name":"Prosetta Biosciences, 670 5th Street, San Francisco, CA 94107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan C.","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Global Health, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"ref_1","unstructured":"UNAIDS (2021, January 19). 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