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Herein, the virologic properties of the HIV-1 capsid inhibitors VH4004280 (VH-280) and VH4011499 (VH-499), including potency, mechanisms of action, and resistance profiles, are described. VH-280 and VH-499 inhibited panels of HIV-1 laboratory strains and viruses containing capsid sequences from clinical isolates with half-maximal effective concentrations in the picomolar range. Time-of-addition experiments determined that the primary block to HIV-1 replication occurred after nuclear import and before integration; however, measurements of replication intermediates by quantitative polymerase chain reaction, Gag degradation, p24 release, and virion morphology by cryo-electron microscopy indicate that VH-280 and VH-499 also block nuclear import, total reverse transcript production, integration, virion assembly, and maturation.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      resistance selection identified Q67H, A105E, T107D\/N, and combinations of these substitutions as conferring 6- to &gt;5,000-fold reductions in susceptibility to both compounds. Certain resistance-associated mutations selected by other capsid inhibitors also reduced susceptibility. Overall, the preclinical virology profiles and other drug-like properties support the potential of VH-280 and VH-499 as long-acting agents for HIV-1 treatment and prevention.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00309-25","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:07:36Z","timestamp":1756901256000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8132-8520","authenticated-orcid":true,"given":"Chunfu","family":"Wang","sequence":"first","affiliation":[{"name":"Discovery Biology, ViiV Healthcare","place":["Branford, 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