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Here, we identified a characteristic RSSL tetrapeptide deletion in the gp41 region of CRF01_AE Cluster 4 strains. Compared with a Cluster 5 control strain (GX-C5), the RSSL-deficient mutant GX-C4 exhibited a higher replication peak in MT-4 cells, outcompeted the GX-C5 control in co-culture, and showed significantly enhanced infectivity in TZM-bl and MT-2 cells, accompanied by increased fusion activity but no difference in viral attachment. GX-C4 also showed reduced susceptibility to the fusion inhibitor Enfuvirtide (T20), with a 1.67-fold increase in IC\n                      <jats:sub>50<\/jats:sub>\n                      , and displayed even greater resistance to LP-98 (a novel and potent fusion inhibitor), with an approximately 12-fold increase in IC\n                      <jats:sub>50<\/jats:sub>\n                      . Further experiments revealed that RSSL mutation does not upregulate intracellular Env expression but significantly enhances Env incorporation into virions. Transcriptomic analysis identified 61 strain-specific differentially expressed genes between GX-C4- and GX-C5-infected groups, which were enriched in pathways related to muscle cytoskeleton regulation and motor protein function. The myosin gene\n                      <jats:italic toggle=\"yes\">MYH4<\/jats:italic>\n                      was significantly downregulated in GX-C4-infected cells, and the expression of the key immune molecule\n                      <jats:italic toggle=\"yes\">TICAM2<\/jats:italic>\n                      was also suppressed. The differential expression of these genes in host cells may further contribute to the differences in viral pathogenicity. Collectively, RSSL deletion significantly enhances viral pathogenic characteristics and reduces drug susceptibility, likely by promoting cytoskeletal rearrangement, and enhancing membrane fusion. These findings provide important theoretical insights into the differential pathogenicity of HIV-1 CRF01_AE Clusters 4 and 5.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study identifies the RSSL tetrapeptide deletion in the gp41 region as a key molecular signature of CRF01_AE Cluster 4 strains and demonstrates its central role in enhancing viral replication capacity and resistance to fusion inhibitors through modulation of viral fusion efficiency. Notably, the RSSL-deleted strain exhibited up to 12-fold increased resistance to the clinical fusion inhibitor LP-98, suggesting that this deletion may impact therapeutic efficacy. Transcriptomic analysis further reveals enrichment in cytoskeletal pathways, the significant downregulation of\n                        <jats:italic toggle=\"yes\">MYH4<\/jats:italic>\n                        offering potential new targets for antiviral intervention. These findings provide a critical scientific basis for understanding the molecular evolution of CRF01_AE clusters, informing epidemic surveillance, and optimizing treatment strategies.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01158-26","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:00:31Z","timestamp":1791205231000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A four-amino-acid deletion in gp41 enhances HIV-1 CRF01_AE Cluster 4 pathogenicity and fusion inhibitor resistance"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1224-1663","authenticated-orcid":true,"given":"Dong","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"NHC Key Laboratory of Human Disease 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