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The replication fates of these RNAs differ, with viral particles encapsidating almost exclusively\n                      <jats:sup>cap<\/jats:sup>\n                      1G RNAs and\n                      <jats:sup>cap<\/jats:sup>\n                      3G RNAs retained in cells where they are enriched on polysomes and among spliced viral RNAs. Here, we studied replication properties of virus promoter mutants that produced only one RNA 5\u2032 isoform or the other: separately, in combination, and during spreading infection. Results showed that either single-start RNA could serve as both mRNA and genomic RNA when present as the only form in cells, although\n                      <jats:sup>cap<\/jats:sup>\n                      3G RNA was more efficiently translated and spliced, while\n                      <jats:sup>cap<\/jats:sup>\n                      1G RNA was packaged into nascent virions slightly better than RNAs from the parental virus. When co-expressed from separate vectors,\n                      <jats:sup>cap<\/jats:sup>\n                      1G RNA was preferentially packaged into virions. During spreading infection, the\n                      <jats:sup>cap<\/jats:sup>\n                      1G-only virus displayed only minor defects, but the\n                      <jats:sup>cap<\/jats:sup>\n                      3G-only virus showed severe replication delays in both the highly permissive MT-4 cell line and in primary human CD4+ T cells. Passage of\n                      <jats:sup>cap<\/jats:sup>\n                      3G-only virus yielded revertants that replicated as well as the twinned (\n                      <jats:sup>cap<\/jats:sup>\n                      1G+\n                      <jats:sup>cap<\/jats:sup>\n                      3G) transcription start-site parent. These revertants displayed restored packaging and splicing levels and had regained multiple transcription start-site use.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>HIV-1 generates two RNAs during its replication that differ by only two nucleotides in length. Despite this very minor difference, the RNAs perform different and complementary replication functions. When mutants that expressed only one RNA were forced to revert, they regained functions associated with the second RNA.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.02139-24","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T09:00:36Z","timestamp":1741078836000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["HIV-1 single-transcription start-site mutants display complementary replication functions that are restored by reversion"],"prefix":"10.1128","volume":"99","author":[{"given":"K.","family":"GC","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Lesko","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Institute for Molecular Virology, & Carbone Cancer Center, University of Wisconsin","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Emery","sequence":"additional","affiliation":[{"name":"UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Burnett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Gopal","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Program, University of Michigan Medical School","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-0773","authenticated-orcid":true,"given":"R.","family":"Swanstrom","sequence":"additional","affiliation":[{"name":"UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, USA"]},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill","place":["Chapel Hill, USA"]},{"name":"UNC Center for AIDS Research, University of North Carolina at Chapel Hill","place":["Chapel Hill, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9974-236X","authenticated-orcid":true,"given":"N. 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