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Understanding the mechanisms by which HIV-1 controllers maintain and eventually lose this ability would be highly valuable in HIV-1 cure or vaccine research. Previous work revealed the ability of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells isolated from HIV-1 controllers to suppress HIV-1 replication in matched CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and PBMCs\n                      <jats:italic>\n                        <jats:italic>ex vivo<\/jats:italic>\n                      <\/jats:italic>\n                      and suggested the loss of control may be tied to CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We explored whether CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion plays a role in the maintenance and loss of control by examining immune characteristics of HIV-1 persistent controllers and transient controllers who lost control within the duration of the study. Using flow cytometry, we analyzed exhaustion marker expression on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from HIV-1 controllers and determined that they maintain a unique exhaustion profile as compared to people without HIV-1 and HIV-1 standard progressors. The low level of T cell exhaustion seen in HIV-1 controllers was reversed when these individuals lost control and showed increased viral loads. Combinatorial immune checkpoint blockade targeting exhaustion markers was able to restore\n                      <jats:italic>\n                        <jats:italic>ex vivo<\/jats:italic>\n                      <\/jats:italic>\n                      control in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from former controllers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results suggest that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion compromises the ability to control viral replication in HIV-1 controllers. The character of exhaustion in response to HIV-1 and therapy is distinct in HIV-1 persistent controllers, transient controllers and standard progressors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0328706","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T17:24:53Z","timestamp":1756401893000},"page":"e0328706","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["HIV-1 controllers possess a unique CD8+ T cell activation phenotype and loss of control is associated with increased expression of exhaustion markers"],"prefix":"10.1371","volume":"20","author":[{"given":"Amber D.","family":"Jones","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Capriotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Van Duyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9158-6136","authenticated-orcid":true,"given":"Stephen","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-5768","authenticated-orcid":true,"given":"Zachary","family":"Klase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"issue":"1","key":"pone.0328706.ref001","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/j.1365-2796.2008.02043.x","article-title":"Immune dysregulation in human immunodeficiency virus infection: know it, fix it, prevent it?","volume":"265","author":"A Boasso","year":"2009","journal-title":"J Intern Med"},{"key":"pone.0328706.ref002","article-title":"The interactions of retroviruses and their hosts.","volume-title":"Retroviruses","author":"JM Coffin","year":"1997"},{"issue":"8","key":"pone.0328706.ref003","doi-asserted-by":"crossref","first-page":"678","DOI":"10.7326\/0003-4819-114-8-678","article-title":"NIH conference. 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