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HIV-2 exhibits lower viral loads and slower disease progression, and most patients remain long-term non-progressors. Differentiation is crucial for selecting appropriate viral load monitoring tests and avoiding ineffective antiretroviral treatments, particularly non-nucleoside reverse transcriptase inhibitors, and certain protease inhibitors that do not work against HIV-2. Increased PrEP use may result in new infections testing negative for viral markers. This study aims to identify circulating tRNA expression profiles that could serve as non-viral biomarkers to detect and differentiate HIV-2 from HIV-1 infections. An initial pilot study analyzed 88 tRNAs in plasma samples from HIV-1- (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 4) and HIV-2 (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 4)-infected individuals, plus four healthy controls, using a tRNA-based PCR array for target identification. Eighteen selected tRNAs were further analyzed in a larger independent group of samples: HIV-1 (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 20), HIV-2 (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 20), and healthy controls (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 20) for independent verification. A plasma tRNA diagnostic model was developed from these results and evaluated in 24 independent samples to detect and differentiate HIV-2 from HIV-1 infection. We identified a tRNA-based model (Model-II) containing six differentially expressed tRNAs (Leu-TAA, mt-Asp-GTC, mt-Ala-TGC, mt-Lys-TTT, mt-LeuT-AA, and Gly-CCC-1) that could detect HIV-2 infection and distinguish it from HIV-1 infection and healthy controls with 100% accuracy, sensitivity, and specificity. We also found that other blood-borne viruses such as HTLV, HBV, and HCV had no cross-reactivity with HIV-2, demonstrating that Model-II is specific for HIV-2 infection. This study establishes proof of concept for tRNA expression profiles as HIV diagnostic biomarkers. The tRNA-based Model-II represents a promising diagnostic tool for identifying HIV-2 infection and differentiating it from HIV-1.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>HIV-2 infection requires accurate differentiation from HIV-1 to guide appropriate antiretroviral therapy, as HIV-2 exhibits intrinsic resistance to non-nucleoside reverse transcriptase inhibitors and certain protease inhibitors. Current diagnostic challenges include the absence of FDA-approved HIV-2 RNA quantification assays and potential false-negative results in LEVI (low-level viremia with evolving viral infection) syndrome patients on pre-exposure prophylaxis (PrEP), in whom viral markers may be undetectable. We developed a novel diagnostic approach using circulating transfer RNA (tRNA) expression profiles as host-derived, non-viral biomarkers. Our six-tRNA panel (Model-II) achieved 100% accuracy, sensitivity, and specificity in detecting HIV-2 infection while distinguishing it from HIV-1 and other blood-borne viral infections (HTLV, HBV, and HCV). This represents the first tRNA-based diagnostic model for HIV, offering a promising complementary tool for early detection and accurate viral differentiation, particularly in clinical scenarios where traditional viral markers are absent or unreliable.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jcm.00378-26","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:00:37Z","timestamp":1788181237000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A novel biomarker signature based on circulating transfer RNA (tRNA) can detect and differentiate HIV-2 infection from HIV-1"],"prefix":"10.1128","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4056-4305","authenticated-orcid":false,"given":"Santanu","family":"Biswas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05hvrsg85","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration","place":["Silver Spring, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-5087","authenticated-orcid":true,"given":"David R.","family":"McGivern","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05hvrsg85","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration","place":["Silver Spring, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira K.","family":"Hewlett","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05hvrsg85","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration","place":["Silver Spring, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2658-1264","authenticated-orcid":false,"given":"Krishnakumar","family":"Devadas","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05hvrsg85","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration","place":["Silver Spring, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(18)30094-8"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6903a2"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1293.2011.00963.x"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3282f15637"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10111377"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00580"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(18)30254-6"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciq248"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1177\/135965350400900112"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-006-0008-6"},{"key":"e_1_3_5_12_2","unstructured":"Shah SS Fine SM Vail RM. 2023. 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