{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:59:50Z","timestamp":1753891190034,"version":"3.41.2"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017035","name":"Center for AIDS Research, Johns Hopkins University","doi-asserted-by":"publisher","award":["3P30AI094189-13S2"],"award-info":[{"award-number":["3P30AI094189-13S2"]}],"id":[{"id":"10.13039\/100017035","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>HIV-1 alternative reading frame proteins (ARFPs) have been shown to elicit CD8+ T cell responses, but less is known about the recognition of these proteins by CD4+ T cells. In this study, we analyzed responses of CD8-depleted peripheral blood mononuclear cells from chronic progressors (CPs) on suppressive antiretroviral therapy to ARFP peptide pools derived from HIV Gag, polymerase (Pol), and envelope (Env) proteins. Memory CD4+ T cell responses were detected to Gag ARFP peptide pools in 7 out of 13 CPs and to Env ARFP peptide pools in 2 out of 13 CPs. Individual peptide stimulation identified immunogenic peptides that were predicted to bind to major histocompatibility complex class II (MHC-II) proteins. HIV RNA was detected in culture supernatants from 3 of 6 CPs following stimulation of CD4+ T cells with ARFP peptide pools. These findings demonstrate that ARFP-derived peptides elicit antigen-specific CD4+ T cell responses and may contribute to latency reversal. Our data expand the known HIV immunopeptidome and suggest that ARFPs may serve as potential targets for immune-based interventions.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1600132","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T05:25:25Z","timestamp":1747891525000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD4+ T cell recognition of HIV-1 alternate reading frame proteins"],"prefix":"10.3389","volume":"16","author":[{"given":"Joel","family":"Sop","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler P.","family":"Beckey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel N.","family":"Blankson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092060","article-title":"CD8 T cell response and evolutionary pressure to HIV-1 cryptic epitopes derived from antisense transcription","volume":"207","author":"Bansal","year":"2010","journal-title":"J Exp Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031869","article-title":"Identification of cryptic MHC I\u2013restricted epitopes encoded by HIV-1 alternative reading frames","volume":"199","author":"Cardinaud","year":"2004","journal-title":"J Exp Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1084\/jem.20091808","article-title":"Viral adaptation to immune selection pressure by HLA class I\u2013restricted CTL responses targeting epitopes in HIV frameshift sequences","volume":"207","author":"Berger","year":"2010","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1742-4690-6-8","article-title":"Mechanisms employed by retroviruses to exploit host factors for translational control of a complicated proteome","volume":"6","author":"Bolinger","year":"2009","journal-title":"Retrovirology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.042499-0","article-title":"Non-canonical translation in RNA viruses","volume":"93","author":"Firth","year":"2012","journal-title":"J Gen Virol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"3061","DOI":"10.1038\/s41467-020-16961-8","article-title":"High-throughput interrogation of programmed ribosomal frameshifting in human cells","volume":"11","author":"Mikl","year":"2020","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf3546","article-title":"Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome","volume":"372","author":"Bhatt","year":"2021","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1042\/BST0321081","article-title":"Programmed -1 ribosomal frameshifting in the SARS coronavirus","volume":"32","author":"Dos Ramos","year":"2004","journal-title":"Biochem Soc Trans"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1700255","DOI":"10.1002\/pmic.201700255","article-title":"Viral short ORFs and their possible functions","volume":"18","author":"Finkel","year":"2018","journal-title":"PROTEOMICS"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000048","article-title":"A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach","volume":"4","author":"Wang","year":"2008","journal-title":"PloS Comput Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1186\/1471-2105-11-568","article-title":"Peptide binding predictions for HLA DR, DP and DQ molecules","volume":"11","author":"Wang","year":"2010","journal-title":"BMC Bioinf"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01454-15","article-title":"Reactivation kinetics of HIV-1 and susceptibility of reactivated latently infected CD4+ T cells to HIV-1-specific CD8+ T cells","volume":"89","author":"Walker-Sperling","year":"2015","journal-title":"J Virol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70036","article-title":"Translation of the downstream ORF from bicistronic mRNAs by human cells: Impact of codon usage and splicing in the upstream ORF","volume":"34","author":"Paget-Bailly","year":"2025","journal-title":"Protein Sci Publ. 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