{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T19:35:42Z","timestamp":1783020942671,"version":"3.54.6"},"reference-count":49,"publisher":"Microbiology Society","issue":"7","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012728","name":"Frederick National Laboratory for Cancer Research","doi-asserted-by":"crossref","award":["HHSN261200800001E."],"award-info":[{"award-number":["HHSN261200800001E."]}],"id":[{"id":"10.13039\/100012728","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,2]]},"abstract":"<jats:p>\n                    We recently reported that GADD34, an integrated stress response (ISR)-associated protein expressed at low levels in many cell lines, functions as a novel HIV-1 restriction factor. To elucidate the mechanism underlying GADD34-mediated inhibition of HIV replication, we investigated the role of long non-coding RNAs (lncRNAs). Here, we identify and characterize a novel lncRNA, GRHAL1 (GADD34-regulated HIV accessory lncRNA-1), which is highly expressed in GADD34-knockout (GADD34-KO) cells relative to WT cells. GRHAL1 is expressed at low basal levels in Jurkat and MT-2 CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell lines and in primary human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and is upregulated following HIV-1 infection. T cell activation signals that promote HIV-1 replication also induced GRHAL1 expression; however, this induction was independent of IFN and ISR signalling. Transfection of\n                    <jats:italic>in vitro<\/jats:italic>\n                    \u2013 synthesized GRHAL1 significantly enhanced HIV-1 LTR-driven gene expression from both integrated and unintegrated promoters. GRHAL1 stimulated both Tat-independent and Tat-dependent LTR activation, with a more pronounced effect observed at suboptimal Tat levels, indicating functional synergy between GRHAL1 and Tat under limiting Tat conditions. Mutational analysis of the LTR demonstrated that GRHAL1-mediated activation requires an intact Tat-responsive TAR element and upstream Sp1-binding sites, linking GRHAL1 activity to Tat and Sp1 in transcriptional regulation. This synergy was further confirmed using a minimal HIV-1 promoter containing Sp1 sites and a TAR sequence. Moreover, GRHAL1 alone was sufficient to activate a heterologous promoter containing Sp1-binding elements. The Sp1-selective inhibitor mithramycin suppressed both Tat-independent LTR activation and the cooperative activation mediated by GRHAL1 and Tat. Electrophoretic mobility shift assays, RNA immunoprecipitation and RNA-pulldown experiments demonstrated that GRHAL1 directly interacts with Sp1 and that Tat enhances this interaction, suggesting that GRHAL1 modulates Sp1 activity through direct binding. In summary, we identify GRHAL1 as a novel HIV-1-induced lncRNA that regulates viral gene expression by interacting with Sp1 and synergizing with Tat to enhance HIV-1 transcription.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.002288","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T18:16:24Z","timestamp":1783016184000},"source":"Crossref","is-referenced-by-count":0,"title":["GRHAL1, a novel lncRNA, regulates HIV-1 gene expression by modulating Tat- and Sp1-mediated HIV-1 LTR activation"],"prefix":"10.1099","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4087-9772","authenticated-orcid":false,"given":"Mohammad","family":"Ishaq","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD, 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Marshall","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD, 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ven","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. 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