{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T06:19:27Z","timestamp":1770445167988,"version":"3.49.0"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"16","license":[{"start":{"date-parts":[[2016,8,15]],"date-time":"2016-08-15T00:00:00Z","timestamp":1471219200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["SERB\/F\/3630\/2014-15"],"award-info":[{"award-number":["SERB\/F\/3630\/2014-15"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/01CEIB\/10\/III\/01"],"award-info":[{"award-number":["BT\/01CEIB\/10\/III\/01"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,8,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Of the various genetic subtypes of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), only in subtype C of HIV-1 is a genetically variant NF-\u03baB binding site found at the core of the viral promoter in association with a subtype-specific Sp1III motif. How the subtype-associated variations in the core transcription factor binding sites (TFBS) influence gene expression from the viral promoter has not been examined previously. Using panels of infectious viral molecular clones, we demonstrate that subtype-specific NF-\u03baB and Sp1III motifs have evolved for optimal gene expression, and neither of the motifs can be replaced by a corresponding TFBS variant. The variant NF-\u03baB motif binds NF-\u03baB with an affinity 2-fold higher than that of the generic NF-\u03baB site. Importantly, in the context of an infectious virus, the subtype-specific Sp1III motif demonstrates a profound loss of function in association with the generic NF-\u03baB motif. An additional substitution of the Sp1III motif fully restores viral replication, suggesting that the subtype C-specific Sp1III has evolved to function with the variant, but not generic, NF-\u03baB motif. A change of only two base pairs in the central NF-\u03baB motif completely suppresses viral transcription from the provirus and converts the promoter into heterochromatin refractory to tumor necrosis factor alpha (TNF-\u03b1) induction. The present work represents the first demonstration of functional incompatibility between an otherwise functional NF-\u03baB motif and a unique Sp1 site in the context of an HIV-1 promoter. Our work provides important leads as to the evolution of the HIV-1 subtype C viral promoter with relevance for gene expression regulation and viral latency.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Subtype-specific genetic variations provide a powerful tool to examine how these variations offer a replication advantage to specific viral subtypes, if any. Only in subtype C of HIV-1 are two genetically distinct transcription factor binding sites positioned at the most critical location of the viral promoter. Since a single promoter regulates viral gene expression, the promoter variations can play a critical role in determining the replication fitness of the viral strains. Our work for the first time provides a scientific explanation for the presence of a unique NF-\u03baB binding motif in subtype C, a major HIV-1 genetic family responsible for half of the global HIV-1 infections. The results offer compelling evidence that the subtype C viral promoter not only is stronger but also is endowed with a qualitative gain-of-function advantage. The genetically variant NF-\u03baB and the Sp1III motifs may be respond differently to specific cell signal pathways, and these mechanisms must be examined.\n          <\/jats:p>","DOI":"10.1128\/jvi.00308-16","type":"journal-article","created":{"date-parts":[[2016,5,19]],"date-time":"2016-05-19T03:03:55Z","timestamp":1463627035000},"page":"7046-7065","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Functional Incompatibility between the Generic NF-\u03baB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter"],"prefix":"10.1128","volume":"90","author":[{"given":"Anjali","family":"Verma","sequence":"first","affiliation":[{"name":"HIV-AIDS Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 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