Multiple NF-κB Sites in HIV-1 Subtype C Long Terminal Repeat Confer Superior Magnitude of Transcription and Thereby the Enhanced Viral Predominance

• Published in: The Journal of biological chemistry Vol. 287; no. 53; pp. 44714 - 44735
• Main Authors: Bachu, Mahesh, Yalla, Swarupa, Asokan, Mangaiarkarasi, Verma, Anjali, Neogi, Ujjwal, Sharma, Shilpee, Murali, Rajesh V., Mukthey, Anil Babu, Bhatt, Raghavendra, Chatterjee, Snehajyoti, Rajan, Roshan Elizabeth, Cheedarla, Narayana, Yadavalli, Venkat S., Mahadevan, Anita, Shankar, Susarla K., Rajagopalan, Nirmala, Shet, Anita, Saravanan, Shanmugam, Balakrishnan, Pachamuthu, Solomon, Suniti, Vajpayee, Madhu, Satish, Kadappa Shivappa, Kundu, Tapas K., Jeang, Kuan-Teh, Ranga, Udaykumar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.12.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Adult; Cohort Studies; Female; Gene Expression Regulation, Viral; Gene Transcription; HIV Infections - genetics; HIV Infections - metabolism; HIV Infections - virology; HIV Long Terminal Repeat; HIV-1; HIV-1 - chemistry; HIV-1 - classification; HIV-1 - genetics; HIV-1 - physiology; Humans; Male; Molecular Bases of Disease; Molecular Sequence Data; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB; Protein Binding; Replication Competence; Subtype-C; Transcription Enhancers; Transcription Regulation; Transcription, Genetic; Viral Evolution; Viral Transcription; Virus Replication; Young Adult; Gene Transcription; HIV-1; Viral Transcription; NF-κB; Transcription Regulation; Transcription Enhancers; Viral Evolution; Subtype-C; Replication Competence
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.397158

We demonstrate that at least three different promoter variant strains of HIV-1 subtype C have been gradually expanding and replacing the standard subtype C viruses in India, and possibly in South Africa and other global regions, over the past decade. The new viral strains contain an additional NF-κB, NF-κB-like, or RBEIII site in the viral promoter. Although the acquisition of an additional RBEIII site is a property shared by all the HIV-1 subtypes, acquiring an additional NF-κB site remains an exclusive property of subtype C. The acquired κB site is genetically distinct, binds the p50-p65 heterodimer, and strengthens the viral promoter at the levels of transcription initiation and elongation. The 4-κB viruses dominate the 3-κB “isogenic” viral strains in pairwise competition assays in T-cell lines, primary cells, and the ecotropic human immunodeficiency virus mouse model. The dominance of the 4-κB viral strains is also evident in the natural context when the subjects are coinfected with κB-variant viral strains. The mean plasma viral loads, but not CD4 counts, are significantly different in 4-κB infection suggesting that these newly emerging strains are probably more infectious. It is possible that higher plasma viral loads underlie selective transmission of the 4-κB viral strains. Several publications previously reported duplication or deletion of diverse transcription factor-binding sites in the viral promoter. Unlike previous reports, our study provides experimental evidence that the new viral strains gained a potential selective advantage as a consequence of the acquired transcription factor-binding sites and importantly that these strains have been expanding at the population level. Viral evolution of HIV-1 is dynamic and moving towards a higher order of replicative fitness. HIV-1 subtype C acquires an extra (4th) NF-κB site to achieve a higher degree of transcription and in turn enhances its replicative fitness and preponderance. Subtype C with an extra NF-κB site adopts a novel strategy of strengthening its promoter to gain fitness. Learning how the new strains could impact viral prevalence, pathogenesis, and disease management strategies is critical.