title: Multiple NF-κB sites in HIV-1 subtype C long terminal repeat confer superior magnitude of transcription and thereby the enhanced viral predominance.
abstract: 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.
authors.affiliation: HIV-AIDS Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Bachu
authors.forename: Swarupa
authors.initials: S
authors.lastname: Yalla
authors.forename: Mangaiarkarasi
authors.initials: M
authors.lastname: Asokan
authors.forename: Anjali
authors.initials: A
authors.lastname: Verma
authors.forename: Ujjwal
authors.initials: U
authors.lastname: Neogi
authors.forename: Shilpee
authors.initials: S
authors.lastname: Sharma
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Murali
authors.forename: Anil Babu
authors.initials: AB
authors.lastname: Mukthey
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Bhatt
authors.forename: Snehajyoti
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Roshan Elizabeth
authors.initials: RE
authors.lastname: Rajan
authors.forename: Narayana
authors.initials: N
authors.lastname: Cheedarla
authors.forename: Venkat S
authors.initials: VS
authors.lastname: Yadavalli
authors.forename: Anita
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Susarla K
authors.initials: SK
authors.lastname: Shankar
authors.forename: Nirmala
authors.initials: N
authors.lastname: Rajagopalan
authors.forename: Anita
authors.initials: A
authors.lastname: Shet
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Saravanan
authors.forename: Pachamuthu
authors.initials: P
authors.lastname: Balakrishnan
authors.forename: Suniti
authors.initials: S
authors.lastname: Solomon
authors.forename: Madhu
authors.initials: M
authors.lastname: Vajpayee
authors.forename: Kadappa Shivappa
authors.initials: KS
authors.lastname: Satish
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
authors.forename: Udaykumar
authors.initials: U
authors.lastname: Ranga
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014158:Transcription, Genetic; D014779:Virus Replication; D055815:Young Adult
chemical_list: D016328:NF-kappa B