Multiple NF-κB sites in HIV-1 subtype C long terminal repeat confer superior magnitude of transcription and thereby the enhanced viral predominance

Mahesh Bachu, Swarupa Yalla, Mangaiarkarasi Asokan, Anjali Verma, Ujjwal Neogi, Shilpee Sharma, Rajesh V. Murali, Anil Babu Mukthey, Raghavendra Bhatt, Snehajyoti Chatterjee, Roshan Elizabeth Rajan, Narayana Cheedarla, Venkat S. Yadavalli, Anita Mahadevan, Susarla K. Shankar, Nirmala Rajagopalan, Anita Shet, Shanmugam Saravanan, Pachamuthu Balakrishnan, Suniti SolomonMadhu Vajpayee, Kadappa Shivappa Satish, Tapas K. Kundu, Kuan Teh Jeang, Udaykumar Ranga

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)44714-44735
Number of pages22
JournalJournal of Biological Chemistry
Volume287
Issue number53
DOIs
StatePublished - Dec 28 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Bachu, M., Yalla, S., Asokan, M., Verma, A., Neogi, U., Sharma, S., Murali, R. V., Mukthey, A. B., Bhatt, R., Chatterjee, S., Rajan, R. E., Cheedarla, N., Yadavalli, V. S., Mahadevan, A., Shankar, S. K., Rajagopalan, N., Shet, A., Saravanan, S., Balakrishnan, P., ... Ranga, U. (2012). Multiple NF-κB sites in HIV-1 subtype C long terminal repeat confer superior magnitude of transcription and thereby the enhanced viral predominance. Journal of Biological Chemistry, 287(53), 44714-44735. https://doi.org/10.1074/jbc.M112.397158