The Evolution of Regulatory Elements in the Emerging Promoter-Variant Strains of HIV-1 Subtype C

Author:

Bhange Disha,Prasad Nityanand,Singh Swati,Prajapati Harshit Kumar,Maurya Shesh Prakash,Gopalan Bindu Parachalil,Nadig Sowmya,Chaturbhuj Devidas,Jayaseelan Boobalan,Dinesha Thongadi Ramesh,Ahamed Syed Fazil,Singh Navneet,Brahmaiah Anangi,Mehta Kavita,Gohil Yuvrajsinh,Balakrishnan Pachamuthu,Das Bimal Kumar,Dias Mary,Gangakhedkar Raman,Mehendale Sanjay,Paranjape Ramesh S,Saravanan Shanmugam,Shet Anita,Solomon Sunil Suhas,Thakar Madhuri,Ranga Udaykumar

Abstract

In a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not the coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but no significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a coinfection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.

Publisher

Frontiers Media SA

Subject

Microbiology (medical),Microbiology

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