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.
Highlights
Based on phylogenetic association, the viral strains of HIV-1 are classified into four groups (M, N, O, and P), and within group M, into 10 different genetic subtypes, A, B, C, D, F, G, H, J, K, L (Yamaguchi et al, 2020), and numerous recombinant forms
While the appearance of genetic diversity and such diversity impacting viral evolution are common to the various genetic subtypes of HIV-1, the genetic variation we describe in HIV-1 subtype C (HIV-1C) is non-sporadic and radically different in an important aspect
Viral evolution in HIV-1C appears to be directional toward modulating transcriptional strength of the promoter by creating additional copies of the existing transcription factor binding sites (TFBS), such as NF-κB, AP-1, RBEIII, and TCF-1α/LEF-1 motifs, by sequence duplication and co-duplication
Summary
The viral strains of HIV-1 are classified into four groups (M, N, O, and P), and within group M, into 10 different genetic subtypes, A, B, C, D, F, G, H, J, K, L (Yamaguchi et al, 2020), and numerous recombinant forms. Of the TFBS variations, differences in the copy number and sequence of the NF-κB motif are unique to HIV-1C. A small number of reports reported RBEIII duplication in HIV-1C infection, without evaluating its effect on the replication fitness of the viral strains and disease progression (Rodriguez et al, 2007). Viral evolution in HIV-1C appears to be directional toward modulating transcriptional strength of the promoter by creating additional copies of the existing TFBS, such as NF-κB, AP-1, RBEIII, and TCF-1α/LEF-1 motifs, by sequence duplication and co-duplication. Any variation in the constitution of the TFBS (copy number difference and/or genetic variation) may have a profound impact on viral replication fitness. This work provides important insights into the HIV-1 evolution taking place at the level of population in India
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