Differential Codon Usage Pattern of HIV-1 tat Gene in Those with Slower and Faster Rates of Disease Progression

Editor: All organisms exhibit unique codon usage signatures that reflect the functional category and evolutionary history of their genes and genomes. ¹ The extent of codon usage bias in a gene/genome can be interpreted as an outcome of either mutational bias or translational selection. ² While genomic bias due to mutational selection is solely the property of the pathogen, translational selection involves an interplay between the host and the pathogen, where the pathogen evolves to match its codon usage pattern with that of the host for faster translation of highly expressed genes, and consequently rapid multiplication. ²

The human immunodeficiency virus (HIV) is a well-known translational parasite of humans that uses the host's translation machinery to translate its own mRNA. HIV has a remarkable nucleotide composition with an above average percentage of “A” nucleotide resulting in a codon usage pattern that differs markedly from that of the human host with preferential occupancy of A at the flexible third codon position. ³ In a recent study, we reported that the tat (transcriptor of transactivation) gene of HIV-2 has a higher effective number of codons (ENCs) value as compared to HIV-1, reflecting lower level of expression of HIV-2 Tat protein, and hypothesized that lower levels of HIV-2 Tat protein, particularly in the early stages of infection, result in decreased viral load, lower viral set point, and delayed disease progression that distinguishes HIV-2 infection from that of HIV-1 infection. ⁴ In the present study, we expanded our previous observations by comparing the codon usage pattern of HIV-1 genes among different groups of HIV disease progressors, viz. Long-Term Nonprogressors (LTNPs), Elite Controllers (ECs), Slow Progressors (SPs), and Typical Progressors (P), to understand the influence of differential codon usage pattern of the viruses on the pathogenic manifestation in the host.

Complete genome sequences of HIV-1 strains isolated from ECs (n = 8), LTNPs (n = 58), SPs (n = 26), and Progressors/Typical Progressors (n = 38) were downloaded from the Los Alamos National Laboratory (LANL) HIV database as available as on December 2015. Base composition analysis was performed using codon W (http://codonw.sourceforge.net/) for each of the nine genes in the different groups. Mean frequency of nucleotides at third codon position, G + C at synonymous variable third codon position (GC3s), and total G + C composition were calculated for each gene. The extent of codon usage bias for the different genes in each of the groups was analyzed based on the ENCs.

Interestingly, we found that the tat gene in EC, LTNP, and SP groups had a significantly higher ENC value as compared to that of typical progressors/progressors (p < .05), whereas that of all other genes was comparable (Table 1). Universally, codon usage has been suggested to be a reliable correlate of gene expression, with higher ENC values correlating with lower levels of gene expression, and vice versa. Tat being an overlapping regulatory gene, participates in a positive feedback mechanism that ensures high levels of HIV transcription following the activation of cells carrying HIV proviruses. The lower ENC value of tat gene in typical progressors reflects higher levels of tat protein expression leading to higher viral load, higher viral set point, and faster disease progression in these individuals as compared with the EC, LTNP, and SP.

In most instances, HIV infection is associated with progressive viral transcription and replication resulting in disease progression and clinical symptoms of AIDS. Several factors contribute to the control of viral transcription and replication, such as defective viral strains, robust host cell-mediated immune responses, and other host genetic factors that can affect viral replication. We hypothesize based on the provided evidence that codon bias of the tat gene may also contribute to the course of disease and extent of pathogenicity in HIV infection, along with other host and viral factors.