Evolution of gag and gp41 in Patients Receiving Ritonavir-Boosted Protease Inhibitors.

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• Protease inhibitors (PIs) are crucial for HIV-1 treatment.
• Genotypic determinants in gag and gp41 cytoplasmic domain (gp41-CD) have been proposed to reduce PI susceptibility.
• No specific gag or gp41-CD mutations have been definitively linked to reduced PI susceptibility in individuals with virological failure (VF) on PI-containing regimens.

Purpose of the Study:

• To identify gag and gp41 mutations under selective pressure from boosted PI (PI/r)-containing regimens.
• To investigate potential genotypic determinants of PI resistance outside the protease gene.

Main Methods:

• Sequencing of gag and/or gp41 genes in 61 individuals with VF on PI/r or NNRTI regimens.
• Quantification of nonsynonymous and synonymous changes in gag and gp41.
• Identification of sites with signals for directional or diversifying selection.
• Analysis of gag and gp41 polymorphism data to identify mutations with a high selection index (conserved to uncommon amino acid change).

Main Results:

• Numerous amino acid mutations were observed in gag and gp41-CD in both PI/r and NNRTI-treated groups.
• No significant differences were found between the groups in the overall number of mutations, selected mutations, or mutations with a high selection index.
• The study did not identify distinct gag or gp41-CD mutations associated with PI/r treatment failure.

Conclusions:

• The findings do not support a significant role for specific gag or gp41-CD mutations in reducing PI susceptibility in the context of PI/r treatment failure.
• If gag and/or gp41 encode PI resistance, these mutations may be diverse and not confined to a few specific sites.
• Further research is needed to fully elucidate the role of viral genetic determinants in PI resistance.