Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins

The ability of HIV-1 to rapidly mutate leads to antiretroviral therapy (ART) failure among infected patients. Drug-resistance mutations (DRMs), which cause a fitness penalty to intrinsic viral fitness, are compensated by accessory mutations with favorable epistatic interactions which cause an evolutionary trapping effect, but the kinetics of this overall process has not been well characterized. Here, using a Potts Hamiltonian model describing epistasis combined with kinetic Monte Carlo simulations of evolutionary trajectories, we explore how epistasis modulates the evolutionary dynamics of HIV DRMs. We show how the occurrence of a drug-resistance mutation is contingent on favorable epistatic interactions with many other residues of the sequence background and that subsequent mutations entrench DRMs. We measure the time-autocorrelation of fluctuations in the likelihood of DRMs due to epistatic coupling with the sequence background, which reveals the presence of two evolutionary processes controlling DRM kinetics with two distinct time scales. Further analysis of waiting times for the evolutionary trapping effect to reverse reveals that the sequences which entrench (trap) a DRM are responsible for the slower time scale. We also quantify the overall strength of epistatic effects on the evolutionary kinetics for different mutations and show these are much larger for DRM positions than polymorphic positions, and we also show that trapping of a DRM is often caused by the collective effect of many accessory mutations, rather than a few strongly coupled ones, suggesting the importance of multiresidue sequence variations in HIV evolution. The analysis presented here provides a framework to explore the kinetic pathways through which viral proteins like HIV evolve under drug-selection pressure

Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins

The ability of HIV-1 to rapidly mutate leads to antiretroviral therapy (ART) failure among infected patients. Drug-resistance mutations (DRMs), which cause a fitness penalty to intrinsic viral fitness, are compensated by accessory mutations with favorable epistatic interactions which cause an evolutionary trapping effect, but the kinetics of this overall process has not been well characterized. Here, using a Potts Hamiltonian model describing epistasis combined with kinetic Monte Carlo simulations of evolutionary trajectories, we explore how epistasis modulates the evolutionary dynamics of HIV DRMs. We show how the occurrence of a drug-resistance mutation is contingent on favorable epistatic interactions with many other residues of the sequence background and that subsequent mutations entrench DRMs. We measure the time-autocorrelation of fluctuations in the likelihood of DRMs due to epistatic coupling with the sequence background, which reveals the presence of two evolutionary processes controlling DRM kinetics with two distinct time scales. Further analysis of waiting times for the evolutionary trapping effect to reverse reveals that the sequences which entrench (trap) a DRM are responsible for the slower time scale. We also quantify the overall strength of epistatic effects on the evolutionary kinetics for different mutations and show these are much larger for DRM positions than polymorphic positions, and we also show that trapping of a DRM is often caused by the collective effect of many accessory mutations, rather than a few strongly coupled ones, suggesting the importance of multiresidue sequence variations in HIV evolution. The analysis presented here provides a framework to explore the kinetic pathways through which viral proteins like HIV evolve under drug-selection pressure

Comparison of nucleotide diversity in acute Vs chronic infection.

<p>Nucleotide diversity in the (A) surface gene, (B) BCP/PC region and (C) X gene has been compared. The nucleotide sequences of the chronic sequences were compared to that of the acute sequences using Shannon’s Entropy. The blue lines indicated the specific positions where changes were noted. The red lines indicate the positions where the frequency of substitution between acute and chronic sequences was significantly different. (D) The average ΔH (average difference in entropy between chronic and acute infection) was highest in the BCP region of the HBV genome. (E) Calculation of genetic diversity at the genotype level showing that the BCP/PC region of genotype C isolates exhibit highest average ΔH.</p

Phylogenetic analysis of HBV isolates from Eastern India with acute infection created using the neighbour-joining method.

<p>Phylogenetic tree was constructed from surface gene sequences of this study (denoted by AEI) along with reference sequences derived from GenBank (denoted by accession numbers).</p

Frequencies of some principal mutations in the HBV genome compared in acute and chronic Hepatitis B patients.

<p>Figure depicts some signature mutations in the surface gene (S), basal core promoter/pre-core regions (BCP/PC) and X gene.</p

Demographic, biochemical and virological characteristics of acute and chronic subjects from eastern India.

<p>Statistically significant values are denoted by *(p<0.05) or **(p<0.001).</p

Association of HBV occurrence with the modes of transmission, patients’ age groups and HBV genotypes among samples included in the study.

<p>(A) Sexual promiscuity is the major mode by which HBV is transmitted in the study population. (B) Occurrence of HBV is highest in the age bracket between 15 to 30 years. (C) HBV/D2 is the dominant sub-genotype and is associated majorly with sexual promiscuity. (D) Occurrence of HBV/D2 is highest in the age bracket between 15 to 30 years.</p

Distribution of HBV genotypes and sub-genotypes among acute and chronic patients of eastern India.

<p>(A) Difference in HBV genotype distribution among acute and chronic patients. (B) Difference in the distribution of HBV sub-genotypes under genotype D among acute and chronic patients. Only significant results (*p<0.05, **P<0.01) have been marked in the figure.</p

Analysis of the association of HBV sub-genotypes with biochemical parameters.

<p>Median (A) ALT (IU/liter) and (B) bilirubin (IU/liter) levels in patients vary with circulating HBV sub-genotypes. Only significant differences (p<0.05) have been marked in the figure.</p

Mutations in the Basal Core Promoter/PreCore and the Core regions of the HBV Genome.

<p>(A) The frequency of the major mutations found in the BCP/precore region of the HBV strains circulating among the treatment naive HIV infected cohort of eastern India are presented here. The frequency of the G1896A precore mutation was higher compared to the BCP double mutations in our settings with majority of the strains harboring the C1858T mutation. (B) The frequencies of the amino acid mutations found in the immune-active regions of the core gene are shown. The major mutations in the MHC class I restricted (amino acids 18–27, 88–96, 130–140, 141–151) and MHC class II-restricted (amino acids 1–20, 50–69, 81–105, 117–131, 141–165) T-cell epitopes of core antigen includes the V27I and T12S respectively.</p