The effect of interference on the CD8+ T cell escape rates in HIV

TL;DR

This study explores how genetic interference among HIV escape strains influences the observed decrease in escape rates over time, using a mathematical model and experimental data to reveal the importance of linkage effects.

Contribution

The paper introduces a multi-epitope stochastic model of HIV dynamics that demonstrates interference effects can cause decreasing escape rates, challenging previous assumptions about immune response strength.

Findings

Interference among escape strains can slow escape rates.

Synchronous immune responses enhance genetic interference.

Linkage measures are crucial for accurate escape rate estimation.

Abstract

In early HIV infection, the virus population escapes from multiple CD8+ cell responses. The later an escape mutation emerges, the slower it outgrows its competition, i. e. the escape rate is lower. This pattern could indicate that the strength of the CD8+ cell responses is waning, or that later viral escape mutants carry a larger fitness cost. In this paper, we investigate whether the pattern of decreasing escape rate could also be caused by genetic interference among different escape strains. To this end, we developed a mathematical multi-epitope model of HIV dynamics, which incorporates stochastic effects, recombination and mutation. We used cumulative linkage disequilibrium measures to quantify the amount of interference. We found that nearly synchronous, similarly strong immune responses in two-locus systems enhance the generation of genetic interference. This effect, combined with densely spaced sampling times at the beginning of infection, leads to decreasing successive escape rate estimates, even when there were no selection differences among alleles. These predictions are supported by experimental data from one HIV-infected patient. Thus, interference could explain why later escapes are slower. Considering escape mutations in isolation, neglecting their genetic linkage, conceals the underlying haplotype dynamics and can affect the estimation of the selective pressure exerted by CD8+ cells. In systems in which multiple escape mutations appear, the occurrence of interference dynamics should be assessed by measuring the linkage between different escape mutations.