  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.
