Recombination Rate and Selection Strength in HIV Intra-patient Evolution

Abstract

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Yet, little is known about the distribution of selection differentials between individual viruses and the impact of single polymorphisms on viral fitness. Here, we estimate the rate of recombination and the distribution of selection coefficients from time series sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be ρ = 1.4±0.6×10⁻⁵ recombinations per site and generation. Furthermore, we provide evidence that the selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible as soon as data with higher time resolution and greater sample sizes are available. Evolution, in viruses and other organisms, is the result of random genetic diversification by mutation or recombination and selection for survival. In most organisms, evolution is too slow to be observed directly and the evolutionary past has to be reconstructed from static snapshots of the population. This reconstruction requires simple models of evolution that typically neglect selection or recombination. In vigorously evolving organisms like HIV, such assumptions are questionable. However, HIV evolves rapidly enough that substantial evolution is observable during a chronic HIV infection within single patients. Using such time series data of evolution, we estimate the effective recombination rate of HIV (the rate of viral sex) to be similar to the mutation rate, rather than much larger as previously reported. We also study the strength of selection exerted on the virus by the immune system. We find that about 15% of the observed virus variants with mutations in the surface protein are favored and selected at a rate of 0.8% to 2% per virus replication cycle. Knowledge of the recombination rate and the strength of selection is essential for quantitative modeling and understanding of HIV evolution.