title: Influence of mutation and recombination on HIV-1 in vitro fitness recovery.
abstract: The understanding of the evolutionary processes underlying HIV-1 fitness recovery is fundamental for HIV-1 pathogenesis, antiretroviral treatment and vaccine design. It is known that HIV-1 can present very high mutation and recombination rates, however the specific contribution of these evolutionary forces in the "in vitro" viral fitness recovery has not been simultaneously quantified. To this aim, we analyzed substitution, recombination and molecular adaptation rates in a variety of HIV-1 biological clones derived from a viral isolate after severe population bottlenecks and a number of large population cell culture passages. These clones presented an overall but uneven fitness gain, mean of 3-fold, respect to the initial passage values. We found a significant relationship between the fitness increase and the appearance and fixation of mutations. In addition, these fixed mutations presented molecular signatures of positive selection through the accumulation of non-synonymous substitutions. Interestingly, viral recombination correlated with fitness recovery in most of studied viral quasispecies. The genetic diversity generated by these evolutionary processes was positively correlated with the viral fitness. We conclude that HIV-1 fitness recovery can be derived from the genetic heterogeneity generated through both mutation and recombination, and under diversifying molecular adaptation. The findings also suggest nonrandom evolutionary pathways for in vitro fitness recovery.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Centre for Molecular Biology "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. Electronic address: marenas@ipatimup.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arenas
authors.affiliation: Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. Electronic address: ramon.lorenzo@northwestern.edu.
authors.forename: Ramon
authors.initials: R
authors.lastname: Lorenzo-Redondo
authors.affiliation: Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. Electronic address: clopez@isciii.es.
authors.forename: Cecilio
authors.initials: C
authors.lastname: Lopez-Galindez
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics; D019143:Evolution, Molecular; D056084:Genetic Fitness; D015658:HIV Infections / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D009154:Mutation; D010802:Phylogeny; D011995:Recombination, Genetic / Q000502:physiology*
keywords: Fitness recovery; Genetic heterogeneity; HIV-1 molecular evolution; Molecular adaptation; Mutation; Viral recombination