Dynamics of In Vitro Fitness Recovery of HIV-1

Abstract

The study on the evolutionary consequences of an RNA viral population's fluctuations can be approached by in vitro experiments. This work describes the fitness recovery of HIV-1 after 20 large-population passages in 10 debilitated clones. The serial passages promoted an increase in viral fitness. In addition, we detected a significant number of mutations fixed in the complete genome consensus sequence of the final viral populations. Among the mutations, events of convergent evolution with important phenotypic characteristics occurred in several independent clones. One common change, V35I, in the nuclear localization signal of the p17 protein appeared in four viruses of three different lineages. Other common alterations mapped in position E196K of the reverse transcriptase or in position S316K of the V3 loop of the gp120 residue that is associated with the X4/R5 phenotype. Together with this mutational analysis, we studied the quasispecies heterogeneity of the initial and final viruses, revealing that fitness increase correlated with an augmentation in the genetic heterogeneity of viral quasispecies. However, while heterogeneity was mostly composed of synonymous (dS) mutations in the first 10 passages performed, at passage 21 it switched to nonsynonymous (dN) substitutions, with significant differences in dN ؊ dS values between passages 11 and 21. In summary, the HIV-1 in vitro fitness recovery depicts a multiphase process occurring first by generation of mutations followed by fixation of the beneficial ones, depicting a classical Darwinian process.

Viral Quasispecies Evolution

“…In contrast to the case for bottlenecks that lead to fitness decreases, viruses passaged as large populations in a given environment tend to gain fitness in that environment (254,496,600). Fitness gain can be viewed as the result of competitive optimization of a viral quasispecies in its tendency toward a mutationselection equilibrium in a given environment (861).…”

“…A broad mutant spectrum means higher accessibility to multiple points in sequence space and, therefore, higher adaptability reflected in fitness gain and its biological derivations, including clinical outcome (130,265,404,496,705). Occupation of sequence space is multifactorial, but an important parameter is the error rate exhibited by the viral replication machinery.…”

Realistic Three Dimensional Fitness Landscapes Generated by Self Organizing Maps for the Analysis of Experimental HIV-1 Evolution

“…In this study, the labelling of the SOM map was carried out with the experimental fitness values [4], [6], [7] and Lorenzo-Redondo et al (manuscript in preparation). This tagging required a set of DNA sequences from viruses with its fitness calculated from competition experiments in the laboratory [6], [7].…”

Resurrecting ancestral structural dynamics of an antiviral immune receptor: adaptive binding pocket reorganization repeatedly shifts RNA preference

“…Short-term evolution of macromolecular interactions has been examined through experimental evolution and studies of protein affinity maturation [33–36], and a few ASR studies have begun investigating the evolution of protein interactions with larger macromolecules [37–40]. However, the long-term molecular evolution of macromolecular interactions remains under-studied.…”