Viruses with small genomes (including all RNA viruses) tend to use overlapping genes expressed in different reading frames and to encode proteins that have multiple functions. The HIV envelope encodes for such proteins [26] , and the subtle biochemical equilibrium that regulates their functionality is very possibly limiting tolerance to recombination. The low recombination tolerance of the gp120-encoding region could only be imprecisely predicted based on computational estimates of recombination induced protein fold disruption using the SCHEMA algorithm [3] . This may have been due to either our SCHEMA analyses being based on incomplete gp41 and gp120 structures or the fact that the structures used only reflected a single conformation of these two proteins. Therefore this analysis neither takes into account the conformational changes required for Env functionality, nor the quaternary arrangement of the proteins within Env trimers. Despite these issues, the SCHEMA analysis indicated that, amongst the HIV env sequences sampled from nature, selection has been acting against recombinants with disrupted protein folding (Table S1 ). Unravelling the molecular reasons for the reduced functionality of certain recombinants could provide valuable insights into the nature of the molecular interaction networks required for proper Env function.