Implications of HIV RNA structure for recombination, speciation, and the neutralism-selectionism controversy

The conflict between the needs to encode both a protein (impaired by non-synonymous mutation), and nucleic acid structure (impaired by synonymous or non-synonymous mutation), can sometimes be resolved in favour of the nucleic acid because its structure is critical for a selectively advantageous genome-wide activity – recombination. However, above a sequence difference threshold, recombination is impaired. It may then be advantageous for new species to arise. Building on the work of Grantham and others critical of the neutralist viewpoint, heuristic support for this hypothesis emerged from studies of the base composition and structure of retroviral genomes. The extreme enrichment in the purine A of the RNA of human immunodeficiency virus (HIV-1), parallels the mild purine-loading of the RNAs of most organisms, for which there is an adaptive explanation – immune evasion. However, human T cell leukaemia virus (HTLV-1), with the potential to invade the same host cell, shows extreme enrichment in the pyrimidine C. Assuming the low GC% HIV and the high GC% HTLV-1 to share a common ancestor, it was postulated that differences in GC% had arisen to prevent homologous recombination between these emerging lentiviral species. Sympatrically isolated by this intracellular reproductive barrier, prototypic HIV-1 seized the AU-rich (low GC%) high ground (thus committing to purine A rather than purine G). Prototypic HTLV-1 forwent this advantage and evolved an independent evolutionary strategy – similar to that of the GC%-rich Epstein-Barr virus – profound latency maintained by transcription of one purine-rich mRNA. The evidence supporting these interpretations is reviewed.