Nucleotide substitution rates of HIV-1

The molecular evolution of human immunodeficiency virus type 1 (HIV-1) is reviewed from the viewpoint of the rate of nucleotide substitution, which is defined as the number of nucleotide substitutions per site per year. The rate of nucleotide substitution is useful not only for estimating the origin and history of HIV-1 epidemics, but also for detecting natural selection operating at the amino acid sequence level. The RNA viruses may be classified into two groups, the rapidly and slowly evolving RNA viruses, according to their rates of nucleotide substitution; 10^-3-10^-4 and 10^-6-10^-7 per site per year for the former and the latter, respectively. HIV-1 is a member of the rapidly evolving RNA viruses, with the rate of 10^-3 per site per year, which is several million times faster than the eukaryotic and prokaryotic genes. The linear regression analysis of a large number of HIV-1 sequences revealed that HIV-1 has a weak molecular clock. The latest divergence time between human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) was estimated as about 30 years ago, and that between HIV-1 and SIV as several hundred years ago. These observations, as well as the inconsistency between the topologies of phylogenetic tress reconstructed for primate lentiviruses and for their host species, indicate that the interspecies transmission occurred during the evolution of primate lentiviruses. The intrahost evolution of HIV-1 has been studied to elucidate the mechanisms of producing immune escape mutants and drug resistant mutants of HIV-1. In particular, the comparison of the rate of non-synonymous substitution with that of synonymous substitution clarified that positive selection is operating on the third variable region of the envelope glycoprotein, which is known as the major target of the immune response and determinant of cell tropism. An asymmetric pattern of nucleotide substitutions for HIV-1, represented by the G to A hyper-mutation, predicts a decrease in the GC content and an increase in the AT content in the HIV-1 genome. The extremely high rate of nucleotide substitution for HIV-1 provides us with a unique opportunity to test evolutionary theories using this virus. Further examination of the mechanisms of molecular evolution for HIV-1 is required for developing effective therapies and vaccines against HIV-1 infection.