The introduction and global dissemination of the retrovirus human immunodeficiency virus type-1 (HIV-1) in humans represents a dramatic and deadly example of recent genome emergence and expansion; since the beginning of the pandemic, over 50 million people have been infected and over 16 million of those have died of AIDS. As with all RNA viruses, HIV-1 replication is characterized by very high mutation rates. Technical advances made in DNA sequencing and the recovery of rare nucleic acids from diverse sources have facilitated the sequencing of HIV-1 on a massive scale. These studies have revealed the remarkable genome plasticity and continuing diversification of HIV-1 strains; the significance of this diversity for viral pathogenesis remains a major question in the field.

The replication of HIV-1, like that of all retroviruses, involves reverse transcription of the viral genome into a DNA copy that integrates into the host cell genome. As with other viral RNA replicases, reverse transcriptases lack proofreading capabilities owing to the absence of 3′→ 5′ exonuclease activity. In the case of HIV-1, the misincorporation, deletion, insertion, or duplication of nucleotides occurs during reverse transcription with a frequency of 10− 4 to 10− 5. This error frequency, coupled with an in vivo virus production rate exceeding 10 9 per day in an individual, the large number of infected people, and the persistent nature of infections, provides HIV-1 with tremendous scope for the generation of viral diversity (Figure 1a). For instance, circulating HIV-1 strains are continuing to diversify at about 0.0024 substitutions per base pair per year (