Host-specific modulation of the selective constraints driving human immunodeficiency virus type 1 env gene evolution

To address the evolution of human immunodeficiency virus type 1 (HIV-1) wit hin a single host, we analyzed the HIV-1 C2-V5 env regions of both cell-fre e genomic-RNA- and proviral-DNA-derived clones. Sequential samples were col lected over a period of 3 years from six untreated subjects (three typical progressors [TPs] and three slow progressors [SPs], all with a comparable l ength of infection except one. The evolutionary analysis of the C2-V5 env s equences performed on 506 molecular clones (253 RNA- and 253 DNA-derived se quences) highlighted a series of differences between TPs and SPs. In partic ular, (i) clonal sequences from SPs (DNA and RNA) showed lower nucleotide s imilarity than those from TPs (P = 0.0001), (ii) DNA clones from SPs showed higher intra- and intersample nucleotide divergence than those from TPs (P < 0.05), (iii) higher host-selective pressure was generally detectable in SPs (DNA and RNA sequences), and (iv) the increase in the genetic distance of DNA and RNA sequences over time was paralleled by an increase in both sy nonymous (Ks) and nonsynonymous (Ka) substitutions in TPs but only in nonsy nonymous substitutions in SPs. Several individual peculiarities of the HIV- 1 evolutionary dynamics emerged when the V3, V4, and V5 env regions of both TPs and SPs were evaluated separately. These peculiarities, probably refle cting host-specific features of selective constraints and their continuous modulation, are documented by the dynamics of Ka/Ks ratios of hypervariable env domains.