272 Evolution of R5 and X4 Human Immunodeficiency Virus Type 1 Gag Sequences in Vivo: Evidence for Recombination Hanneke Schuitemaker*, Janny Visser, Ronald van Rij Sanquin Res and Academic Med Ctr, Amsterdam, The Netherlands
Background: HIV-1 infection is generally established by CCR5-using (R5) viruses, which persist throughout the course of infection. R5 HIV-1 variants evolve into CXCR4-using (X4) HIV-1 variants in approximately half of the infected individuals. We have previously observed an ongoing genetic evolution with a continuous divergence of envelope gp120 sequences of co-existing R5 and X4 virus variants over time. Here, we studied evolution of p17gag sequences in 2 patients (pts) who developed X4 variants in the course of infection.
Methods: Phylogenetic analyses were performed on gp120 env and p17gag sequences of biological virus clones from 2 pts (ACH039 and ACH208) who developed X4 variants during follow-up in the Amsterdam cohort on HIV-1 infection and AIDS.
Results: The overall diversity in gp120 V3 was higher than in p17gag. In p17gag the rate of synonymous mutations was higher than the rate of non-synonymous mutations for both pts, whereas the opposite was observed for the gp120 V3 sequences, confirming previous studies and pointing to stronger positive selection on the envelope. Divergence between the R5 and X4 virus population increased over time and always exceeded diversity within the R5 or within the X4 virus population in the gp120 V3 region. In contrast, the divergence from R5 to X4 virus population in the p17gag region was similar to the diversity within the R5 or within the X4 virus population. The divergence from the R5 to the X4 virus population in the gp120 V3 region was significantly higher than the diversity within the R5 and X4 virus population at all time points (p-values ranging from < 0.001 to 0.01, Mann Whitney U test), whereas no significant differences were observed in the p17gag region. In conclusion, we observed an ongoing evolution of the p17gag region of both R5 and X4 virus populations, but these virus populations did not diverge over time.
Conclusions: We previously suggested that the divergence between R5 and X4 populations was evidence for independent evolution of these virus variants and that this could be explained by their separate niches in naive and memory T-cells. Here we demonstrate the absence of this divergence for p17gag sequences. Independent evolution of different genomic regions is considered as evidence for the occurrence of recombination. Therefore, our data imply that recombination between R5 and X4 HIV-1 variants occurs in vivo and consequently that X4 and R5 variants share common target cells.
