Evidence for negative selective pressure in HIV-2 evolution in vivo

HIV-2 sequence divergence and evolution in vivo has not been well characterized so far. To investigate the extent of HIV-2 genetic diversity and better understand how HIV-2 evolves in vivo, env C2-C3 nucleotide sequences were obtained from the plasma and PBMCs virus populations of four HIV-2 patients with different infection periods. Phylogenetic analysis showed that three patients were infected with subtype A HIV-2 and the remaining patient was infected with a divergent HIV-2 that could not be genotyped. Virus populations from the plasma and PBMCs clustered together in all patients suggesting that there is continuous and unrestricted virus flow between plasma and PBMCs. HIV-2 genetic diversity was not correlated with CD4+ cell counts and plasma viral load. There was a direct association between the period of infection and genetic divergence of virus populations both in the env C2-C3 and V3 regions such that higher genetic diversity was observed in long-term infected patients. In three patients, the average frequency of synonymous substitutions (d_S) was significantly higher than the nonsynonymous substitutions (d_N) whereas in the fourth patient the d_N/d_S ratio approached the unity. These data demonstrate that negative selective pressure determines the evolution of the HIV-2 env C2-C3 region in vivo. Our results suggest that throughout HIV-2 infection low virus adaptation to strong selective pressures (e.g. immune pressure) promotes the predominance of a few optimally adapted forms.