IMPAIRED FITNESS OF FOSCARNET-RESISTANT STRAINS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Foscarnet (PFA) is a pyrophosphate analogue antiviral active against h uman immunodeficiency virus (HIV-1) and herpesviruses, Strains of HIV- 1 resistant to PFA have mutations in the HIV-1 reverse transcriptase ( RT), We examined the influence of PFA resistance mutations, in differe nt genetic backgrounds, on HIV-1 replication competency in both replic ation kinetics and growth competition assays. In replication kinetics assays, the recombinant strains HX89K, HX92I, and HX156A (encoding RT mutations E89K, L92I, and S156A, respectively, in the HXB2-D genetic b ackground) replicated to lower titers than the wild-type parent in the absence of drug, and the degree of replication impairment increased a s PFA resistance increased. PFA-resistant strains LAI 92I and LAI 156A (encoding RT mutations L92I and S156A, respectively) were replication impaired in comparison to the wild-type parent LAI to a similar degre e as observed for strains in the HXB2-D background. In growth competit ion assays with wild-type LAI, strains LAI 92I and LAI 156A had relati ve fitness values of 0.5 and 0.8, respectively. These results show tha t the RT mutations E89K, L92I and S156A, observed in PFA-resistant str ains selected in cell culture, reduce replication competence. Furtherm ore, these data show a correlation of increasing PFA resistance and de creasing replication competence mediated by single amino acid substitu tions in the RT.