BROAD-SPECTRUM OF IN-VIVO FITNESS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 SUBPOPULATIONS DIFFERING AT REVERSE-TRANSCRIPTASE CODON-41 AND CODON-215

Viral populations in a human immunodeficiency virus type 1 (HIV-1)-inf ected individual behave as a quasispecies with a rated distribution of fitness variants. Fitness distributions in naturally occurring viral populations have been difficult to study due to the lack of markers fo r individual virus clones and complicating inter- and intrahost factor s like the presence of multiple cell types with distinct tropisms, dif ferences in route of transmission, and intervening immunity. Here, we quantitated the relative fitness in vivo of three subpopulations of HI V-1 marked by mutations at codons 41 and 215 of reverse transcriptase (RT) directly related to zidovudine resistance in an untreated individ ual who was infected by a zidovudine-resistant strain transmitted from a donor on therapy. The transmission event did not have a substantial impact on the distribution of mutants within the dominant virus popul ation replicating to high levels in the recipient. The evolution of th e RT gene was monitored for 20 months. All 102 clones obtained from th e donor and the recipient at the different time points contained the M 41L mutation, which is associated with a fourfold reduction in zidovud ine sensitivity. The leucine at position 41 was stable, although it wa s encoded by TTG and CTG triplets that fluctuated in abundance partial ly due to founder effects of clones with nonsilent mutations at codon 215. Of the three subpopulations in the patient, distinguished by a ty rosine (TAG), aspartic acid (GAG), or serine (TCC) at the 215 position of RT, the relative fitness of the GAC variant was calculated to be 1 0 to 25% higher than the initial TAC variant, and the relative fitness of the TCC variant was 1% higher than that of the GAC variant. Simila r to other RNA viruses, lentivirus populations like HIV-1 in patients with a high virus load apparently consist of a broader spectrum of fit ness variants than the 1 to 2% fitness difference sufficient for signi ficant replicative advantage.