12th International AIDS Conference Geneva, Switzerland - June 28-July 3, 1998

Int Conf AIDS 1998 Jun 28-Jul 3; 12:13-4 (abstract no. 11157)

de Ronde A, Bouwhuis D, de Rooy ER, Maas G, de Boer R, Goudsmit G;;; Dept. of Human Retrovirology, AMC, Univ. Amsterdam, The Netherlands.

OBJECTIVE: Study of evolutio of zidovudine-resistant HIV-1 in a newly infected patient after virus transmission from a zidovudine treated patient in 1993. The recipient was not treated with zidovudine during the study period.

BACKGROUND: Long-term fitness of reverse tranciptase (RT) has been adjusted to an intra-host environment without RT-inhibitors. With the introduction of RT-inhibitors of which zidovudine is the longest in use, a new evolutionary pressure was introduced that rapidly generated variants resistant to anti-viral drug.

METHODS: By using RT-PCR cloning, individual RT-sequences of the viral quasispecies from serum of donor and recipient at different intervals after seroconversion were determined and compared at the zidovudine resistance conferring amino acid positions 41 and 215.

RESULTS: The RT of both donor and recipient had the zidovudine resistance conferring mutations M41L and T215Y. In the absence of drug in the recipient, while the 41L (leucine) remained unchanged, the 215Y (tyrosine) evolved to a 215D (aspartic acid) and later to a mixture of 215D and 215S (serine). The 215T (threonine), naturally occurring in an environment without zidovudine, did not arise after 36 months of infection suggesting that the 215T variant would be less fit in the newly arisen background of this zidovudine resistant HIV-1. To substantiate this hypothesis, a patient RT with the 215Y was cloned into an HIV-Lai background and by in vitro mutagenesis infectious molecular clones were created that differed only at the 215-position: 215Y, 215D, 215S, and 215T. The relative fitness of the viruses derived from the different molecular clones was tested by in vitro competition experiments in peripheral blood monocytic cells (PBMC). The order of fitness of the variants was 215S & ap; D > Y > T.

CONCLUSIONS: The in vitro observed relative fitness of RT-variants was in agreement with the in vivo observed succession of variants. It suggested that the evolutionary pathway back to the naturally occurring 215T variant is a least favoured option. Our data would fit in the hypothesis that, after a bottleneck transmission, the evolution of zidovudine resistant RT is moving in a distinctive direction as a Muller's ratchet.

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