3rd Conference on Retroviruses and Opportunistic Infections Washington, DC - January 28-February 1, 1996

Conf Retroviruses Opportunistic Infect 1996 Jan 28-Feb 1; 3rd:53 (abstract no. 1)

De Jong M, Jan Veenstra J, Stilianakis N, Schuurman R, Lange J, De Boer R, Boucher C

Zidovudine remains the mainstay of current antiretroviral treatment strategies. While the appearance of HIV-1 isolates with reduced susceptibility to zidovudine during treatment is well established, the consequences of zidovudine-resistance for the antiviral activity of zidovudine in vivo are unclear. We investigated the association between HIV-1 RNA load changes and the emergence of resistant virus variants during treatment with zidovudine. Serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 41 (M -> L), 70 (K -> R), and 215 (T -> Y/F) were measured sequentially in 24 asymptomatic zidovudine-treated subjects during a two year follow-up period. Maximal suppression of RNA load by zidovudine was observed during the first month of treatment, and was followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modelling demonstrates that this initial resurgence can be explained by host-parasite dynamics, in which the transient increase of CD4⁺ lymphocytes increases viral replication. Between 3 and 6 months of treatment, RNA load returned to baseline values. This ultimate loss of replications inhibition by zidovudine was solely caused by the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, which only confers an 8-fold reduction in susceptibility. Despite the loss of RNA load suppression, selection towards mutations at RT codons 215 and 41 continued. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance.

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Copyright © 1996 - Foundation for Retrovirology and Human Health . Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health.