Difference in Resistance Contributes More Strongly to the Evolution of Zidovudine Resistance in HIV-1 Infected Patients Than Difference in Replication Capacity

W. Keulen, R. de Boer, L. de Graaf, B. Berkhout, R. Jeeninga, J. Whitcomb, R. Schuurman and C. Boucher.

The evolution of drug resistance in HIV-1 infected patients is directed by several factors such as mutational frequency of the viral RT enzyme, replication capacity and drug susceptibility of the selected virus variants. In this study, we determined these factors for nine different AZT resistant variants containing either the individual mutations (M41L, K70R, T215F/Y) or several combinations of mutations. Pairwise competition experiments in primary cells demonstrated a strong reduction of the replication capacity of the M41L and the M41L+K70R variant. Interestingly, only minor differences were observed between the replication capacity of the other variants. Analysis of the drug susceptibility showed increasing AZT resistance that coincided with the accumulation of the resistance conferring mutations. In addition, cross- resistance to ddC and ddI was determined for the complete set of variants and demonstrated low level of cross-resistance for the T215Y variant. Based on the data, we propose that due to the minor differences in replication capacity, differences in resistance contribute more strongly to the evolution of AZT resistant variants during AZT mono-and combination therapy. In combination with the nucleotide substitution bias of the RT enzyme, differences in resistance can explain the observed evolution of AZT resistant variants in vivo.

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