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Genotypic and phenotypic changes of HIV-1 mutants as propagated in the presence of AZT or ddI in vitro.


Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:136.

We attempted to examine the biological properties of multiple mutations (T39 to A[17/19 clones sequenced], M41 to L[19/19], K43 to E[10/20], G45 to E[1/20], L74 to V[20/20], A98 to S[20/20], V118 to I[16/20],I142 to V [16/20], M184 to V[15/20], L210 to W [15/20], R211 to K[19/20], T215 to Y[17/20], and L228 to H[18/20]) in the pol gene of an HIV isolate (ERS203 post) obtained from a pt receiving AZT and ddI (Shirasaka et al. PNAS, 90:562, 1993). To this end, we propagated ERS203 post in PHA-PBM using a cell-free transmission system in which virions in the cell-free supernatant was transmitted to fresh PHA-PBM every 7 days. The virus passaged in the presence of AZT remained resistant to AZT. By contrast, the virus passaged in the presence of ddI or no drug resumed sensitivity to AZT, but remained sensitive to ddI for 12 mo. Genetic analysis revealed that when propagated with AZT, V118 to I, I142 to V, L210 to W, R211 to K, and T215 to Y persisted for 12 mo, while L74 to V tapered from 6/6 clones in 2 wk to 1/6 in 6 mo and 0/6 in 12 mo. Moreover, G45 to R, undetected before propagation with AZT, emerged in 1/6 clones in 2 wk, 4/6 in 6 mo, and 6/6 in 12 mo. When propagated with ddI, L74 to V and M184 to V persisted for 12 mo, while L210 to W, R211 to K, and T215 to Y became undetectable [0/6] in as early as 2 wk. T39 to A, M41 to L, A98 to S, and L228 to H persisted without regard to the presence or absence of drug. I142 to V persisted when propagated with either AZT or ddI, but not without drug. These data suggest that in this particular strain, G45 to R, V118 to I,I142 to V, L210 to W, R 211 to K, and T215 to Y are related to AZT, while L74 to V, I142 to V, and M184 to V are ddI-related. The complexity of mutation development seen here highlights the capacity of HIV to develop alternative mutations under drug pressure.

Cells, Cultured Deoxycytidine/ANALOGS & DERIVATIVES/*PHARMACOLOGY Drug Resistance, Microbial/*GENETICS Drug Synergism HIV-1/*DRUG EFFECTS/ENZYMOLOGY/GENETICS Mutagenesis, Site-Directed RNA-Directed DNA Polymerase/GENETICS Thionucleosides/*PHARMACOLOGY Zalcitabine/ANALOGS & DERIVATIVES/*PHARMACOLOGY Zidovudine/PHARMACOLOGY ABSTRACT


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