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Sturmer et al. presented an interesting paper (1) on the influence of the classic zidovudine (ZDV) mutation patterns and the role of the additional mutations at positions 208, 211, 214, and 333 on phenotypic ZDV resistance. The presence of the 211/214 mutation combination in the background of genotypic highly ZDV-resistant viruses increased ZDV resistance 2.4-fold, and the 208/211/214 combination increased ZDV resistance 8-fold. The authors suspect a stabilization mechanism of the three-dimensional structure of the enzyme that could be explained by the vicinity of the mutations at positions 208, 211, and 214 to the ZDV-associated mutations L210W and T215Y/F.These mutations are likely involved in the compensation of the possible loss of fitness caused by the T215Y/F mutation.  We investigated the drug susceptibility of human immunodeficiency virus (HIV) strains of 19 HIV-infected patients failing double nucleoside reverse transcriptase inhibitor (NRTI) therapy by using the genotypic and the phenotypic assays. We identified four patterns of genotypic resistance (Table ​(Table1),1), namely, pattern 1, in patients with the 184V mutation alone; pattern 2, in patients with the 184V mutation combined with the 208Y, 211K, and/or 214F mutations; pattern 3, in patients with the 184V mutation and thymidine analogue mutations (TAMs) (including 41L, 210W, 215Y/F, and/or 219Q/E); and pattern 4, in patients with TAMs and the 184V mutation combined with the 208Y, 211K, and/or 214F mutations. As expected, genotypic patterns 1 and 3 showed a phenotypic resistant pattern to lamivudine (3TC) alone and to both 3TC and ZDV, respectively. The presence of 208/211/214 polymorphism combined with the 184V mutation (genotypic pattern 2) was related to a high phenotypic cross-resistance within all NRTIs analyzed. The presence of TAMs in addition to this pattern (genotypic pattern 4) showed a reduced phenotypic resistance for stavudine (d4T) and, to a smaller extent, for didanosine, ZDV, and abacavir.    TABLE 1.  Pattern of genotypic and phenotypic resistance of 19 HIV strains of patients failing double NRTI therapy    The impact of the 208/211/214 polymorphism in terms of NRTI drug susceptibility on a background of a resistant virus appears to be related to the presence of the 184V mutation alone. High cross-resistance to all NRTIs has been detected only in HIV strains with this polymorphism combined with the 184V mutation in absence of TAMs. This particular genotypic-phenotypic pattern was detected among patients treated with d4T and 3TC. This phenomenon is likely to be related to the presence of different pathways in the emergence of NRTI resistance mutations in HIV-infected patients failing a d4T-3TC or ZDV-3TC regimen. Longitudinal studies are needed to evaluate the significance of this polymorphism in the clinical outcome of patients treated with highly active antiretroviral therapy.

Human Immunodeficiency Virus Polymorphisms and Zidovudine Resistance