Multidrug resistance genotypes (insertions in the beta 3-beta 4 finger subdomain and MDR mutations) of HIV-1 reverse transcriptase from extensively treated patients: Incidence and association with other resistance mutations

Multiple nucleoside resistance involves specific mutational patterns of the HIV-1 pol gene that are independent of the classic mutations conferring re sistance to individual dideoxynucleosides. These include a cluster of five mutations in the reverse-transcriptase (RT) coding region (A62V, V751, F77L , F116Y, and Q151M) generally referred to as multidrug resistance (MDR) mut ations, and insertions of one or several amino acid residues between codons 67 and 70 of RT,a flexible region joining two antiparrallel beta sheets (b eta 3-beta 4 insertions). The objectives of this study were (i) to determin e the prevalence of multidrug resistance genotypes (MDR mutations and beta 3-beta 4 insertions) in a cohort of 632 patients who were extensively pretr eated with anti-HIV drugs and not responding to their current antiretrovira l therapy, and (ii) to analyze the association of multidrug resistance geno types with other resistance mutations in the RT and protease genes. Among v iruses sequenced from these patients, 15 (2.4%) of them contained an insert ion and 2 (0.3%) contained a deletion in the beta 3-beta 4 finger subdomain of RT. In 9 cases, the insertion was associated with a D67S, G, or E mutat ion. In addition, we identified 13 (2.1%) Viruses harboring specific MDR mu tations (mainly Q151M and/or A62V, V751, F116Y). Interestingly, the A62V mu tation was found in 6 of the 15 strains with an insertion, whereas the othe r MDR mutations were not observed in insertion mutant strains. Especially h igh levels of resistance to zidovudine were observed for viruses with a bet a 3-beta 4 insertion in the background of A62V, L210W, and T215Y. Otherwise , MDR mutations and beta 3-beta 4 insertions were found in association with the classic mutations conferring resistance to zidovudine, lamivudine, non nucleoside RT inhibitors, and protease inhibitors, according to treatment h istory. Finally, we observed a genome with a deletion of codon 70 associate d with a Q151M MDR mutation. These data suggest that the emergence of HIV-1 multidrug resistance, which may occur in various genetic contexts, poses a challenging problem in formulating treatment strategies. (C) 2000 Academic Press.