4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

EVIDENCE FOR A ROLE OF THE Q151L MUTATION AND THE VIRAL BACKGROUND IN THE DEVELOPMENT OF MULTIPLE DIDEOXYNUCLEOSIDE-RESISTANT HIV-1

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):17 (Abstract 20

JG García Lerma¹, PJ Gerrish², AC Wright¹, SH Qari¹ and W Heneine^1
1HIV and Retrovirology Branch, Centers for Disease Control and Prevention, Atlanta Ga.; and ²Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, N.M., USA

The majority of HIV-1-infected patients treated with zidovudine plus zalcitabine/didanosine develop zidovudine resistance mediated by mutations such as T215Y and M41L. Only a small proportion of patients develop multiple dideoxynucleoside resistance (MDNR) mediated by the Q151M mutation. To gain insight into the factors responsible for the low frequency of selection of Q151M, we evaluated replication capabilities of recombinant viruses carrying two possible intermediates (151L or 151K) of the Q151M mutation generated in different reverse transcriptase (RT) genetic backgrounds. The 151L and 151K mutations were introduced by site-directed mutagenesis in RTs from two HIV-1 isolates obtained from the same patient that had either wild-type (WT) Q or the Q151M (post-treatment isolate) mutation. For comparison, both mutations were also introduced in a laboratory-adapted HIV-1 strain (HIV-1_HXB2). Analysis of replication capabilities showed that both 151L and 151K were lethal in RT genetic backgrounds of the WT isolate and in HIV-1_HXB2. In contrast, 151L but not 151K allowed virus replication in RT backgrounds of the post-treatment isolate. Three mutations (V35I, S68G and I178M) were present in the RT background of the post-treatment isolate but not in the WT isolate. Introduction of S68G in the RT of both the WT isolate and HIV-1_HXB2 partially restored replication capacity of recombinant viruses carrying the 151L mutation. The S68G mutation alone did not confer a significant replicative disadvantage in WT viruses. HIV-1_151L had a level of zidovudine resistance similar to that of HIV-1_151M. However, HIV-1_151L was found to be less fit than HIV-1_151M, which may explain the preferential selection of HIV-1_151M observed in vivo. The demonstrated ability of HIV-1_151L/68G to replicate and the associated zidovudine resistance suggest that 151L is a potential intermediate of Q151M. The dependence of HIV-1_151L on other mutations such as S68G for replication may explain the low frequency of the Q151M-mediated pathway of resistance.

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2000-06-12
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