Related Experiment Video
Updated: Sep 25, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Pathways for the emergence of multi-dideoxynucleoside-resistant HIV-1 variants
Shintaro Matsumi1, Pope Kosalaraksa, Hsinyi Tsang
1The Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Objective:
To investigate the mechanism by which the Q151M mutation in reverse transcriptase (RT) that confers multi-dideoxynucleoside resistance on HIV-1 and that requires a two base change (CAG-->ATG) develops, and to understand the reason for the relatively lengthy period of time required for its emergence under therapy with multiple nucleoside RT inhibitors (NRTI).
Design And Methods:
Propagation assays and competitive HIV-1 replication assays were used to evaluate the fitness of various infectious clones, including two putative intermediates (HIV-1(Q151K(AAG)) and HIV-(1Q151L(CTG))) for HIV-1(Q151M(ATG)), in terms of sensitivity to zidovudine and didanosine. Steady-state kinetic constants of recombinant RT were also determined.
Results:
HIV-1(Q151L) replicated relatively poorly while HIV-1(Q151K) failed to replicate. When HIV-1(Q151L) was propagated further, it took three pathways in continuing to replicate: (i) HIV-1(Q151L) changed to HIV-1(Q151M) in eight of 16 experiments; (ii) HIV-1(Q151L) reverted to wild-type HIV-1 (HIV-1(WT)) in four of 16 experiments; and (iii) HIV-1(Q151L) acquired an additional mutation M230I in four of 16 experiments improving HIV-1 fitness. The relative order of replicative fitness without drugs was: HIV-1(Q151M) > HIV-1(WT) > HIV-1(Q151L/M230I) > HIV-1(M230I) >> HIV-1(Q151L) >>> HIV-1(Q151K), HIV-1(Q151K/M230I). HIV-1(Q151M) was less susceptible to drugs, while HIV-1(Q151L/M230I) was as sensitive as HIV-1(WT). Enzymatic assays corroborated that HIV-1(Q151L) is more replication-competent than HIV-1(WT) and HIV-1(Q151K) in the presence of drugs.
Conclusion:
HIV-1(Q151M) probably develops through a poorly replicating HIV-1(Q151L); however, it is also possible that it occurs through two concurrent base changes. The present data should explain the mechanism by which HIV-1(Q151M) emerges after long-term chemotherapy with NRTI.
Related Concept Videos
Retrovirus Life Cycles
Viral Mutations
Antiviral Nucleoside Inhibitors
Inhibitors of Virion Maturation and Assembly
Retroviruses
Viruses with RNA Genomes

