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Abstract:
Resistance to antivirals is a complex and dynamic phenomenon that involves more
mutations than are currently known. Here, we characterize 10 additional
mutations (L74V, K101Q, I135M/T, V179I, H221Y, K223E/Q, and L228H/R) in human
immunodeficiency virus type 1 (HIV-1) reverse transcriptase which are involved
in the regulation of resistance to nonnucleoside reverse transcriptase
inhibitors (NNRTIs). These mutations are strongly associated with NNRTI failure
and strongly correlate with the classical NNRTI resistance mutations in a data
set of 1,904 HIV-1 B-subtype pol sequences from 758 drug-naïve patients, 592
nucleoside reverse transcriptase inhibitor (NRTI)-treated but NNRTI-naïve
patients, and 554 patients treated with both NRTIs and NNRTIs. In particular,
L74V and H221Y, positively correlated with Y181C, were associated with an
increase in Y181C-mediated resistance to nevirapine, while I135M/T mutations,
positively correlated with K103N, were associated with an increase in
K103N-mediated resistance to efavirenz. In addition, the presence of the I135T
polymorphism in NNRTI-naïve patients significantly correlated with the
appearance of K103N in cases of NNRTI failure, suggesting that I135T may
represent a crucial determinant of NNRTI resistance evolution. Molecular
dynamics simulations show that I135T can contribute to the stabilization of the
K103N-induced closure of the NNRTI binding pocket by reducing the distance and
increasing the number of hydrogen bonds between 103N and 188Y. H221Y also
showed negative correlations with type 2 thymidine analogue mutations (TAM2s);
its copresence with the TAM2s was associated with a higher level of zidovudine
susceptibility. Our study reinforces the complexity of NNRTI resistance and the
significant interplay between NRTI- and NNRTI-selected mutations. Mutations
beyond those currently known to confer resistance should be considered for a
better prediction of clinical response to reverse transcriptase inhibitors and
for the development of more efficient new-generation NNRTIs.
