Background: Natural variability of integrase (IN) across HIV-1 variants may influence the
emergence of resistant viruses. The most apparent explanation of this fact is the IN polymorphism and
the associated differences in codon usage, which in turn, influence the probability and the terms of
DRMs acquisition. Possible mechanisms by which polymorphisms affect DRMs emergence remain
disputed and should still be clarified because these substitutions may be associated with a reduced activity
of some INSTIs and may impact on ART regimen choice depending of HIV-1 subtype.
Objective: The aim of this work was to assess the prevalence of naturally occurring polymorphisms
within the HIV-1 integrase gene, which might influence the susceptibility to INSTIs, among the patients
from Russia and former USSR countries, according to HIV-1 subtypes.
Method: A study involved 506 HIV-1 IN sequences of INSTI-naive patients from Russia, Ukraine,
Armenia, Kyrgyzstan, Kazakhstan, Uzbekistan, Belarus, and Georgia. Among them, 194 sequences
were newly obtained in this study and 312 were downloaded from Los-Alamos database. The proviral
DNA was sequenced using an in-house PCR protocol designed on the basis of a well-conserved
integrase region in order to detect all HIV-1 variants.
Results: The phylogenetic analyses based on IN population sequencing found subtype A6 being the
most prevalent (259) (51.2%) in the collection studied, followed by subtype G (36) (7.1%), AGrecombinants
(148) (29.3%), subtype B (50) (9.9%), and CRF03_AB (5) (1.0%). The major INSTI
resistance-associated mutations (DRMs) were found only in two A6 samples. The prevalence of minor/
accessory substitutions depended on HIV-1 variants, while the most notable findings were L74I
in subtype A6 (93.1%) and E157Q in subtype B (44.0%). Most of minor DRMs and polymorphic
substitutions were concentrated in the central catalytic domain of the IN molecule. Both the DDE
triad and HHCC zinc binding motifs were fully conserved.
Conclusion: The results of the study suggest a very low risk of initiating INSTI-based therapy in patients
with pre-existing polymorphic mutations in Russia and FSU countries. The therapy response
in dominating HIV-1 genetic variants might be further studied in the future for a better understanding
of their effect on INSTI susceptibility. The INSTI TDR is absent for the moment, but the risk
may increase with expanded use of INSTIs, indicating the need for ongoing surveillance.