Abstract
BackgroundDetailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We therefore set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs).MethodsWe determined 337 HIV-1 integrase subtype B sequences (amino acids 1–278) from stored plasma samples of antiretroviral treatment-naïve individuals newly diagnosed with HIV-1 between 1986 and 2006. Shannon entropy was calculated to determine the variability at each amino acid position. Time trends in the frequency of amino acid variants were identified by linear regression. Direct coupling analysis was applied to detect covarying sites.ResultsTwenty-two time trends in the frequency of amino acid variants demonstrated either single amino acid exchanges or variation in the degree of polymorphy. Covariation was observed for 17 amino acid variants with a temporal trend. Some minor INSTI resistance mutations (T124A, V151I, K156 N, T206S, S230 N) and some INSTI-selected mutations (M50I, L101I, T122I, T124 N, T125A, M154I, G193E, V201I) were identified at overall frequencies >5%. Among these, the frequencies of L101I, T122I, and V201I increased over time, whereas the frequency of M154I decreased. Moreover, L101I, T122I, T124A, T125A, M154I, and V201I covaried with non-resistance-associated variants.ConclusionsTime-trending, covarying polymorphisms indicate that long-term evolutionary changes of the HIV-1 integrase involve defined clusters of possibly structurally or functionally associated sites independent of selective pressure through INSTIs at the inter-patient level. Linkage between polymorphic resistance- and non-resistance-associated sites can impact the selection of INSTI resistance mutations in complex ways. Identification of these sites can help in improving genotypic resistance assays, resistance prediction algorithms, and the development of new integrase inhibitors.
Highlights
Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor
Characteristics of the study population All 337 individuals were newly diagnosed with HIV-1, antiretroviral treatment (ART)-naïve, and infected with an HIV-1 subtype B strain
Frequency of integrase strand inhibitors (INSTIs) resistance mutations As expected, no major INSTI resistance mutations were detected in this ART-naïve study population from the period prior to INSTI release
Summary
Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs). The HIV-1 integrase catalyses the integration of the reverse transcribed viral DNA into the host genomic DNA via a two-step process. Raltegravir was the first integrase strand inhibitor (INSTI) to be approved in Europe in 2007, followed by elvitegravir in 2012 and dolutegravir in 2014. INSTIs target the CCD, thereby inhibiting the strand transfer of the double-stranded viral DNA into the host genome [1]. Various allosteric inhibitors of integrase (ALLINIs), which modulate integrase multimerisation [9] and interfere with the cellular transcription factor LEDGF/p75 [10] are in development but have not so far made it further than Phase I clinical trial [11]
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