A uniquely prevalent nonnucleoside reverse transcriptase inhibitor resistance mutation in Russian subtype A HIV-1 viruses

Abstract

Background The subtype A variant in the Former Soviet Union (AFSU) causes most of Russia’s HIV-1 infections. However, the spectrum of drug-resistance mutations (DRMs) in antiretroviral experienced patients with this variant has not been studied. Methods Between 2010 and 2013, genotypic resistance testing was performed on plasma samples from 366 antiretroviral-experienced patients in Siberia. Results Three-hundred patients (82%) had subtype AFSU and 55 (15%) had CRF02_AG viruses. The pattern of DRMs was consistent with patient antiretroviral history with one exception. G190S was the most common nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutation, occurring in 55 (33%) subtype AFSU viruses from 167 NNRTI-experienced patients compared with none of 37 CRF02_AG viruses from NNRTI-experienced patients (P < 0.001). The next most common subtype AFSU NNRTI-resistance mutation, K103N, occurred in 25 (15%) viruses. Wild-type glycine (G) at position 190 is encoded by GGC in more than 99% of published AFSU strains. By contrast, G190 is encoded by GGA or GGG in 97% of other subtypes and in subtype A strains outside of the FSU. Therefore, G190S results from a single G→A transition: G (GGC) → S (AGC) almost exclusively in subtype AFSU viruses. Conclusion The predisposition of subtype AFSU to G190S is concerning because G→A is the most common HIV-1 mutation and because G190S causes higher levels of nevirapine and efavirenz resistance than K103N. This study exemplifies the need for characterizing the genetic mechanisms of resistance in diverse populations and warrants studies to verify that NRTI/NNRTI regimens are as efficacious in treating subtype AFSU as viruses belonging to other subtypes.

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

“…The A62V RT alone is rare in subtype B, TN-samples as it reduces the replication capacity of these variants to 50% compared to the wild type (wt) virus [37]. In A6 samples, A62V RT is an endemic polymorphism with similarly high prevalence among TN and TE patients [9,38,39]. These prevalence trends strongly suggest that this mutation probably does not lead to a sharp reduction of replication capacity in the context of sub-subtype A6, though no experimental data to confirm this hypothesis are available yet.…”

HIV-1 Epidemiology, Genetic Diversity, and Primary Drug Resistance in the Tyumen Oblast, Russia

“…In Russia and the CIS countries, the HIV variants carrying DR mutations in pol gene are most frequently detectable in the individuals with inefficient ART. Among them, the mutations G190S, K103N, M184V, Y181C, K101E, M41L, and T215F/Y, influencing the HIV resistance to NRTIs and NNRTIs, are observed at a high rate [19–24]. Mutations K103N, M184I, T215Y, G190S, Y181C, K65R, and V108I with prevalences of 0.3 to 7% depending on the region are most frequently detected in the naïve HIV-infected individuals [21–28].…”

HIV-1 drug resistance and resistance testing

“…The NNRTI DRM V106M occurs more often in subtype C viruses from patients treated with NVP or EFV because V106M requires a single base-pair change in subtype C viruses – GTG (V) => ATG (M) – but a two base-pair change in all other subtypes – GTA (V) => ATG (M) (Brenner et al, 2003). CRF01_AE viruses preferentially develop the NRTI DRM V75M (Ariyoshi et al, 2003), subtype G viruses preferentially develop the PI DRM V82M (Palma et al, 2012), and subtype A viruses from the former Soviet Union (AFSU) preferentially develop the NNRTI DRM G190S (Kolomeets et al, 2014) by a similar mechanism.…”