An Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase Inhibitors

Abstract

Viral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or expanded into new patient populations. We developed an evolutionary model-based counting method to quickly quantify the population genetic potential to resistance and assess population differences. We demonstrate its applicability to HIV-1 integrase inhibitors, as their increasing use globally contrasts with limited availability of non-B subtype resistant sequence data and corresponding knowledge gap. A large sequence data set encompassing most prevailing HIV-1 subtypes and resistance-associated mutations of currently approved integrase inhibitors was investigated. A complex interplay between codon predominance, polymorphisms, and associated evolutionary costs resulted in a subtype-dependent varied genetic potential for 15 resistance mutations against integrase inhibitors. While we confirm the lower genetic barrier of subtype B for G140S, we convincingly discard a similar effect previously suggested for G140C. A supplementary analysis for HIV-1 reverse transcriptase inhibitors identified a lower genetic barrier for K65R in subtype C through differential codon usage not reported before. To aid evolutionary interpretations of genomic differences for antiviral strategies, we advanced existing counting methods with increased sensitivity to identify subtype dependencies of resistance emergence. Future applications include novel HIV-1 drug classes or vaccines, as well as other viral pathogens.

Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

“…Our data showed polymorphisms and mutations in the integrase in both groups, similar to previous studies showing that mutations and resistance to INSTIs can occur in both clades-B, CRF02_AG and non-AG subtypes [70,71,73]. However, the frequencies of such mutations can vary based on viral genotype [74]. The aa substitutions E92Q, S119R, E138A, Y143R, G148H/R, and S230R/N are more prevalent in subtype-B than in non-B subtypes [71,[74][75][76], whereas mutations such as L74I/M, T97A, L101I, E157Q, T214A, and V201I are more prevalent in non-B subtypes compared to HIV-1 subtype B [71,74,77].…”

“…However, the frequencies of such mutations can vary based on viral genotype [74]. The aa substitutions E92Q, S119R, E138A, Y143R, G148H/R, and S230R/N are more prevalent in subtype-B than in non-B subtypes [71,[74][75][76], whereas mutations such as L74I/M, T97A, L101I, E157Q, T214A, and V201I are more prevalent in non-B subtypes compared to HIV-1 subtype B [71,74,77]. Because the vast majority of PLWH on INSTIs are people infected with HIV-1 subtype B, most INSTIs resistance-conferring mutations that have been characterized pertain to HIV-1 subtype B.…”

“…It is likely that several mutations prevalent in non-B subtypes could affect the genetic barrier and INSTIs efficacy. In fact, computational modeling of INSTIs resistance development across different HIV-1 subtypes showed that compared to subtype B, the presence of M50I in subtypes A and C, L74I in subtypes A and CRF02_AG, G163R in CRF01_AE, and V165I in subtypes F and CRF01_AE would be associated with lower genetic barrier to resistance in these non-B clades [74]. With increased use of INSTIs by individuals infected with non-B viruses, it is important to monitor these subjects for viral escape in the context of selection pressure [74] and identify the RAM and polymorphic mutations that alter the genetic barrier to resistance and INSTIs efficacy and the role of viral genotype.…”

“…The genetic barrier is measured by evolutionary time to viral escape in the context of a selection pressure [74] and previous studies showed that development of HIV resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors resulted in part to subtype-associated preferential codon usages and that different amino acid substitutions influenced the likelihood of development of drug resistance [78][79][80]. INSTIs are the newest class of anti-HIV drugs approved for use in HIV/AIDS treatment, and modeling of HIV-1 integrase sequences showed that viral subtypes and codon substitution would differentially affect the genetic barrier to the development of INSTIs resistance [74]. Most mutational pathways linked to higher or lower genetic barrier to resistance to INSTIs come from subtype B infected subjects in resource-rich countries.…”

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

“…Moreover, data about the role of DRMs in INSTI and about the natural variability of integrase are predominantly available for viruses of subtype B, which represents less than 10% of the globally circulating viruses. However, because of the high variability in codon usage between subtypes, particular HIV-1 subtypes could have different genetic barriers for DRMs [31][32][33].…”