Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing

Melikian, George; Rhee, Soo-Yon; Varghese, Vici; Porter, Danielle; White, Kirsten; Taylor, Jonathan; Towner, William; Troia, Paolo; Burack, Jeffrey H.; DeJesus, Edwin; Robbins, Gregory K.; Razzeca, Kristin; Kagan, Ron M.; Liu, Tommy F.; Fessel, W. Jeffrey; Israelski, Dennis; Shafer, Robert W.

doi:10.1093/jac/dkt316

Cited by 107 publications

(108 citation statements)

References 35 publications

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“…Differences in susceptibility between subtypes B and C with substitutions at position 138, including E138A, which did not confer resistance in our study, were also noted in another study (40). In a comprehensive analysis of genotype-phenotype correlations performed predominantly on clinical subtype B sequences, amino acid substitutions K101P, Y181I/V, Y188L, and M230L have also been shown to contribute toward decreased susceptibility or resistance to ETR/RPV (41). The K101P amino acid substitution conferred a level of reduction in ETR susceptibility higher than that found in the current study.…”

Section: Discussionsupporting

confidence: 76%

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Basson

Rhee

Parry

et al. 2015

Antimicrob Agents Chemother

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The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in an in vitro single-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients. Highly active antiretroviral therapy (HAART), which comprises the concomitant use of multiple potent antiretroviral drugs, has contributed to a significant decrease in the morbidity and mortality of people infected with HIV-1 (1). The failure of HAART through the acquisition of HIV drug resistance-associated substitutions that cause a decrease in viral susceptibility is usually due to poor adherence and insufficient drug concentrations. Although more than two-thirds of the global HIV-1 infections occur in sub-Saharan African countries, where HIV-1 infections are dominated by non-B subtypes, HAART regimens have largely been developed and tested against HIV-1 subtype B isolates (2). Subtype C accounts for almost half of all global infections and dominates the epidemic in southern Africa (3). While HAART agents are effective against all subtypes (4), greatly aiding the global response to HIV infection, specific resistance mutations and disparities in drug susceptibilities can differ by subtype (5). Examples include the K65R (6) and V106M (7) resistance-associated amino acid substitutions, which develop more frequently under drug pressure in HIV-1 subtype C than subtype B.Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are a component of most first-line HAART regimens. For efavirenz (EF...

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Section: Discussionsupporting

confidence: 76%

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Basson

Rhee

Parry

et al. 2015

Antimicrob Agents Chemother

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“…The E138K mutation emerges both in vitro and in vivo and confers cross-resistance to ETR and RPV by reducing susceptibility 2-to 3-fold (38)(39)(40)92), but E138K was shown to have no cross-resistance to NVP or EFV (40). In the ECHO and THRIVE clinical trials that led to the approval of RPV for use in treatmentnaive patients, E138K was the most frequent NNRTI mutation at treatment failure (36,87), indicating that E138K is a signature mutation for this drug.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the E138K mutation in RT is associated with RPV-related virologic failure (36) and has also been selected by both ETR and RPV in cell culture (37,38). Although E138K confers modestly reduced susceptibility to ETR and RPV (37)(38)(39)(40), it does not result in reduced susceptibility to EFV and NVP (40)(41)(42). The mechanism of E138K-mediated RPV resistance is an increase in the dissociation rate of RPV, which overcomes a smaller enhancement in its rate of association (11).…”

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The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Colby-Germinario

Oliveira

et al. 2014

J Virol

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Clinical resistance to rilpivirine (RPV), a novel nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI), is associated an E-to-K mutation at position 138 (E138K) in RT together with an M184I/V mutation that confers resistance against emtricitabine (FTC), a nucleoside RT inhibitor (NRTI) that is given together with RPV in therapy. These two mutations can compensate for each other in regard to fitness deficits conferred by each mutation alone, raising the question of why E138K did not arise spontaneously in the clinic following lamivudine (3TC) use, which also selects for the M184I/V mutations. In this context, we have investigated the role of a N348I connection domain mutation that is prevalent in treatment-experienced patients. N348I confers resistance to both the NRTI zidovudine (ZDV) and the NNRTI nevirapine (NVP) and was also found to be associated with M184V and to compensate for deficits associated with the latter mutation. Now, we show that both N348I alone and N348I/ M184V can prevent or delay the emergence of E138K under pressure with RPV or a related NNRTI, termed etravirine (ETR). N348I also enhanced levels of resistance conferred by E138K against RPV and ETR by 2.2-and 2.3-fold, respectively. The presence of the N348I or M184V/N348I mutation decreased the replication capacity of E138K virus, and biochemical assays confirmed that N348I, in a background of E138K, impaired RT catalytic efficiency and RNase H activity. These findings help to explain the low viral replication capacity of viruses containing the E138K/N348I mutations and how N348I delayed or prevented the emergence of E138K in patients with M184V-containing viruses.

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“…As other CYP isoforms are also (partially) inhibited by the boosters, the treatment of co-morbidities with additional drugs may require individual modifications, and the overall assessment of all potential drug-drug-interactions is highly complex 39,[43][44][45] . Furthermore, these issues come in hand with another relevant problem: when there are many drugs against a single viral target, virus variation may generate cross-resistant mutants that would reduce therapy efficiency 46,47 . Thus there is a need to develop antiviral drugs that could alone be effective against different viral pathogens.…”

Section: Many For One: Many Drugs One Targetmentioning

confidence: 99%

Antiviral drug discovery: broad-spectrum drugs from nature

et al. 2015

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, but cannot be converted to PDF. You must view these files (e.g. movies) online.Scheme 1_(structures 1-5)_named.cdx Scheme 2_(structures 6-8)_named.cdx Scheme 3_(structure 9)_named.cdx Scheme 4_(structure 10)_named.cdx Scheme 5_ (structures 11-12) The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with skepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has rebloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, taking particular focus on natural products as promising starting points for antiviral lead development.

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Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing

Cited by 107 publications

References 35 publications

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Antiviral drug discovery: broad-spectrum drugs from nature

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