Combined doravirine and islatravir cooperate to inhibit NRTI and NNRTI resistant HIV-1 in vitro

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research Pub Date : 2025-04-18 DOI:10.1016/j.antiviral.2025.106157

Federica Giammarino , Chiara Paletti , Niccolò Bartolini , Lia Fiaschi , Camilla Biba , Ilenia Varasi , Emanuele Focà , Roberto Gulminetti , Micol Ferrara , Laura Comi , Ilaria Vicenti , Antonella Castagna , Maurizio Zazzi , Francesco Saladini , PRESTIGIO Study Group

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引用次数: 0

Abstract

Doravirine and islatravir have shown promising activity against multidrug resistant HIV-1. In this study we aimed to evaluate the in vitro susceptibility to doravirine and islatravir as well as their combinatorial activity in a panel of 38 recombinant viruses harboring multiple NRTI and NNRTI mutations. One additional recombinant virus had the M184V mutation alone. According to the IC₅₀ fold-change (FC) values calculated with respect to the NL4-3 wild-type strain, full susceptibility to doravirine was detected in 15/39 (38.5 %) samples, while high-level resistance was mainly associated with specific doravirine resistance mutations. Decreased susceptibility to islatravir was associated with the presence of the M184V/I mutation and increasing numbers of TAMs and NRTI resistance mutations. According to ZIP model of the SynergyFinder Plus tool, the combination of doravirine and islatravir showed additive activity in 37/40 (92.5 %) viruses (including the NL4-3 strain), while synergy and antagonism in one and two cases, respectively. The combination sensitivity score calculated by SynergyFinder Plus indicated a cooperative effect between doravirine and islatravir higher than that observed for the reference NL4-3 strain in 22 (56 %) recombinant viruses. The Multi-dimensional Synergy of Combinations (MuSyC) tool predicted synergy and antagonism in 25 (62.5 %, including NL4-3 virus) and 15 (37.5 %) cases, respectively. MuSyC scores showed a negative correlation with doravirine FC values, number of NRTI mutations and presence of M184V/I, but not with islatravir FC values. Doravirine and islatravir may cooperatively inhibit NRTI and NNRTI resistant viruses despite complex mutational profiles, however the accumulation of resistance mutations may reduce the combinatorial activity.

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doravirine和islatravir联合体外抑制NRTI和NNRTI耐药HIV-1。

Doravirine和islatravir已经显示出对多药耐药HIV-1的有希望的活性。在这项研究中，我们旨在评估doravirine和islatravir的体外敏感性，以及它们在38个含有多种NRTI和NNRTI突变的重组病毒中的组合活性。另外一个重组病毒仅具有M184V突变。根据NL4-3野生型菌株的IC50倍变（FC）值计算，15/39（38.5%）株对doravirine完全敏感，而高水平耐药主要与特异的doravirine耐药突变相关。对islatravir的敏感性降低与M184V/I突变的存在以及tam和NRTI耐药突变数量的增加有关。根据SynergyFinder Plus工具的ZIP模型，doravirine和islatravir联合对37/40（92.5%）病毒（包括NL4-3毒株）具有加性活性，而对1例和2例分别具有协同和拮抗作用。使用SynergyFinder Plus计算的联合敏感性评分显示，doravirine与islatravir在22种（56%）重组病毒中的协同效果高于参考NL4-3菌株。Multi-dimensional Synergy of combination （MuSyC）工具分别预测了25例（62.5%，包括NL4-3病毒）和15例（37.5%）的协同作用和拮抗作用。MuSyC评分与doravirine FC值、NRTI突变数和M184V/I的存在呈负相关，而与islatravir FC值无相关性。Doravirine和islatravir可以协同抑制NRTI和NNRTI耐药病毒，尽管有复杂的突变谱，但耐药突变的积累可能会降低组合活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Antiviral research 医学-病毒学

CiteScore

17.10

自引率

3.90%

发文量

157

审稿时长

34 days

期刊介绍： Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.