The impact of HIV-1 within-host evolution on transmission dynamics

Theys, Kristof; Libin, Pieter; Pineda-Peña, Andrea-Clemencia; Nowé, Ann; Vandamme, Anne‐Mieke; Abecasis, Ana

doi:10.1016/j.coviro.2017.12.001

Cited by 43 publications

(33 citation statements)

References 85 publications

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“…As the strength of selective pressure diminishes, resistance development becomes more likely and differences in genetic barriers more pronounced. Related to this, the transmission and persistence of transmitted drug resistance in drug-naive patients could be explored using our estimated cumulative substitution costs (38)(39)(40). Furthermore, our methodology is well suited to explore the effects of global virus diversity for new interventional agents, such as small-molecule integrase inhibitors (e.g., LEDGINS) with a new mechanism of action (41), for which drug resistance mutations are known based only upon in vitro drug resistance selection on July 10, 2020 by guest http://aac.asm.org/ experiments using a limited number of laboratory or clinical strains (41), or even for ongoing drug development efforts guided by structural modeling that can identify new mutational interactions and hence for which the mutational sequence space related to the genetic barrier can be explored.…”

Section: Discussionmentioning

confidence: 99%

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

Theys

Libin

Laethem

et al. 2019

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

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

Theys

Libin

Laethem

et al. 2019

Antimicrob Agents Chemother

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“…Although proviral variants closely related to and including the TF virus persist in the reservoir, reservoir variants are distributed throughout the viral phylogenies for each individual. Plasma variants from one year post-EDI and the last pre-therapy time point exhibited a "ladder-like" topology characteristic of within-host phylogenies [34], where plasma sequences from a given time point formed distinct clades in all intrapatient trees, and reservoir variants fell within or between these clades. In an initial analysis, we classified individual reservoir variants as being most closely related to variants of the clade within which they fall, or as…”

Section: Plos Pathogensmentioning

confidence: 99%

HIV-1 variants are archived throughout infection and persist in the reservoir

et al. 2020

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The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ARTnaïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.

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“…However, the high replication rate of the virus together with the low fidelity of the viral reverse transcriptase, recombination, and hypermutation altogether are responsible for the presence of high amounts of genetic variation. Whenever viral replication is ongoing in the presence of antiretroviral drugs, these variants that may escape the inhibitory effects of the drugs will be selected inducing the development of antiretroviral drug resistance [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Molecular Epidemiology of HIV-1 Infected Migrants Followed Up in Portugal: Trends between 2001–2017

Pimentel

Pingarilho

Alves

et al. 2020

Viruses

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Migration is associated with HIV-1 vulnerability. Objectives: To identify long-term trends in HIV-1 molecular epidemiology and antiretroviral drug resistance (ARV) among migrants followed up in Portugal Methods: 5177 patients were included between 2001 and 2017. Rega, Scuel, Comet, and jPHMM algorithms were used for subtyping. Transmitted drug resistance (TDR) and Acquired drug resistance (ADR) were defined as the presence of surveillance drug resistance mutations (SDRMs) and as mutations of the IAS-USA 2015 algorithm, respectively. Statistical analyses were performed. Results: HIV-1 subtypes infecting migrants were consistent with the ones prevailing in their countries of origin. Over time, overall TDR significantly increased and specifically for Non-nucleoside reverse transcriptase inhibitor (NNRTIs) and Nucleoside reverse transcriptase inhibitor (NRTIs). TDR was higher in patients from Mozambique. Country of origin Mozambique and subtype B were independently associated with TDR. Overall, ADR significantly decreased over time and specifically for NRTIs and Protease Inhibitors (PIs). Age, subtype B, and viral load were independently associated with ADR. Conclusions: HIV-1 molecular epidemiology in migrants suggests high levels of connectivity with their country of origin. The increasing levels of TDR in migrants could indicate an increase also in their countries of origin, where more efficient surveillance should occur.

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The impact of HIV-1 within-host evolution on transmission dynamics

Cited by 43 publications

References 85 publications

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

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

HIV-1 variants are archived throughout infection and persist in the reservoir

Molecular Epidemiology of HIV-1 Infected Migrants Followed Up in Portugal: Trends between 2001–2017

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