In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors &amp; In Silico Phenotypic Analysis

Rath, Barbara; Yousef, Kaveh Pouran; Katzenstein, David; Shafer, Robert W.; Schütte, Christof; Kleist, Max von; Merigan, Thomas C.

doi:10.1371/journal.pone.0061102

Cited by 7 publications

(6 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the MMOA model allows to assess the fitness costs associated with these mutations. In line with ex vivo experiments, both the M184V and K65R mutant conferred a fitness disadvantage predicted by the MMOA model. (

f (mut) =

63, 55 and 46% of the wildtype fitness for M184V, K65R, and the M184V/K65R double mutant).…”

Section: Resultssupporting

confidence: 64%

Multiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1

Duwal

Sunkara

Kleist

2016

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

While HIV‐1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target‐cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir‐diphosphate builds up too slowly to halt infection when taken “on demand” and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy.

show abstract

f (mut) =

63, 55 and 46% of the wildtype fitness for M184V, K65R, and the M184V/K65R double mutant).…”

Section: Resultssupporting

confidence: 64%

Multiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1

Duwal

Sunkara

Kleist

2016

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

show abstract

“…in vivo data demonstrate that there are several pathways the virus takes in an effort to achieve a resistant phenotype. Published work also shows the unique pathways to resistance to other RT inhibitors [37], [38] as well as the incompatibility of certain DRM combinations, which might influence the eventual resistant genotype [36]. As previously observed after ARV treatment of SHIV-infected macaques, the proportion of plasma sequences with DRMs increased with time on drug [39] and with unsuppressed viral replication [40].…”

Section: Discussionsupporting

confidence: 64%

Exposure to MIV-150 from a High-Dose Intravaginal Ring Results in Limited Emergence of Drug Resistance Mutations in SHIV-RT Infected Rhesus Macaques

et al. 2014

View full text Add to dashboard Cite

When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.

show abstract

“…When treating influenza infections in infants for example, a lag in virologic response could be an early indicator for resistance development (14). This resembles experiences made with the use of antiretrovirals (58–60). Whenever we think about antiviral resistance development, we need to check for adequate dosing and routes of administration.…”

Section: Questions and Answersmentioning

confidence: 54%

Advancing challenges in Paediatric Virology: An interview with Professor Barbara A. Rath, Co‑founder and Chair of the Vienna Vaccine Safety Initiative

Mammas

Spandidos

2019

Exp Ther Med

View full text Add to dashboard Cite

The Vienna Vaccine Safety Initiative (ViVI) is an international, scientific, non-profit, research organization, which aims to promote research, clinical practice and communication on Paediatric Infectious Diseases (PID) in a globalized healthcare setting, to facilitate the implementation of high standards in vaccine safety and efficacy and to support international and interdisciplinary scientific collaboration. Professor Barbara A. Rath, Chair and Co-founder of the Vienna Vaccine Safety Initiative, advocates for the establishment of global research networks in the field of neonatal and paediatric viral infections. Viruses do not respect borders, and large datasets are required and joint action is necessary to further strengthen efforts towards viral diseases eradication and prevention. She encourages the paediatric community to embrace the new opportunities technology offers for healthcare and medical education. To date, the Vienna Vaccine Safety Initiative has developed a number of innovative mobile applications and diagnostic tools, such as the 'VAccApp', which helps parents understand which vaccines were administered to their children, the 'ViVI Disease Severity Score', which measures clinical severity in patients with acute respiratory infections and flu-like illnesses, the 'VACC Tool', which assesses patient's clinical presentation to a set of diagnostic algorithms for adverse events following immunization and the 'ViVI Health Survey', which enables children and young adults on the move to report health needs securely and confidentially. Professor Rath agrees that during this decade there is momentum in the field of Paediatric Virology, as new antivirals and vaccines emerge and are finally becoming available to children. In the future, 'in-house' specialists for Paediatric Virology could be helpful to provide quality of care and reduce antimicrobial resistance by providing individual as well as hospital-wide consultations and advice. She estimates that Paediatric Virology will eventually find its place in the context of PID and Vaccinology. Contents 1. Introduction 2. Questions and Answers

show abstract

In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis

Cited by 7 publications

References 54 publications

Multiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1

Multiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1

Exposure to MIV-150 from a High-Dose Intravaginal Ring Results in Limited Emergence of Drug Resistance Mutations in SHIV-RT Infected Rhesus Macaques

Advancing challenges in Paediatric Virology: An interview with Professor Barbara A. Rath, Co‑founder and Chair of the Vienna Vaccine Safety Initiative

Contact Info

Product

Resources

About