scholarly journals Early selection of resistance-associated mutations in HIV-1 RT C-terminal domains across different subtypes: role of the genetic barrier to resistance

2014 ◽  
Vol 69 (10) ◽  
pp. 2741-2745 ◽  
Author(s):  
C. P. Muniz ◽  
M. A. Soares ◽  
A. F. Santos
Keyword(s):  
Early Selection ◽  
Genetic Barrier ◽  
Hiv 1 ◽  
Selection Of ◽  
Selection Of Resistance ◽  
Terminal Domains

Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness

2020 ◽  
Vol 7 (1) ◽  
pp. 385-402
Author(s):  
Bernadien M. Nijmeijer ◽  
Catharina J.M. Langedijk ◽  
Teunis B.H. Geijtenbeek
Keyword(s):  
Dendritic Cell ◽  
Sexual Transmission ◽  
Treatment Strategies ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Novel Treatment Strategies ◽  
Hiv 1 ◽  
Selection Of

Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.

scholarly journals In vitro study of the trans-epithelial crossing of HIV-1 through the female genital mucosa and of the role of epithelial cells in the selection of CCR5-tropic virus

Retrovirology ◽  
2012 ◽  
Vol 9 (S1) ◽  
Author(s):  
R Terrasse ◽  
O Delezay ◽  
A Brunon-Gagneux ◽  
L Heyndrickx ◽  
H Hamzeh-Cognasse ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
In Vitro Study ◽  
Vitro Study ◽  
Genital Mucosa ◽  
Hiv 1 ◽  
Selection Of ◽  
Female Genital

scholarly journals Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

2013 ◽  
Vol 57 (9) ◽  
pp. 4105-4113 ◽  
Author(s):  
Wei Huang ◽  
Arne Frantzell ◽  
Signe Fransen ◽  
Christos J. Petropoulos
Keyword(s):  
Amino Acid ◽  
Amino Acid Position ◽  
Amino Acid Sequences ◽  
Resistance Testing ◽  
Cross Resistance ◽  
Genetic Barrier ◽  
Lower Resistance ◽  
Secondary Amino ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTY143C,R substitutions in HIV-1 integrase define one of three primary raltegravir (RAL) resistance pathways. Here we describe clinical isolates with alternative substitutions at position 143 (Y143A, Y143G, Y143H, and Y143S [Y143A,G,H,S]) that emerge less frequently, and we compare the genotypic and phenotypic profiles of these viruses to Y143C,R viruses to reconcile the preferential selection of Y143C,R variants during RAL treatment. Integrase amino acid sequences and RAL susceptibility were characterized in 117 patient isolates submitted for drug resistance testing and contained Y143 amino acid changes. The influence of specific Y143 substitutions on RAL susceptibility and their preferential association with particular secondary substitutions were further defined by evaluating the composition of patient virus populations along with a large panel of site-directed mutants. Our observations demonstrate that the RAL resistance profiles of Y143A,G,H,S viruses and their association with specific secondary substitutions are similar to the well-established Y143C profile but distinct from the Y143R profile. Y143R viruses differ from Y143A,C,G,H,S viruses in that Y143R confers a greater reduction in RAL susceptibility as a single substitution, consistent with a lower resistance barrier. Among Y143A,C,G,H,S viruses, the higher prevalence of Y143C viruses is the result of a lower genetic barrier than that of the Y143A,G,S viruses and a lower resistance barrier than that of the Y143H viruses. In addition, Y143A,C,G,H,S viruses require multiple secondary substitutions to develop large reductions in RAL susceptibility. Patient-derived viruses containing Y143 substitutions exhibit cross-resistance to elvitegravir.

scholarly journals Trimeric, Coiled-coil Extension on Peptide Fusion Inhibitor of HIV-1 Influences Selection of Resistance Pathways

2012 ◽  
Vol 287 (11) ◽  
pp. 8297-8309 ◽  
Author(s):  
Min Zhuang ◽  
Wei Wang ◽  
Christopher J. De Feo ◽  
Russell Vassell ◽  
Carol D. Weiss
Keyword(s):  
Coiled Coil ◽  
Fusion Inhibitor ◽  
Hiv 1 ◽  
Peptide Fusion Inhibitor ◽  
Selection Of ◽  
Selection Of Resistance

Role of CD8+T Cells in the Selection of HIV-1 Immune Escape Mutations

2017 ◽  
Vol 30 (1) ◽  
pp. 3-12 ◽  
Author(s):  
David Arcia ◽  
Liliana Acevedo-Sáenz ◽  
María Teresa Rugeles ◽  
Paula A. Velilla
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Hiv 1 ◽  
Selection Of

scholarly journals The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to Nucleoside Analogs than to Nonnucleoside Polymerase or Protease Inhibitors

2008 ◽  
Vol 52 (5) ◽  
pp. 1604-1612 ◽  
Author(s):  
Matthew F. McCown ◽  
Sonal Rajyaguru ◽  
Sophie Le Pogam ◽  
Samir Ali ◽  
Wen-Rong Jiang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Nucleoside Analogs ◽  
Genetic Barrier ◽  
Nonnucleoside Inhibitors ◽  
Nucleoside Inhibitors ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT Specific inhibitors of hepatitis C virus (HCV) replication that target the NS3/4A protease (e.g., VX-950) or the NS5B polymerase (e.g., R1479/R1626, PSI-6130/R7128, NM107/NM283, and HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug-resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and nonnucleoside inhibitors during clinical trials and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine whether nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors at 10 and 15 times the 50% effective concentration resulted in clearance of the replicon, while treatment with a nonnucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors. Furthermore, the combination of a nonnucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.

scholarly journals Selection of HIV-1 for Resistance to Fourth Generation Protease Inhibitors Reveals Two Independent Pathways to High-Level Resistance

2019 ◽  
Author(s):  
Ean Spielvogel ◽  
Sook-Kyung Lee ◽  
Shuntai Zhou ◽  
Gordon J. Lockbaum ◽  
Mina Henes ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Selective Pressure ◽  
Viral Fitness ◽  
Fourth Generation ◽  
Genetic Barrier ◽  
High Level ◽  
Hiv 1 ◽  
Level Resistance ◽  
Selection Of

SummaryWell-designed viral protease inhibitors (PIs) potently inhibit replication as well as create a high genetic barrier for resistance. Through in vivo selective pressure, we have generated high-level resistance against ten HIV-1 PIs and their precursor, the FDA-approved drug darunavir (DRV), achieving 1,000-fold resistance over the starting EC50. The accumulation of mutations revealed two pathways to high-level resistance, resulting in protease variants with up to 14 mutations in and outside of the active site. The two pathways demonstrate the interplay between drug resistance and viral fitness. Replicate selections showed that one inhibitor could select for resistance through either pathway, although subtle changes in chemical structure of the inhibitors led to preferential use of one pathway over the other. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high-level of selective pressure that is attainable with these fourth-generation protease inhibitors, and the interplay between selection of mutations to confer resistance while maintaining viral fitness.

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