Pub Date : 2019-10-26DOI: 10.1186/s12977-019-0491-0
C. Shepard, Joella Xu, J. Holler, Dong-Hyun Kim, L. M. Mansky, R. Schinazi, Baek Kim
{"title":"Effect of induced dNTP pool imbalance on HIV-1 reverse transcription in macrophages","authors":"C. Shepard, Joella Xu, J. Holler, Dong-Hyun Kim, L. M. Mansky, R. Schinazi, Baek Kim","doi":"10.1186/s12977-019-0491-0","DOIUrl":"https://doi.org/10.1186/s12977-019-0491-0","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0491-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46631894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-22DOI: 10.1186/s12977-019-0489-7
Amanda R Smith, Matthew T Weinstock, Amanda E Siglin, Frank G Whitby, J Nicholas Francis, Christopher P Hill, Debra M Eckert, Michael J Root, Michael S Kay
Background: PIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifically binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub-femtomolar affinity. This extremely high affinity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to prevent the viral resistance pathway of stepwise accumulation of modest affinity-disrupting mutations. Such modest mutations would not affect PIE12-trimer potency and therefore not confer a selective advantage. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely extended timeframe (> 1 year) in comparison to other entry inhibitors. Eventually, HIV developed resistance to PIE12-trimer by mutating Q577 in the gp41 pocket.
Results: Using deep sequence analysis, we identified three mutations at Q577 (R, N and K) in our two PIE12-trimer resistant pools. Each point mutant is capable of conferring the majority of PIE12-trimer resistance seen in the polyclonal pools. Surface plasmon resonance studies demonstrated substantial affinity loss between PIE12-trimer and the Q577R-mutated gp41 pocket. A high-resolution X-ray crystal structure of PIE12 bound to the Q577R pocket revealed the loss of two hydrogen bonds, the repositioning of neighboring residues, and a small decrease in buried surface area. The Q577 mutations in an NL4-3 backbone decreased viral growth rates. Fitness was ultimately rescued in resistant viral pools by a suite of compensatory mutations in gp120 and gp41, of which we identified seven candidates from our sequencing data.
Conclusions: These data show that PIE12-trimer exhibits a high barrier to resistance, as extended passaging was required to develop resistant virus with normal growth rates. The primary resistance mutation, Q577R/N/K, found in the conserved gp41 pocket, substantially decreases inhibitor affinity but also damages viral fitness, and candidate compensatory mutations in gp160 have been identified.
{"title":"Characterization of resistance to a potent D-peptide HIV entry inhibitor.","authors":"Amanda R Smith, Matthew T Weinstock, Amanda E Siglin, Frank G Whitby, J Nicholas Francis, Christopher P Hill, Debra M Eckert, Michael J Root, Michael S Kay","doi":"10.1186/s12977-019-0489-7","DOIUrl":"10.1186/s12977-019-0489-7","url":null,"abstract":"<p><strong>Background: </strong>PIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifically binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub-femtomolar affinity. This extremely high affinity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to prevent the viral resistance pathway of stepwise accumulation of modest affinity-disrupting mutations. Such modest mutations would not affect PIE12-trimer potency and therefore not confer a selective advantage. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely extended timeframe (> 1 year) in comparison to other entry inhibitors. Eventually, HIV developed resistance to PIE12-trimer by mutating Q577 in the gp41 pocket.</p><p><strong>Results: </strong>Using deep sequence analysis, we identified three mutations at Q577 (R, N and K) in our two PIE12-trimer resistant pools. Each point mutant is capable of conferring the majority of PIE12-trimer resistance seen in the polyclonal pools. Surface plasmon resonance studies demonstrated substantial affinity loss between PIE12-trimer and the Q577R-mutated gp41 pocket. A high-resolution X-ray crystal structure of PIE12 bound to the Q577R pocket revealed the loss of two hydrogen bonds, the repositioning of neighboring residues, and a small decrease in buried surface area. The Q577 mutations in an NL4-3 backbone decreased viral growth rates. Fitness was ultimately rescued in resistant viral pools by a suite of compensatory mutations in gp120 and gp41, of which we identified seven candidates from our sequencing data.</p><p><strong>Conclusions: </strong>These data show that PIE12-trimer exhibits a high barrier to resistance, as extended passaging was required to develop resistant virus with normal growth rates. The primary resistance mutation, Q577R/N/K, found in the conserved gp41 pocket, substantially decreases inhibitor affinity but also damages viral fitness, and candidate compensatory mutations in gp160 have been identified.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"16 1","pages":"28"},"PeriodicalIF":2.7,"publicationDate":"2019-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10849366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-22DOI: 10.1186/s12977-019-0490-1
A. Vallinoto, Mateus I. Otake, Paulo V. N. R. Sousa, F. T. Lopes, E. R. P. Sacuena, M. A. F. Queiroz, Greice L. C. Costa, M. Ishak, I. Cayres-Vallinoto, J. Guerreiro, R. Ishak
{"title":"Isolation of the Arawete and Asurini Indians keeps the tribes free from HTLV infection during 36 years of follow-up","authors":"A. Vallinoto, Mateus I. Otake, Paulo V. N. R. Sousa, F. T. Lopes, E. R. P. Sacuena, M. A. F. Queiroz, Greice L. C. Costa, M. Ishak, I. Cayres-Vallinoto, J. Guerreiro, R. Ishak","doi":"10.1186/s12977-019-0490-1","DOIUrl":"https://doi.org/10.1186/s12977-019-0490-1","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0490-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44249714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-14Epub Date: 2019-08-26DOI: 10.1098/rstb.2019.0073
Paul R Johnston, Véronique Paris, Jens Rolff
During metamorphosis, holometabolous insects completely replace the larval gut and must control the microbiota to avoid septicaemia. Rapid induction of bactericidal activity in the insect gut at the onset of pupation has been described in numerous orders of the Holometabola and is best-studied in the Lepidoptera where it is under control of the 20-hydroxyecdysone (20E) moulting pathway. Here, using RNAseq, we compare the expression of immune effector genes in the gut during metamorphosis in a holometabolous (Galleria mellonella) and a hemimetabolous insect (Gryllus bimaculatus). We find that in G. mellonella, the expression of numerous immune effectors and the transcription factor GmEts are upregulated, with peak expression of three antimicrobial peptides (AMPs) and a lysozyme coinciding with delamination of the larval gut. By contrast, no such upregulation was detectable in the hemimetabolous Gr. bimaculatus. These findings support the idea that the upregulation of immune effectors at the onset of complete metamorphosis is an adaptive response, which controls the microbiota during gut replacement. This article is part of the theme issue 'The evolution of complete metamorphosis'.
{"title":"Immune gene regulation in the gut during metamorphosis in a holo- versus a hemimetabolous insect.","authors":"Paul R Johnston, Véronique Paris, Jens Rolff","doi":"10.1098/rstb.2019.0073","DOIUrl":"10.1098/rstb.2019.0073","url":null,"abstract":"<p><p>During metamorphosis, holometabolous insects completely replace the larval gut and must control the microbiota to avoid septicaemia. Rapid induction of bactericidal activity in the insect gut at the onset of pupation has been described in numerous orders of the Holometabola and is best-studied in the Lepidoptera where it is under control of the 20-hydroxyecdysone (20E) moulting pathway. Here, using RNAseq, we compare the expression of immune effector genes in the gut during metamorphosis in a holometabolous (Galleria mellonella) and a hemimetabolous insect (Gryllus bimaculatus). We find that in G. mellonella, the expression of numerous immune effectors and the transcription factor GmEts are upregulated, with peak expression of three antimicrobial peptides (AMPs) and a lysozyme coinciding with delamination of the larval gut. By contrast, no such upregulation was detectable in the hemimetabolous Gr. bimaculatus. These findings support the idea that the upregulation of immune effectors at the onset of complete metamorphosis is an adaptive response, which controls the microbiota during gut replacement. This article is part of the theme issue 'The evolution of complete metamorphosis'.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"11 1","pages":"20190073"},"PeriodicalIF":5.4,"publicationDate":"2019-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88247270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1186/s12977-019-0488-8
A. Abdala, I. Álvarez, Hélène Brossel, L. Calvinho, H. Carignano, Lautaro Franco, Hélène Gazon, Christelle Gillissen, Malik Hamaidia, Clotilde Hoyos, J. Jacques, T. Joris, F. Laval, M. Petersen, Florent Porquet, N. Porta, V. Ruiz, Roghaiyeh Safari, G. Suárez Archilla, K. Trono, L. Willems
{"title":"BLV: lessons on vaccine development","authors":"A. Abdala, I. Álvarez, Hélène Brossel, L. Calvinho, H. Carignano, Lautaro Franco, Hélène Gazon, Christelle Gillissen, Malik Hamaidia, Clotilde Hoyos, J. Jacques, T. Joris, F. Laval, M. Petersen, Florent Porquet, N. Porta, V. Ruiz, Roghaiyeh Safari, G. Suárez Archilla, K. Trono, L. Willems","doi":"10.1186/s12977-019-0488-8","DOIUrl":"https://doi.org/10.1186/s12977-019-0488-8","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0488-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48334505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-06DOI: 10.1186/s12977-019-0487-9
R. Harrod
{"title":"Silencers of HTLV-1 and HTLV-2: the pX-encoded latency-maintenance factors","authors":"R. Harrod","doi":"10.1186/s12977-019-0487-9","DOIUrl":"https://doi.org/10.1186/s12977-019-0487-9","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"16 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0487-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65721116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-01DOI: 10.1186/1742-4690-2-S1-S131
R. Castillo, Ngo Quy Chau, Vu Van Giap, L. Hoan, C. Wong
{"title":"Abstract withdrawn","authors":"R. Castillo, Ngo Quy Chau, Vu Van Giap, L. Hoan, C. Wong","doi":"10.1186/1742-4690-2-S1-S131","DOIUrl":"https://doi.org/10.1186/1742-4690-2-S1-S131","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"2 1","pages":"1"},"PeriodicalIF":3.3,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4690-2-S1-S131","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42101410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-22DOI: 10.1186/s12977-019-0484-z
M. Kannagi, A. Hasegawa, Yoshiko Nagano, Shuichi Kimpara, Y. Suehiro
{"title":"Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL","authors":"M. Kannagi, A. Hasegawa, Yoshiko Nagano, Shuichi Kimpara, Y. Suehiro","doi":"10.1186/s12977-019-0484-z","DOIUrl":"https://doi.org/10.1186/s12977-019-0484-z","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0484-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44910110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-21DOI: 10.1186/s12977-019-0485-y
M. Benkirane, B. Berkhout, P. Borrow, A. Fassati, Masahiro Fujii, J. Garcia-Martinez, D. Margolis, M. Nijhuis, Leslie Parent, K. Strebel, François Venter, F. Kirchhoff, Andrew Lever, Susan R Ross, Johnson Mak
{"title":"A trip down memory lane with Retrovirology","authors":"M. Benkirane, B. Berkhout, P. Borrow, A. Fassati, Masahiro Fujii, J. Garcia-Martinez, D. Margolis, M. Nijhuis, Leslie Parent, K. Strebel, François Venter, F. Kirchhoff, Andrew Lever, Susan R Ross, Johnson Mak","doi":"10.1186/s12977-019-0485-y","DOIUrl":"https://doi.org/10.1186/s12977-019-0485-y","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2019-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12977-019-0485-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43740713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号