Early Steps of HIV-1 Fusion Define the Sensitivity to Inhibitory Peptides That Block 6-Helix Bundle Formation
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{"title"=>"Early steps of HIV-1 fusion define the sensitivity to inhibitory peptides that block 6-helix bundle formation", "type"=>"journal", "authors"=>[{"first_name"=>"Kosuke", "last_name"=>"Miyauchi", "scopus_author_id"=>"8840469600"}, {"first_name"=>"Michael M.", "last_name"=>"Kozlov", "scopus_author_id"=>"7102868223"}, {"first_name"=>"Gregory B.", "last_name"=>"Melikyan", "scopus_author_id"=>"7003570310"}], "year"=>2009, "source"=>"PLoS Pathogens", "identifiers"=>{"sgr"=>"70349677167", "doi"=>"10.1371/journal.ppat.1000585", "issn"=>"15537366", "pui"=>"355378749", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "pmid"=>"19763181", "scopus"=>"2-s2.0-70349677167"}, "id"=>"b5c9402d-dd0e-3ba6-a83a-4df0746deb2a", "abstract"=>"The HIV envelope (Env) glycoprotein mediates membrane fusion through sequential interactions with CD4 and coreceptors, followed by the refolding of the transmembrane gp41 subunit into the stable 6-helix bundle (6HB) conformation. Synthetic peptides derived from the gp41 C-terminal heptad repeat domain (C-peptides) potently inhibit fusion by binding to the gp41 pre-bundle intermediates and blocking their conversion into the 6HB. Our recent work revealed that HIV-1 enters cells by fusing with endosomes, but not with the plasma membrane. These studies also showed that, for the large part, gp41 pre-bundles progress toward 6HBs in endosomal compartments and are thus protected from external fusion inhibitors. Here, we examined the consequences of endocytic entry on the gp41 pre-bundle exposure and on the virus' sensitivity to C-peptides. The rates of CD4 and coreceptor binding, as well as the rate of productive receptor-mediated endocytosis, were measured by adding specific inhibitors of these steps at varied times of virus-cell incubation. Following the CD4 binding, CCR5-tropic viruses recruited a requisite number of coreceptors much faster than CXCR4-tropic viruses. The rate of subsequent uptake of ternary Env-CD4-coreceptor complexes did not correlate with the kinetics of coreceptor engagement. These measurements combined with kinetic analyses enabled the determination of the lifetime of pre-bundle intermediates on the cell surface. Overall, these lifetimes correlated with the inhibitory potency of C-peptides. On the other hand, the basal sensitivity to peptides varied considerably among diverse HIV-1 isolates and ranked similarly with their susceptibility to inactivation by soluble CD4. We conclude that both the longevity of gp41 intermediates and the extent of irreversible conformational changes in Env upon CD4 binding determine the antiviral potency of C-peptides.", "link"=>"http://www.mendeley.com/research/early-steps-hiv1-fusion-define-sensitivity-inhibitory-peptides-block-6helix-bundle-formation", "reader_count"=>34, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>1, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>1, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>24, "Medicine and Dentistry"=>4, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>2, "Portugal"=>1, "India"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/882890"], "description"=>"<p>(A) The kinetics of HXB2 binding to CD4 and CXCR4 was determined by the time-of-addition experiments using BMS-806 and AMD3100 (see also <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-g001\" target=\"_blank\">Fig. 1B</a>), and the rate of productive endocytosis was measured by adding C52L. (B, C) The rates of CD4 and CCR5 engagement by V3BaL (B) and BaL (C) were determined by adding BMS-806 and AD101, respectively. The kinetics of receptor-mediated virus endocytosis was measured by escape from C52L. In all panels, the bulk HIV-1 uptake was determined by accumulation of the intracellular p24 (cyan crosses) and fitted with a single-exponential function (dashed lines). The solid lines were obtained by curve fitting the model equations to experimental points, as described in the text and in the legend to <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-g002\" target=\"_blank\">Figure 2</a>. Since all early steps of BaL fusion occurred virtually simultaneously, only one theoretical curve is shown in panel C.</p>", "links"=>[], "tags"=>["v3bal", "bal", "surface-accessible", "stages"], "article_id"=>553347, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Progression_of_the_HXB2_V3BaL_and_BaL_through_surface_accessible_stages_of_fusion_/553347", "title"=>"Progression of the HXB2, V3BaL and BaL through surface-accessible stages of fusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 00:55:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/883310"], "description"=>"*<p>Standard error of the curve fit.</p>", "links"=>[], "tags"=>["constants", "hiv-1", "fusion"], "article_id"=>553770, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effective_rate_constants_of_HIV_1_fusion_and_inactivation_/553770", "title"=>"Effective rate constants of HIV-1 fusion and inactivation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-18 01:02:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/883057"], "description"=>"<p>(A) Viruses were pre-bound to TZM-bl cells and allowed to fuse for 90 min in the presence of varied concentrations of C34 derived from the HIV-1 IIIB strain. The solid lines were obtained by curve fitting experimental data using the following equation: Fusion = 1/(1+[C34]/IC<sub>50</sub>), where [C34] is the C34 concentration (see <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-t002\" target=\"_blank\">Table 2</a> for the IC<sub>50</sub> values). (B) Viruses were fused with TZM-bl cells in the presence of different concentrations of C34 derived from either IIIB or JRFL gp41 (denoted C34<sub>IIIB</sub> and C34<sub>JRFL</sub>, respectively). (C) HIV-1 inactivation by different doses of soluble CD4 was carried out as described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#s4\" target=\"_blank\">Materials and Methods</a>. (D) Amino acid sequences of the C34 peptide derived from the IIIB/HXB2, JRFL and BaL gp41. The error bars are SEM of at least three independent measurements.</p>", "links"=>[], "tags"=>["inhibition", "c34", "peptide", "inactivation", "soluble"], "article_id"=>553516, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g005", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_1_inhibition_by_the_C34_peptide_and_inactivation_by_soluble_CD4_/553516", "title"=>"HIV-1 inhibition by the C34 peptide and inactivation by soluble CD4.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 00:58:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/883260"], "description"=>"*<p>Standard error of the curve fit.</p>**<p>ND, not determined.</p>***<p>IC<sub>50</sub> for the C34<sub>JRFL</sub> peptide.</p>", "links"=>[], "tags"=>["inhibition", "ad101"], "article_id"=>553710, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_1_sensitivity_to_inhibition_by_AD101_and_C34_/553710", "title"=>"HIV-1 sensitivity to inhibition by AD101 and C34.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-18 01:01:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/437987", "https://ndownloader.figshare.com/files/438006", "https://ndownloader.figshare.com/files/438029", "https://ndownloader.figshare.com/files/438050", "https://ndownloader.figshare.com/files/438076"], "description"=>"<div><p>The HIV envelope (Env) glycoprotein mediates membrane fusion through sequential interactions with CD4 and coreceptors, followed by the refolding of the transmembrane gp41 subunit into the stable 6-helix bundle (6HB) conformation. Synthetic peptides derived from the gp41 C-terminal heptad repeat domain (C-peptides) potently inhibit fusion by binding to the gp41 pre-bundle intermediates and blocking their conversion into the 6HB. Our recent work revealed that HIV-1 enters cells by fusing with endosomes, but not with the plasma membrane. These studies also showed that, for the large part, gp41 pre-bundles progress toward 6HBs in endosomal compartments and are thus protected from external fusion inhibitors. Here, we examined the consequences of endocytic entry on the gp41 pre-bundle exposure and on the virus' sensitivity to C-peptides. The rates of CD4 and coreceptor binding, as well as the rate of productive receptor-mediated endocytosis, were measured by adding specific inhibitors of these steps at varied times of virus-cell incubation. Following the CD4 binding, CCR5-tropic viruses recruited a requisite number of coreceptors much faster than CXCR4-tropic viruses. The rate of subsequent uptake of ternary Env-CD4-coreceptor complexes did not correlate with the kinetics of coreceptor engagement. These measurements combined with kinetic analyses enabled the determination of the lifetime of pre-bundle intermediates on the cell surface. Overall, these lifetimes correlated with the inhibitory potency of C-peptides. On the other hand, the basal sensitivity to peptides varied considerably among diverse HIV-1 isolates and ranked similarly with their susceptibility to inactivation by soluble CD4. We conclude that both the longevity of gp41 intermediates and the extent of irreversible conformational changes in Env upon CD4 binding determine the antiviral potency of C-peptides.</p></div>", "links"=>[], "tags"=>["steps", "hiv-1", "fusion", "inhibitory", "peptides", "6-helix", "bundle"], "article_id"=>146351, "categories"=>["Cancer"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1000585.s001", "https://dx.doi.org/10.1371/journal.ppat.1000585.s002", "https://dx.doi.org/10.1371/journal.ppat.1000585.s003", "https://dx.doi.org/10.1371/journal.ppat.1000585.s004", "https://dx.doi.org/10.1371/journal.ppat.1000585.s005"], "stats"=>{"downloads"=>7, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Early_Steps_of_HIV_1_Fusion_Define_the_Sensitivity_to_Inhibitory_Peptides_That_Block_6_Helix_Bundle_Formation/146351", "title"=>"Early Steps of HIV-1 Fusion Define the Sensitivity to Inhibitory Peptides That Block 6-Helix Bundle Formation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-09-18 01:45:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/882716"], "description"=>"<p>(A) A schematic drawing showing HIV-1 entry via receptor-mediated endocytosis followed by fusion with endosomes. Pathways leading to virus degradation in lysosomes are shown by dashed lines. CR denotes coreceptor. (B) Kinetics of surface-accessible steps of HIV-1 fusion with TZM-bl cells. HXB2 pseudoviruses were pre-bound to cells in the cold and triggered to fuse by raising the temperature at time = 0. Inhibitors of CD4 binding (BMS-806), coreceptor binding (AMD3100) and the 6-helix bundle formation (C52L) were added at varied times of incubation to block the respective steps of fusion. The resulting extent of fusion as a function of incubation time was measured by a BlaM assay. The total virus uptake was measured by the fraction of pronase-resistant viral p24 (see <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#s4\" target=\"_blank\">Materials and Methods</a>). Error bars are SEM. (C) A kinetic model of HIV fusion. The virus (V) progresses through CD4 and coreceptor (CR) binding steps and undergoes endocytosis (V<sub>E</sub>) that leads to fusion (V<sub>F</sub>). Stages of fusion sensitive to inhibitors, BMS-806, AMD3100 (CXCR4 binding), AD101 (CCR5 binding), and C52L are indicated by horizontal red lines. In this scheme, protection from C-peptides occurs via receptor-mediated endocytosis, but not through 6-helix bundle formation and fusion with the plasma membrane. Native viruses and those that engage CD4 and CD4/coreceptor are assumed to be inactivated with the rate constant k<sub>i</sub>, primarily due to a non-productive endocytosis.</p>", "links"=>[], "tags"=>["steps", "hiv-1", "fusion"], "article_id"=>553174, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dissection_of_early_steps_of_HIV_1_fusion_with_target_cells_/553174", "title"=>"Dissection of early steps of HIV-1 fusion with target cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 00:52:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/882817"], "description"=>"<p>(A) Fusion of JRFL pseudoviruses with TZM-bl cells was measured by adding inhibitors of distinct steps of this process (BMS-806, AD101 and C52L) at indicated time points, as described in the legend to <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-g001\" target=\"_blank\">Figure 1B</a>. (B) JRFL fusion with HeLa-derived JC.10 cells expressing a low level of wild-type CCR5. (C) JRFL fusion with JYN.2-15 cells expressing a high level of mutant (Y14N) CCR5. Solid lines are the results of fitting the equations (10–12) of <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat.1000585.s005\" target=\"_blank\">Appendix S1</a> to experimental data. The inactivation rate, k<sub>i</sub>, was determined by fitting a single-exponential function (dashed line) to the p24 uptake data (crosses). The k<sub>1</sub> was obtained by curve fitting the expression (10) for the probability of V<sub>CD4</sub> to the rate of escape from BMS-806 (after entering the k<sub>i</sub> value and assigning arbitrary values to k<sub>2</sub> and k<sub>3</sub>). The k<sub>i</sub> and k<sub>1</sub> were then used to obtain k<sub>2</sub> by fitting the equation (11) for V<sub>CD4CR</sub> to coreceptor binding data. Finally, these three rate constants were used to determine k<sub>3</sub> through curve-fitting the equation (12) for the probability of V<sub>E</sub> to the experimentally determined rate of virus escape from C52L. The lines are color-coded according to the symbols. Because the rates of JRFL escape from BMS-806 and AD101 were identical when TZM-bl cells were used as targets (panel A), only the CD4 binding curve (green line) is shown. Curve fitting was done using the SigmaPlot Regression Wizard (SYSTAT Software, Inc.).</p>", "links"=>[], "tags"=>["jrfl", "fusion", "cells", "expressing", "levels", "wild-type", "mutant"], "article_id"=>553271, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetics_of_JRFL_fusion_with_target_cells_expressing_different_levels_of_wild_type_and_mutant_CCR5_/553271", "title"=>"Kinetics of JRFL fusion with target cells expressing different levels of wild-type and mutant CCR5.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 00:54:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/883168"], "description"=>"<p>(A) Relationship between the C34 IC<sub>50</sub> (normalized to that of JRFL on TZM-bl cells) and the kinetics of escape from a high concentration of C52L parameterized as the time at which half of the viruses acquire resistance to this peptide. Solid line is a linear regression. (B) The C34 IC<sub>50</sub> was normalized to that for the JRFL fusion with TZM-bl cells and plotted vs. the time average in the V<sub>CD4</sub> state. Separate linear regressions are shown for JRFL fusion with different target cells (dotted line, r<sup>2</sup> = 0.99) and for HXB2-BaL-V3BaL constructs fusing with TZM-bl cells (dashed line, r<sup>2</sup> = 0.73). (C) Lack of correlation between the inhibitory activity of C34 and the lifetime of the V<sub>CD4CR</sub> state. (D) Correlation between the time averages in both intermediate stages (V<sub>CD4</sub> plus V<sub>CD4CR</sub>) and the potency of C34. Separate linear regressions are shown for BaL, HXB2 and V3BaL (dashed line, r<sup>2</sup> = 1.00) and for JRFL fusion with different target cells (dotted line, r<sup>2</sup> = 0.93). The IC<sub>50</sub> for the C34<sub>JRFL</sub> against JRFL (star) is shown for comparison. Note that the more potent C34<sub>JRFL</sub> peptide inhibited JRFL almost as efficiently as the C34<sub>IIIB</sub> inhibited BaL (<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-t002\" target=\"_blank\">Table 2</a>).</p>", "links"=>[], "tags"=>["potency", "c34", "hiv-1", "intermediate"], "article_id"=>553627, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g006", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlation_between_the_potency_of_C34_and_the_time_average_of_HIV_1_in_intermediate_states_/553627", "title"=>"Correlation between the potency of C34 and the time average of HIV-1 in intermediate states.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 01:00:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/882951"], "description"=>"<p>(A–D) The probabilities of finding the virus in CD4-bound (V<sub>CD4</sub>) and coreceptor-bound (V<sub>CD4CR</sub>) states and of undergoing receptor-mediated endocytosis (V<sub>E</sub>) as a function of time were obtained by entering the respective rate constants (<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000585#ppat-1000585-t001\" target=\"_blank\">Table 1</a>) into the equations (6–8). (E) Time averages for HIV-1 in the CD4-bound and coreceptor-bound states were determined from equations (13) and (14), using the respective rate constants. The total time averages of HIV-1 in intermediate stages prior to undergoing endocytosis (the sum of V<sub>CD4</sub> and V<sub>CD4CR</sub>) are shown by open bars.</p>", "links"=>[], "tags"=>["hiv-1", "progression", "intermediate", "states", "times"], "article_id"=>553405, "categories"=>["Infectious Diseases", "Virology"], "users"=>["Kosuke Miyauchi", "Michael M. Kozlov", "Gregory B. Melikyan"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1000585.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetics_of_HIV_1_progression_through_intermediate_states_and_the_residence_times_in_these_states_/553405", "title"=>"Kinetics of HIV-1 progression through intermediate states and the residence times in these states.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-18 00:56:45"}

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Relative Metric

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