WO2010040136A4 - Selection of hiv vaccine antigens by use of intrapatient sequence variation to identify mutations in the hiv envelope glycoprotein that affect the binding of broadly neutralizing antibodies - Google Patents
Selection of hiv vaccine antigens by use of intrapatient sequence variation to identify mutations in the hiv envelope glycoprotein that affect the binding of broadly neutralizing antibodies Download PDFInfo
- Publication number
- WO2010040136A4 WO2010040136A4 PCT/US2009/059583 US2009059583W WO2010040136A4 WO 2010040136 A4 WO2010040136 A4 WO 2010040136A4 US 2009059583 W US2009059583 W US 2009059583W WO 2010040136 A4 WO2010040136 A4 WO 2010040136A4
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hiv
- amino acid
- neutralization
- envelope glycoprotein
- vaccine composition
- Prior art date
Links
- 102100021696 Syncytin-1 Human genes 0.000 title claims abstract 16
- 101710121417 Envelope glycoprotein Proteins 0.000 title claims abstract 14
- 230000003472 neutralizing effect Effects 0.000 title claims abstract 6
- 229960005486 vaccine Drugs 0.000 title claims 11
- 239000000427 antigen Substances 0.000 title abstract 2
- 102000036639 antigens Human genes 0.000 title abstract 2
- 108091007433 antigens Proteins 0.000 title abstract 2
- 230000035772 mutation Effects 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract 10
- 229920001184 polypeptide Polymers 0.000 claims abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims 19
- 238000006386 neutralization reaction Methods 0.000 claims 11
- 239000013612 plasmid Substances 0.000 claims 10
- 235000001014 amino acid Nutrition 0.000 claims 9
- 150000001413 amino acids Chemical class 0.000 claims 7
- 108090000623 proteins and genes Proteins 0.000 claims 7
- 230000035945 sensitivity Effects 0.000 claims 6
- 241001112090 Pseudovirus Species 0.000 claims 5
- 101800001690 Transmembrane protein gp41 Proteins 0.000 claims 5
- 241000700605 Viruses Species 0.000 claims 5
- 210000004027 cell Anatomy 0.000 claims 5
- 108700004025 env Genes Proteins 0.000 claims 5
- 150000001875 compounds Chemical class 0.000 claims 4
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims 4
- 125000000539 amino acid group Chemical group 0.000 claims 3
- 210000004962 mammalian cell Anatomy 0.000 claims 3
- 239000013605 shuttle vector Substances 0.000 claims 3
- 238000006467 substitution reaction Methods 0.000 claims 3
- 239000006228 supernatant Substances 0.000 claims 3
- 239000004475 Arginine Substances 0.000 claims 2
- 241000894006 Bacteria Species 0.000 claims 2
- 108091026890 Coding region Proteins 0.000 claims 2
- 108020004414 DNA Proteins 0.000 claims 2
- 101710091045 Envelope protein Proteins 0.000 claims 2
- 101710188315 Protein X Proteins 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 2
- 230000001580 bacterial effect Effects 0.000 claims 2
- 239000006143 cell culture medium Substances 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 2
- 239000003550 marker Substances 0.000 claims 2
- 108091033319 polynucleotide Proteins 0.000 claims 2
- 239000002157 polynucleotide Substances 0.000 claims 2
- 102000040430 polynucleotide Human genes 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- 239000013638 trimer Substances 0.000 claims 2
- 239000013598 vector Substances 0.000 claims 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims 1
- 108010041986 DNA Vaccines Proteins 0.000 claims 1
- 229940021995 DNA vaccine Drugs 0.000 claims 1
- 108010032976 Enfuvirtide Proteins 0.000 claims 1
- 102000004961 Furin Human genes 0.000 claims 1
- 108090001126 Furin Proteins 0.000 claims 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 1
- 108010076504 Protein Sorting Signals Proteins 0.000 claims 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- 239000012472 biological sample Substances 0.000 claims 1
- 238000003776 cleavage reaction Methods 0.000 claims 1
- 238000010367 cloning Methods 0.000 claims 1
- 210000005220 cytoplasmic tail Anatomy 0.000 claims 1
- 230000002950 deficient Effects 0.000 claims 1
- 230000029087 digestion Effects 0.000 claims 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims 1
- 229960002062 enfuvirtide Drugs 0.000 claims 1
- 101150030339 env gene Proteins 0.000 claims 1
- 239000013613 expression plasmid Substances 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- 108020001507 fusion proteins Proteins 0.000 claims 1
- 102000037865 fusion proteins Human genes 0.000 claims 1
- 235000013922 glutamic acid Nutrition 0.000 claims 1
- 239000004220 glutamic acid Substances 0.000 claims 1
- 239000001963 growth medium Substances 0.000 claims 1
- 238000003306 harvesting Methods 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000005847 immunogenicity Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 238000007747 plating Methods 0.000 claims 1
- 102000054765 polymorphisms of proteins Human genes 0.000 claims 1
- 230000007017 scission Effects 0.000 claims 1
- 239000006152 selective media Substances 0.000 claims 1
- 238000012163 sequencing technique Methods 0.000 claims 1
- 150000003384 small molecules Chemical class 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 229940033330 HIV vaccine Drugs 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
- C12Q1/701—Specific hybridization probes
- C12Q1/702—Specific hybridization probes for retroviruses
- C12Q1/703—Viruses associated with AIDS
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
- G01N33/56988—HIV or HTLV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Wood Science & Technology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Urology & Nephrology (AREA)
- Microbiology (AREA)
- AIDS & HIV (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Selection of HIV vaccine antigens by use of intrapatient sequence variation to identify mutations in the HIV envelope glycoprotein that affect the binding of broadly neutralizing antibodies and polypeptides identified by these methods.
Claims
1. A method of analyzing intra-patient HIV virus variation to identify specific amino acid residues of the HIV envelope glycoproteins that affect sensitivity or resistance to broadly neutralizing antibodies, the method comprising the steps of:
i) providing a plurality of individual subjects who are seropositive for HIV antibodies and taking a biological sample from each subject, wherein the sample contains a multiplicity of HIV viruses with closely related genomes, wherein all subjects had been infected with HIV no more than one year before, and no less than one month before sample collection,
ii) amplifying the env genes of the multiplicity of viruses to produce a library of different env genes,
iii) cloning the amplified env genes into a plasmid shuttle vector that allows the plasmid to replicate in both bacteria and mammalian cells,
iv) transforming bacterial cells with the shuttle vector and plating out the transformed bacterial cells onto a selective medium so that bacteria containing the shuttle vector plasmid containing the cloned envelope gene are selectable,
v) selecting individual colonies at random and preparing plasmid DNA from each colony selected and analyzing the plasmid DNA by restriction digestion so as to identify plasmids containing the full length HlV envelope gene, which plasmids are used to produce pseudoviruses,
vi) co-transfecting mammalian cells with the env-containing vector and simultaneously with a plasmid containing a defective HIV provirus plasmid where the coding sequence of the env gene has been replaced with the coding sequence of a marker gene, and culturing the co-transfected mammalian cells in a culture medium, to produce pseudovirions containing the amplified env genes, which pseudovirions are released into the cell culture medium, vii) harvesting the supernatant from the cell culture medium, wherein the supernatant contains pseudoviruses from the transfected cells, and wherein each supernatant contains a stock of pseudovirus resulting from a single purified expression plasmid,
viii) testing the pseudovirion from the selected colonies to determine infectivity by culturing the pseudovirions with cells capable of being infected by HTV, wherein infectivity is measured by the degree of expression of the marker gene,
ix) selecting pseudovirions that exhibit high infectivity, and testing the selected pseudovirions for sensitivity or resistance to neutralization by one or more broadly neutralizing antibodies,
x) selecting pairs of plasmids from the same individual wherein each pair contains at least one neutralization resistant and at least one neutralization sensitive pseudovirus,
xi) sequencing the envelope genes identified from sensitive and resistant pseudovirus pairs,
xii) comparing the nucleotide sequences of the envelope genes of the neutralization sensitive and resistant pairs thereby identifying specific amino acid differences between the pairs and identifying polymorphisms that may affect sensitivity or resistance to neutralization by broadly neutralizing antibodies,
xiii) at each amino acid residue that differs between the neutralization sensitive and neutralization resistant envelope genes, site-by-site replacement of amino acids from the is performed, substituting one amino acid at a time from neutralization sensitive sequence into the neutralization resistant sequence,
xiv) each new construct is used to create a pseudotype virus which is tested for neutralization sensitivity so as to identify specific amino acid residues of the HlV envelope glycoproteins that affect sensitivity or resistance to broadly neutralizing antibodies.
2. The method of claim 1 wherein all subjects had been infected with HIV 109 days +/- 58 days before specimen collection.
3. A vaccine composition comprising an HIV envelope glycoprotein wherein a glutamine residue at a site identifiable as being homologous to position 655 of SEQ ID No.l is replaced by a substitute amino acid such that the amino acid substitution disrupts an inter- molecular hydrogen-bonded ring structure between the N36 and C34 helices of the gp41 trimer.
4. The vaccine composition of claim 3 wherein possession of the HIV envelope glycoprotein confers greater neutralization sensitivity upon an HIV virus when it is exposed to 2F5 or 4E10 monoclonal antibodies, Enfuvirtide or CD4-lgG, than would be provided by another HIV envelope glycoprotein identical in all respects except for the substitution of the glutamine residue.
5. The vaccine composition of claims 3 or 4 wherein the substitute amino acid is arginine.
6. The vaccine composition of claims 3 or 4 wherein the substitute amino acid is Lysine, Serine or Glutamic acid.
7. The vaccine composition of claims 3 or 4 wherein the HIV envelope glycoprotein has at least 60% sequence identity to SEQ ID No.l.
8. The composition of claims 3 or 4 wherein the HIV envelope glycoprotein comprises a fusion protein that includes a non-HIV signal sequence and a flag epitope.
9. The vaccine composition of claims 3 or 4 wherein the HIV envelope glycoprotein has had a furin cleavage site deleted.
10. The vaccine composition of claims 3 or 4 wherein the HIV envelope glycoprotein comprises a full length gplόO wherein a glutamine residue at a site identifiable as being homologous to position 655 of SEQ ID No.l is replaced by arginine.
11. The vaccine composition of claims 3 or 4 wherein the polypeptide comprises a truncated form of the envelope protein lacking the gp41 transmembrane domain and cytoplasmic tail.
12. A polynucleotide encoding an HIV envelope glycoprotein wherein a glutamine residue at a site identifiable as being homologous to position 655 of SEQ ID No.1 is replaced by a substitute amino acid such that the amino acid substitution disrupts an inter-molecular ring structure between the N36 and C34 helices of the gp41 trimer.
13. The polynucleotide of claim 14 formulated in an vector as a DNA vaccine.
14. A method for inhibiting the fusion of an HlV virus to a host cell, the method comprising exposing the HlV virus to a compound that disrupts the hydrogen-bonded ring structure between the N36 and C34 helices of gp41.
15. A method for increasing the immunogenicity of HIV envelope proteins the method comprising exposing the HlV virus to a compound that disrupts the hydrogen bonded ring structure between the N36 and C34 helices of gp41.
16. The method of claims 14 or 15 wherein the compound is a small molecule.
17. The method of claims 14 or 15 wherein the compound is an antibody.
18. An isolated antibody which specifically binds to the HlV envelope glycoprotein of the vaccine composition of claim 3.
19. an isolated antibody which specifically binds to the HIV envelope glycoprotein of the vaccine composition of claim 4.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/079,472 US9782472B2 (en) | 2008-10-04 | 2011-04-04 | Therapeutic compositions and methods for treating HIV including identification and manipulation of particular domains associated with immunogenicity |
| US15/694,388 US10201603B2 (en) | 2008-10-04 | 2017-09-01 | Therapeutic compositions and methods for treating HIV including identification and manipulation of particular domains associated with immunogenicity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19511208P | 2008-10-04 | 2008-10-04 | |
| US61/195,112 | 2008-10-04 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2010/053637 Continuation-In-Part WO2011050222A2 (en) | 2008-10-04 | 2010-10-22 | Therapeutic compositions that disrupt the hydrogen bonded ring structure in gp41 and methods for treating hiv |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/079,472 Continuation-In-Part US9782472B2 (en) | 2008-10-04 | 2011-04-04 | Therapeutic compositions and methods for treating HIV including identification and manipulation of particular domains associated with immunogenicity |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2010040136A2 WO2010040136A2 (en) | 2010-04-08 |
| WO2010040136A3 WO2010040136A3 (en) | 2010-07-15 |
| WO2010040136A4 true WO2010040136A4 (en) | 2010-09-02 |
Family
ID=42074258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2009/059583 WO2010040136A2 (en) | 2008-10-04 | 2009-10-05 | Selection of hiv vaccine antigens by use of intrapatient sequence variation to identify mutations in the hiv envelope glycoprotein that affect the binding of broadly neutralizing antibodies |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2010040136A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107132066A (en) * | 2017-04-28 | 2017-09-05 | 皖能马鞍山发电有限公司 | A kind of coal sample takes control optimization method |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150065381A1 (en) * | 2013-09-05 | 2015-03-05 | International Aids Vaccine Initiative | Methods of identifying novel hiv-1 immunogens |
| CA2982376A1 (en) * | 2015-05-28 | 2016-12-01 | Immunomedics, Inc. | T20 constructs for anti-hiv (human immunodeficiency virus) therapy and/or vaccines |
| CN114736930A (en) * | 2022-04-30 | 2022-07-12 | 南京医科大学 | Screening method and application of virus protein escape neutralizing antibody |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6841657B2 (en) * | 1997-04-17 | 2005-01-11 | Whitehead Institute For Biomedical Research | Inhibitors of HIV membrane fusion |
| FR2829150B1 (en) * | 2001-09-06 | 2004-09-03 | Bio Merieux | ENV MUTE GENE ENCODING HIV-1 GLYPOPROTEIN AND APPLICATIONS |
| WO2004072099A2 (en) * | 2003-02-11 | 2004-08-26 | The United States Of America As Represented By The Secretary Of Health And Human Services, Nih | Novel peptide inhibitor of hiv fusion that disrupts the internal trimeric coiled-coil of gp41 |
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2009
- 2009-10-05 WO PCT/US2009/059583 patent/WO2010040136A2/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107132066A (en) * | 2017-04-28 | 2017-09-05 | 皖能马鞍山发电有限公司 | A kind of coal sample takes control optimization method |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010040136A2 (en) | 2010-04-08 |
| WO2010040136A3 (en) | 2010-07-15 |
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