WO1994015634A1 - Tat and rev oligopeptides in hiv treatment - Google Patents

Tat and rev oligopeptides in hiv treatment Download PDF

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Publication number
WO1994015634A1
WO1994015634A1 PCT/US1993/012680 US9312680W WO9415634A1 WO 1994015634 A1 WO1994015634 A1 WO 1994015634A1 US 9312680 W US9312680 W US 9312680W WO 9415634 A1 WO9415634 A1 WO 9415634A1
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arg
pro
gin
leu
lys
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PCT/US1993/012680
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French (fr)
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WO1994015634A9 (en
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Matthias Rath
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Matthias Rath
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to the therapeutic use of synthetic oligopeptides homologous to the signal sequences of viral regulatory proteins in the treatment of HIV infection.
  • transactivator protein tat
  • rev regulatory virion protein
  • Tat and rev belong to a group of proteins essential for the regulation of HIV expression.
  • the signal sequences of tat protein and rev protein for their interaction with HIV RNA are oligopeptide sequences enriched in cationic amino acids.
  • the cationic charge of these signal sequences is essential for the binding of these proteins to the transacting responsive region (TAR) of HIV RNA and for RNA function.
  • TAR transacting responsive region
  • Therapeutically this inhibition can be achieved in two ways, i) The parenteral application of synthetic analogs to the signal sequences of viral regulatory proteins, particularly to their RNA binding region. In this case the therapeutic mechanism is the competitive inhibition of the binding of viral regulatory proteins to viral RNA.
  • This therapeutic approach may be particularly valuable in the treatment of manifest HIV infections and AIDS.
  • ii By subcutaneous or intracutaneous injection of these synthetic analogs to the peptide signal sequences of the viral regulatory proteins.
  • the antibodies produced against these antigens would block the signal sequences of these regulatory proteins and prevent the interaction with viral RNA.
  • a vaccine will be available in the prevention and treatment of HIV infections and AIDS.
  • HIV human immunodeficiency viruses
  • AIDS acquired immunodeficiency syndrome
  • Tat is a strong transactivator of genes that are expressed from the viral long terminal repeat (LTR) and is essential for HIV gene expression, viral replication, and virus mediated cythopathicity.
  • the tat protein is 86 to 102 amino acids long, dependent on the viral strain.
  • the sequence of the HIV HXB2 tat protein is given in figure 1.
  • Several highly conserved domains in the tat protein have been identified among the various strains of HIV-1, HIV-2 and simian immunodeficiency virus (SIV)(2). The following domains are essential for tat function:
  • residue lysine is essential and the residues glycine and tyrosine are partially essential for tat function.
  • the information for the entire biological activity of the tat protein are contained in specific oligopeptide sequences within the tat peptide sequence (2).
  • the activity of the tat protein can be inhibited in two ways: a) by the competitive inhibition of its binding to viral RNA via synthetic analogs of the signal sequences
  • oligopeptides would be used a vaccine in the prevention and treatment of HIV infections and AIDS.
  • the regulator of virion protein expression is another regulatory protein involved in HIV gene expression and pathogenicity (review in 1).
  • the tat and rev regulatory pathways share much in common.
  • the virus life cycle is divided into an early phase during which tat and rev proteins are made and a late phase in which virus structural proteins are made and virus particles are assembled.
  • the rev protein mediates the switch from the early to the late phase.
  • the sequence of HIV-1 3HXB2 rev protein is given in figure 2.
  • the following domains are highly conserved among the rev proteins of different types of HIV viruses and they have been shown to be essential for rev function:
  • the strong basic amino acid region of the rev protein determines its binding to RNA and also specifies nuclear and nucleolar localization. This peptide region of the rev protein is responsible for the specific binding of rev to the rev responsive element (RRE), a short sequence in the gene for the viral envelope glycoprotein.
  • RRE rev responsive element
  • the inhibitory effect of synthetic peptides on transactivation can be measured in vitro by competition experiments measuring the decrease of expression of the bacterial chloramphenicol acetyltransferase (CAT) reporter gene linked to the HIV-LTR as described in (2) or by using another assay measuring transactivation or viral replication in the presence of these synthetic peptides.
  • the inhibitory effect of antibodies against synthetic peptides analogous to the signal sequences of viral regulatory proteins can be tested in vitro in the following way. Polyclonal or monoclonal antibodies are raised against specific signal peptides of viral regulatory proteins. The inhibitory effect of these antibodies on transactivation and viral replication can be measured in assays similar to those described above.
  • the synthetic peptides analogous to the signal sequences of viral regulatory proteins can be tested in vivo as vaccines in the prevention and treatment of SIV in suitable animal models. Adequate amounts of these synthetic peptides are injected subcutaneously or intracutaneously as antigens. The effect of this vaccination can be studied by assessing the development of symptoms of HIV infection and AIDS.

Abstract

The invention concerns peptides corresponding the Rev regulatory protein of the Human Immunodeficiency virus and methods of using the peptides.

Description

TAT & REV OLIGOPEPTIDES IN HIV TREATMENT
Field of the Invention
This invention relates to the therapeutic use of synthetic oligopeptides homologous to the signal sequences of viral regulatory proteins in the treatment of HIV infection.
References
1. Haseltine WA. 1991. In Genetic Structure and Regulation of HIV. Hasettine W.A., Wong-Staal F. eds. Harvard AIDS Institutes Series on Gene Regulation of Human Retroviruses Vol. 1 , Raven Press New York: 1.
2. Kuppuswamy M. et al. 1989. Nucl. Acid. Res. 17: 3551.
Background
Two of the essential regulatory proteins of HIV are the transactivator protein (tat) and the regulatory virion protein (rev). The binding of these proteins to specific regions of the viral RNA are essential for RNA function and for viral replication (review in 1). Inhibition of this binding mechanism leads to new therapeutic options in the treatment of AIDS.
In this patent application the conventional three letter abbreviation for amino acids is used and the peptide sequences given are read from the amino-terminal end to the carboxyl-terminal end. Summary of the invention
Tat and rev belong to a group of proteins essential for the regulation of HIV expression. The signal sequences of tat protein and rev protein for their interaction with HIV RNA are oligopeptide sequences enriched in cationic amino acids. The cationic charge of these signal sequences is essential for the binding of these proteins to the transacting responsive region (TAR) of HIV RNA and for RNA function. Inhibition of these binding mechanisms between tat and rev on one side and HIV RNA on the other side inhibits viral replication. Therapeutically this inhibition can be achieved in two ways, i) The parenteral application of synthetic analogs to the signal sequences of viral regulatory proteins, particularly to their RNA binding region. In this case the therapeutic mechanism is the competitive inhibition of the binding of viral regulatory proteins to viral RNA. This therapeutic approach may be particularly valuable in the treatment of manifest HIV infections and AIDS. ii). By subcutaneous or intracutaneous injection of these synthetic analogs to the peptide signal sequences of the viral regulatory proteins. In this case the antibodies produced against these antigens would block the signal sequences of these regulatory proteins and prevent the interaction with viral RNA. In this case a vaccine will be available in the prevention and treatment of HIV infections and AIDS.
Detailed Description of the Invention
The human immunodeficiency viruses (HIV) are etiologically linked with the acquired immunodeficiency syndrome (AIDS). Initial HIV infections appear to be silent with no or low levels of viral replication. Disease progression leads to a state of prolific viral replication and cell death. The different stages of HIV replication are determined by regulatory mechanisms controlling gene expression. In addition to the genes for viral structural proteins the HIV genom includes other genes encoding for virus-associated regulatory proteins. Among these viral regulatory proteins tat and rev are of particular importance ( review in 1). Transactivator Protein (tat)
Tat is a strong transactivator of genes that are expressed from the viral long terminal repeat (LTR) and is essential for HIV gene expression, viral replication, and virus mediated cythopathicity. The tat protein is 86 to 102 amino acids long, dependent on the viral strain. The sequence of the HIV HXB2 tat protein is given in figure 1. Several highly conserved domains in the tat protein have been identified among the various strains of HIV-1, HIV-2 and simian immunodeficiency virus (SIV)(2). The following domains are essential for tat function:
1). A domain rich in proline residues as well as cationic amino acid residues (arginine, lysine, histidine) and anionic amino acid residues (glutamate, aspartate): Glu-Pro-Val- Asp-Pro-Arg-Leu-Glu-Pro-Trp-Lys-His-Pro-Gly-Ser-Gln-Pro-Lys (residue 2 to 19, figure
11
2). A domain containing seven cysteine residues: Cys-Thr-Asn-Cys-Tyr-Cys- ys-Lys-
Cys-Cys-Phe-His-Cys-Gln-Val-Cys (residue 22 to 37, figure 1)
3). A domain containing the motif: Lys-X-Leu-Gly-lle-X-Tyr (residue 41 to 47, figure 1).
In this motif the residue lysine is essential and the residues glycine and tyrosine are partially essential for tat function.
4). A strong basic domain Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg (residue 49 to 57, figure 1). This basic region specifies both RNA binding and nuclear/nucleolar localization.
The claims of this patent are based on the following reported findings and new discoveries:
1. The information for the entire biological activity of the tat protein are contained in specific oligopeptide sequences within the tat peptide sequence (2).
2. These oligopeptide signal sequences are highly antigenic.
3. The activity of the tat protein can be inhibited in two ways: a) by the competitive inhibition of its binding to viral RNA via synthetic analogs of the signal sequences
b) by antibodies raised against these signal sequences which block the binding of transactivating proteins to viral RNA
4. Because of its defined binding properties to viral RNA synthetic analogs to the strongly basic oligopeptide of viral regulatory proteins are the most promising synthetic peptides for therapeutic purposes-
The therapeutic implications of this invention are the following:
1). A parenteral solution containing synthetic analogs to one or more of the signal sequences of viral regulatory proteins. This therapeutic application would be preferentially used, but is not limited to the treatment of manifest HIV infection or AIDS.
2). The subcutaneous or intracutaneous application of synthetic analogs to one or more of the signal sequences of viral regulatory proteins. In this case the oligopeptides would be used a vaccine in the prevention and treatment of HIV infections and AIDS.
Regulatory Virion Protein (rev)
The regulator of virion protein expression (rev) is another regulatory protein involved in HIV gene expression and pathogenicity (review in 1). The tat and rev regulatory pathways share much in common. The virus life cycle is divided into an early phase during which tat and rev proteins are made and a late phase in which virus structural proteins are made and virus particles are assembled. The rev protein mediates the switch from the early to the late phase. The sequence of HIV-1 3HXB2 rev protein is given in figure 2. The following domains are highly conserved among the rev proteins of different types of HIV viruses and they have been shown to be essential for rev function:
1. The domain: Pro-Pro-Pro-Asn-Pro (residues 27 to 31, figure 2)
2. The domain: Arg-Gln-Ala-Arg-Arg-Asn-Arg-Arg-Arg-Arg-Trp-Arg-Glu-Arg-Gln-Arg- (residues 35 to 50, figure 2).
3. The domain: Leu-Gln-Leu-Pro-Pro-Leu-Glu-Arg-Leu-Thr-Leu (residue 73 to 83, figure 2)
Analogous to the tat protein the strong basic amino acid region of the rev protein determines its binding to RNA and also specifies nuclear and nucleolar localization. This peptide region of the rev protein is responsible for the specific binding of rev to the rev responsive element (RRE), a short sequence in the gene for the viral envelope glycoprotein.
The claims of this patent and the therapeutic implications for synthetic analogs of rev protein sequences are based on inventions analogous to those described for the tat protein.
Experimental Design
The inventions disclosed in this patent application can be tested in the following way:
In vitro:
1. The inhibitory effect of synthetic peptides on transactivation can be measured in vitro by competition experiments measuring the decrease of expression of the bacterial chloramphenicol acetyltransferase (CAT) reporter gene linked to the HIV-LTR as described in (2) or by using another assay measuring transactivation or viral replication in the presence of these synthetic peptides. 2. The inhibitory effect of antibodies against synthetic peptides analogous to the signal sequences of viral regulatory proteins can be tested in vitro in the following way. Polyclonal or monoclonal antibodies are raised against specific signal peptides of viral regulatory proteins. The inhibitory effect of these antibodies on transactivation and viral replication can be measured in assays similar to those described above.
In vivo:
3. The therapeutic effect of synthetic peptides analogous to the signal sequences of viral regulatory proteins can be tested in vivo in suitable animal models susceptible to SIV. Therapeutic dosages of these synthetic peptides, given intravenously, decrease the susceptibility of the test animals to HIV exposure. Therapeutic dosages of these synthetic peptides given intravenously can also be tested for reducing the clinical symptoms of AIDS.
4. In an analogous way the synthetic peptides analogous to the signal sequences of viral regulatory proteins can be tested in vivo as vaccines in the prevention and treatment of SIV in suitable animal models. Adequate amounts of these synthetic peptides are injected subcutaneously or intracutaneously as antigens. The effect of this vaccination can be studied by assessing the development of symptoms of HIV infection and AIDS.

Claims

ClaimsThe following amino acid sequences and their therapeutic use are claimed:
1. INFORMATION FOR SEQ ID NO 1 :
(A) LENGTH 6
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Arg Gin Arg Arg Arg
2. INFORMATION FOR SEQ ID NO 2:
(A) LENGTH 6
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Arg Asn Arg Arg Arg
3. INFORMATION FOR SEQ ID NO 3:
(A) LENGTH 10
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Lys Lys Arg Arg Gin Arg Arg Arg Ala
4. INFORMATION FOR SEQ ID NO 4:
(A) LENGTH 10
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Gin Ala Arg Arg Asn Arg Arg Arg Arg
5. INFORMATION FOR SEQ ID NO 5:
(A) LENGTH 17
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Gin Ala Arg Arg Asn Arg Arg Arg Arg Trp Arg Glu Arg Gin Arg Gin
6. INFORMATION FOR SEQ ID NO 6:
(A) LENGTH 24
(B) TYPE: amino acid (D) TOPOLOGY: linear
Arg Lys Lys Arg Arg Gin Arg Arg Arg Ala His Gin Asn Ser Gin Thr His Gin Ala Ser Leu Ser Lys Gin
7. INFORMATION FOR SEQ ID NO 7:
(A) LENGTH 18
(B) TYPE: amino acid (D) TOPOLOGY: linear
Glu Pro Val Asp Pro Arg Leu Glu Pro Tφ Lys His Pro Gly Ser Gin Pro Lys
8. INFORMATION FOR SEQ ID NO 8:
(A) LENGTH 16
(B) TYPE: amino acid (D) TOPOLOGY: linear
Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe His Cys Gin Val Cys
9 INFORMATION FOR SEQ ID NO 9:
(A) LENGTH 24
(B) TYPE: amino acid (D) TOPOLOGY: linear
10. INFORMATION FOR SEQ ID NO 10:
(A) LENGTH 7
(B) TYPE: amino acid (D) TOPOLOGY: linear
Lys Ala Leu Gly He Ser Tyr
11. INFORMATION FOR SEQ ID NO 11 :
(A) LENGTH 6
(B) TYPE: amino acid (D) TOPOLOGY: linear
Pro Pro Pro Asn Pro Glu
12. INFORMATION FOR SEQ ID NO 12:
(A) LENGTH 13
(B) TYPE: amino acid (D) TOPOLOGY: linear
Pro Leu Gin Leu Pro Pro Leu Glu Arg Leu Thr Leu Asp
13. Peptide sequences analogous to the signal sequences of viral regulatory proteins according to claims 1 to 12 in which one or more amino acid residues are substituted with amino acid residues of identical polarity and charge.
14. Peptide sequences analogous to the signal sequences of viral regulatory proteins according to claims 1 to 13 in which one or more amino acid residues are added and/or deleted from the amino terminal and/or carboxyl-terminal end of the represented sequence.
15. The therapeutic use of one or more synthetic peptides analogous to the signal sequences of viral regulatory proteins according to claim 1 to 14 in the treatment of HIV infection comprising a pharmaceutically acceptable carrier for parenteral administration.
16. The therapeutic parenteral use of one or more synthetic peptides analogous to the signal sequences of viral regulatory proteins according to claim 1 to 15 as a competitive inhibitor for the activation of tat and rev proteins and thereby for the function of viral RNA in the treatment of HIV infection.
17. A composition according to Claims 1 to 16 further comprising one or more of the following compounds: ascorbate, N-acetylcysteine, glutathione and/or suitable salts thereof.
18. The therapeutic use of one or more synthetic peptides analogous to the signal sequences of viral regulatory proteins according to claim 1 to 14 comprising a pharmaceutically acceptable carrier for subcutaneous and/or intracutaneous administration.
19. The therapeutic use of one or more synthetic peptides analogous to the signal sequences of viral regulatory proteins according to claim 1 to 14 as a vaccine in the prevention and treatment of HIV infection. 1/2
tat
10
1 met glu pro val asp pro arg leu glu pro trp lys his pro gly ser gin amino terminal proline-rich
30 pro lys thr ala cys thr asn cys tyr cys lys lys cys cys phe his cys proline cysteine-rich rich
40 SO gin val cys | phe ile thr lys ala leu gly ile ser tyr gly [arg lys lys cysteine-rich RNA binding. nuclear/nucleolar localization
60 arg arg gin arg arg arg |ala his gin asn ser gin thr his gin ala ser
RNA binding, nuclear/nucleolar localization 70 80 leu ser lys gin pro thr ser gin ser arg gly asp pro thr gly pro lys exon l →-H-→- exon 2
glu
Figure 1. Primary amino acid sequence of the HIV HXB2 tat protein. Acidic residues are indicated in bold face. The proline-rich and basic regions are indicated. The basic region is also the region which binds RNA and specifies nuclear/nucleolar localization (boxed).
2/2
rev
10 met ala gly arg ser gly asp ser asp glu glu leu ile arg thr val arg
∞ 30 leu ile lys leu leu tyr pro asn pro glu gly thr
Figure imgf000014_0001
40 O arg gin ala arg arg asn arg arg arg arg tφ arg glu arg gin argj gln
RNA binding, nuclear/nucleolar Iocalization to ile his ser ile ser glu arg He leu gly thr tyr leu gly arg ser ala
70 80 glu pro val pro leu gin leu pro pro leu glu arg leu thr leu asp cys leucine motif
90 100 asn glu asp cys gly thr ser gly thr gin gly val gly ser pro gin ile
Figure imgf000014_0002
leu val glu ser pro thr val leu glu ser gly thr lys giu
Figure 2: Primary amino acid sequence of the HIV-1 3HXB2 rev protein. The basic regions, which specifies both RNA binding and nuclear/nucleolar localization, as well as the leucine-rich region are blocked. Acidic residues are indicated in bold face.
PCT/US1993/012680 1992-12-30 1993-12-30 Tat and rev oligopeptides in hiv treatment WO1994015634A1 (en)

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US07/997,734 1992-12-30

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WO1996027389A1 (en) * 1995-03-08 1996-09-12 Neovacs Non-toxic immunogens derived from a retroviral regulatory protein, antibodies, preparation method therefor, and pharmaceutical compositions containing same
FR2731355A1 (en) * 1995-03-08 1996-09-13 Neovacs NOVEL IMMUNOGENS, NEW ANTIBODIES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
WO1996040759A1 (en) * 1995-06-07 1996-12-19 Novartis Ag Antiviral peptoid compounds
WO1998017309A1 (en) * 1996-10-18 1998-04-30 Erasmus Universiteit Rotterdam Induction of rev and tat specific cytotoxic t-cells for prevention and treatment of human immunodeficiency virus (hiv) infection
WO1999027958A2 (en) * 1997-12-01 1999-06-10 Istituto Superiore Di Sanita' Hiv-1 tat, or derivatives thereof for prophylactic and therapeutic vaccination
FR2773156A1 (en) * 1997-12-26 1999-07-02 Biovacs Inc NOVEL ANTI-RETROVIRAL IMMUNOGENS (TOXOIDS), NOVEL PREPARATION METHODS AND APPLICATION TO AIDS PREVENTION AND TREATMENT
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WO2000078969A1 (en) * 1999-06-21 2000-12-28 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv tat peptides and multiple peptide conjugate system
US6200575B1 (en) 1996-03-07 2001-03-13 Neovacs Non-toxic immunogens derived from a retroviral regulatory protein antibodies preparation process and pharmaceutical compositions comprising them
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WO2002020555A2 (en) * 2000-09-04 2002-03-14 Bionor Immuno As Hiv peptides from tat, rev and wef conserved regions and their application as e.g.vaccine components
EP1385881A1 (en) * 2001-04-20 2004-02-04 Man-Wook Hur Anti-obesity polypeptides
US7563437B2 (en) 2005-02-15 2009-07-21 Thymon, Llc Methods and compositions for impairing multiplication of HIV-1
US7927580B2 (en) 2004-03-16 2011-04-19 Nanirx, Inc. Tat-based immunomodulatory compositions and methods of their discovery and use
US9206239B2 (en) 2009-03-23 2015-12-08 Pin Pharma, Inc. Treatment of cancers with immunostimulatory HIV Tat derivative polypeptides
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Title
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THE EMBO JOURNAL, Volume 11, No. 3, issued 1992, KJEMS et al., "Specific Binding of a Basic Peptide from HIV-1 REV", pages 1119-1129. *

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US6200575B1 (en) 1996-03-07 2001-03-13 Neovacs Non-toxic immunogens derived from a retroviral regulatory protein antibodies preparation process and pharmaceutical compositions comprising them
WO1998017309A1 (en) * 1996-10-18 1998-04-30 Erasmus Universiteit Rotterdam Induction of rev and tat specific cytotoxic t-cells for prevention and treatment of human immunodeficiency virus (hiv) infection
US6319666B1 (en) 1996-10-18 2001-11-20 Erasmus Universiteit Rotterdam Induction of REV and TAT specific cytotoxic T-cells for prevention and treatment of human immunodeficiency virus (HIV) infection
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WO1999027958A2 (en) * 1997-12-01 1999-06-10 Istituto Superiore Di Sanita' Hiv-1 tat, or derivatives thereof for prophylactic and therapeutic vaccination
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US7022326B1 (en) 1997-12-26 2006-04-04 Biovacs, Inc. Carboxymethylated retroviral regulatory proteins and interferon-α
US6420141B1 (en) 1997-12-26 2002-07-16 Neovacs Anti-HIV immunogens (toxoids), preparation methods and use for preventing and treating aids
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EP1041888A4 (en) * 1997-12-26 2000-10-18 Zagury Jean Francois Anti-retroviral immunogens, preparation and use
WO2000078969A1 (en) * 1999-06-21 2000-12-28 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv tat peptides and multiple peptide conjugate system
AT408721B (en) * 1999-10-01 2002-02-25 Cistem Biotechnologies Gmbh PHARMACEUTICAL COMPOSITION CONTAINING AN ANTIG
US8277815B2 (en) 1999-10-01 2012-10-02 Intercell Ag Pharmaceutical composition comprising an antigen
US7097971B2 (en) 2000-09-04 2006-08-29 Bionor Immuno As HIV-1 peptide, antigen, immunogenic composition, diagnostic method and immunoassay kit
WO2002020555A3 (en) * 2000-09-04 2002-06-06 Bionor Immuno As Hiv peptides from tat, rev and wef conserved regions and their application as e.g.vaccine components
WO2002020555A2 (en) * 2000-09-04 2002-03-14 Bionor Immuno As Hiv peptides from tat, rev and wef conserved regions and their application as e.g.vaccine components
EP1385881A4 (en) * 2001-04-20 2005-01-26 Univ Yonsei Seoul Anti-obesity polypeptides
EP1385881A1 (en) * 2001-04-20 2004-02-04 Man-Wook Hur Anti-obesity polypeptides
US7927580B2 (en) 2004-03-16 2011-04-19 Nanirx, Inc. Tat-based immunomodulatory compositions and methods of their discovery and use
US7563437B2 (en) 2005-02-15 2009-07-21 Thymon, Llc Methods and compositions for impairing multiplication of HIV-1
US9206239B2 (en) 2009-03-23 2015-12-08 Pin Pharma, Inc. Treatment of cancers with immunostimulatory HIV Tat derivative polypeptides
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US10159707B2 (en) 2013-10-04 2018-12-25 Pin Pharma, Inc. Treatment of cancers with immunostimulatory HIV Tat derivative polypeptides

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