CN106139150B - A kind for the treatment of AIDS vaccine composition and its application - Google Patents
A kind for the treatment of AIDS vaccine composition and its application Download PDFInfo
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- CN106139150B CN106139150B CN201510169136.XA CN201510169136A CN106139150B CN 106139150 B CN106139150 B CN 106139150B CN 201510169136 A CN201510169136 A CN 201510169136A CN 106139150 B CN106139150 B CN 106139150B
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Abstract
The invention belongs to technical field of vaccines, it is related to the therapeutic vaccine of a kind of human immunodeficiency virus persistent infection and its AIDS induced, more particularly to the treating AIDS vaccine composition being used in combination with the fusion inhibitor for targeting human immunodeficiency virus transmembrane protein gp41.The present invention is using the immunogene (such as N63) from the functional areas NHR on HIV-1gp41 as vaccine, induce the specific antibody for immunogene being easy to produce, it is used in combination and acts synergistically with HIV fusion inhibitor Enfuvirtide drug (T20) again, as a result so that nonneutralizing antibody is provided with neutralization activity, while enhancing the antiviral effect of T20 drug；It is particularly due to action target spot difference, which will also have a better effect T20 resistant strain.The present invention provides a kind of new Intervention Strategy for design treating AIDS vaccine.
Description
Technical field
The invention belongs to technical field of vaccines, it is related to a kind of human immunodeficiency virus persistent infection and its is induced
The therapeutic vaccine of AIDS, more particularly to merging inhibition with targeting human immunodeficiency virus transmembrane protein gp41
The treating AIDS vaccine composition that agent is used in combination.
Background technique
Human immunodeficiency virus (Human immunodeficiency virus, HIV) and its persistent infection are drawn
Wide-scale distribution of the Immune Deficiency Syndrome (abbreviation AIDS) of hair in the whole world has become serious public health problem,
Human health, economic growth and social progress are produced with important influence.So far, the effective prevention and thoroughly healing of the disease
It is still a global problem.The assessment display of AIDS Epidemic made by the World Health Organization (WHO), the global model in 2013
There are 35,000,000 people to infect AIDS virus in enclosing, increases 2,100,000 people of patients infected hiv, AIDS associated death 1,500,000 newly
People.Although vaccine is one of the best means for preventing and treating AIDS, regrettably, up to the present, not yet obtaining in the world can
The effective vaccine used.Therefore, effective AIDS vaccine how is developed, can especially generate neutralizing antibody in vivo
HIV vaccine be current international AIDS research field hot and difficult issue.
Studies have shown that HIV-1 (Human immunodeficiency virus type 1) transmembrane protein gp41 is in virus
Crucial effect is played in the film fusion process of target cell infection.When on HIV-1 envelope glycoprotein (Env)
Gp120 and after cell receptor CD4 and auxiliary receptor (CXCR4 or CCR5) combine, occurred conformation variation exposes gp41, with
Afterwards, melt film peptide (fusion peptide, FP) insertion target cell membrane, NHR (N-terminal heptad on gp41
Repeat it) interacts with the functional areas (C-terminal heptad repeats) CHR, forms six spiral (six- of fusion-activity
Helix bundle, 6HB), cause cell membrane and viromembrane close, film fusion occurs.Before the study found that be directed to gp41
NHR (N36 polypeptide) and the antibody of six spiral of fusion-activity (6HB) do not have neutralization at 37 degree, and it is small to be incubated for 1 at 31.5 degree
When after when returning again to 37 degree these antibody be just provided with neutralization activity.Researcher thinks, lead to the phenomenon the possible reason is
The film fusion speed that gp41 is mediated at 31.5 degree is slowed down, and antibody having time and space behavior is made to merge intermediate in gp41
NHR and six spirals, thus the fusion of block film.
The Jiang Shibo professor (national " thousand people plan " scholar) of one of present inventor is internationally famous virologist, long
Phase is engaged in the research of antiviral drugs it is reported that having found that first acts on HIV-1 gp41 fusion intermediate state in the world
AIDS virus resisting C- polypeptide-SJ-2176, and the HIV fusion inhibitor-En Fuwei novel as prototyping using the polypeptide
Peptide (Enfuvirtide also known as T-20).Enfuvirtide was approved by the FDA in the United States listing in 2003, becomes and beats the world
The discovery of a polypeptide HIV entrance/fusion inhibitor, the drug is considered as a milestone of AIDS-treating medicine research field.
Basis of the present inventor based on prior art research achievement, the quasi- one kind that provides is for human immunodeficiency
The therapeutic vaccine of malicious persistent infection and its AIDS induced, especially with targeting human immunodeficiency virus cross-film egg
The treating AIDS vaccine that the fusion inhibitor of white gp41 is used in combination has significant collaboration depression effect, can be significant
Improve the antiviral effect of T20 drug.
Summary of the invention
It is an object of the invention to provide a kind of as treating AIDS type epidemic disease for the status for treating AIDS in the world
The composition of seedling, and in particular to for human immunodeficiency virus persistent infection and its therapeutic epidemic disease of the AIDS induced
The composition of seedling, the AIDS being especially used in combination with the fusion inhibitor of targeting human immunodeficiency virus transmembrane protein gp41
The composition of sick therapeutic vaccine, the composition have significant collaboration depression effect, can significantly improve the antiviral of T20 drug
Effect.
The present invention is based on the immunogenes in the critical function area source NHR on HIV-1 transmembrane protein gp41 as HIV vaccine research
When, discovery using N63 albumen as immunogene in animal body caused by IgG antibody itself not neutralization activity, but with beauty
The HIV fusion inhibitor of state FDA approval -- when Enfuvirtide (hereinafter referred to as T20) is used in combination, produce significant collaboration
Depression effect, effect are similar to 31.5 degree of effects generated to film fusion of sub- temperature, i.e. T20 can act on HIV-1 sense at it
During contaminating target cell, slow down the film fusion process of virus, to keep the non-neutralization that can not be integrated to the area gp41NHR originally anti-
Physical efficiency having time and space combine, and (neutralize and live with the block film fusion generation ability that i.e. blocking virus enters target cell
Property).
Composition of the present invention is epidemic disease caused by immunogene (N63) of the origin derived from HIV-1 transmembrane protein gp41
Seedling (antiserum, the antibody that such as induce in vivo) and fusion inhibitor (such as T20 drug) composition for targeting HIV-1 gp41, two
Person's joint has the synergistic effect of significant mutually enhancing HIV-resistant activity.
In the present invention, the fusion inhibitor of the targeting HIV-1 gp41 in the composition is derived from HIV-1 gp41
The polypeptide of the functional areas CHR (as shown in Figure 1), such as drug Enfuvirtide (also referred to as T20).
Invention further provides the immunogenes and the fusion inhibitor in preparation HIV therapy vaccine group
Close the application in object, wherein vaccine and the fusion inhibitor Combination intervention virus of the immunogene as antigen, tool
There is the synergistic effect of significant mutually enhancing inhibitory activity.
Vaccine and pharmaceutical composition of the invention, has carried out Antiviral breeding, the results show that acting on gp41NHR function
The nonneutralizing antibody in area itself is generated without antiviral activity, but with after the medication combined intervention of fusion inhibitor Enfuvirtide
Significant collaboration inhibitory effect: the nonneutralizing antibody for gp41 is not only made to be provided with the activity for neutralizing virus infection, simultaneously
The antiviral effect of T20 drug is significantly improved, especially to T20 resistant strain.
The immunogene of HIV-1 transmembrane protein gp41 of the present invention is made of 63 amino acid, is specially HIV-
The amino acid sequence of the upper functional areas NHR 1gp41, amino acid sequence N-STMGAASMTLTVQARQLLSGIVQQQNNLLRA
IEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-C (N- indicates N-terminal direction, and C- indicates C-terminal direction, as shown in Figure 1).It (should
Immunogene is referred to as N63 in this application).
The present invention also provides the recombinant proteins for containing above-mentioned amino acid sequence.
The present invention also provides a kind of nucleic acid, which is characterized in that amino acid sequence described in the nucleic acid encode 2.
The present invention also provides a kind of expression vectors, which is characterized in that the expression vector includes the nucleic acid.
The present invention also provides a kind of recombinant cells, which is characterized in that the recombinant cell contains the expression and carries
Body.
In the present invention, in the cell-cell fusion inhibition system that the HIV-1 envelope protein Env established before is mediated
(bibliography Lu, L., Pan, C., Li, Y., Lu, H., Wu, H., Jiang, S.A bivalent recombinant
protein inactivates HIV-1 by targeting the gp41 prehairpin fusion
Intermediate induced by CD4 D1D2domains.Retrovirology.2012,9:104), have detected N63 work
The specific antibody (hereinafter referred to as Anti-N63 IgG) that is induced in animal body for immunogene and its with when T20 Combination intervention pairs
The inhibitory activity of HIV-1 live virus, the results show that individually Anti-N63 IgG do not have HIV-1 inhibitory activity, but its with
It is up to 88% (as shown in Figure 2) to the inhibitory activity of HIV-1 after T20 Combination intervention；Meanwhile passing through HIV-1IIIB(B, X4) sense
The vaccine serum of system detection Anti-N63 is contaminated to HIV-1IIIBThe inhibitory activity of live virus, the results show that individual Anti-
N63 serum does not have inhibitory activity yet, but it significantly improves (as shown in Figure 3) with inhibitory activity after T20 Combination intervention.
In the present invention, also MT-2 infect system and CEMx1745.25M7 infection system (bibliography Tong, P.,
Lu,Z.,Chen,X.,Wang,Q.,Yu,F.,Zou,P.,Yu,X.,Li,Y.,Lu,L.,Chen,Y.H.,Jiang,S.An
engineered HIV-1 gp41 trimeric coiled coil with increased stability and anti-
HIV-1activity:implication for developing anti-HIV microbicides.J Antimicrob
Chemother.2013,68 (11): 2533-44.) had detected on Anti-N63 IgG and its with when T20 Combination intervention to HIV-1
Inhibitory activity；The present invention calculates half inhibitory activity (IC by CalcuSyn program50) and coefficient of concordance (CI) with assess association
(bibliography is Xu W., Wang Q., Yu F., Lu L.*, Jiang S.*.Synergistic Effect to same-action
Resulting From Combinations of a Bifunctional HIV-1 Antagonist With
Antiretroviral Drugs.J Acquir Immune Defic Syndr.2014 Sep 1；67(1):1-6.)；Collaboration
The intensity of effect is expressed as follows with CI value: CI < 0.1, indicates very strong synergistic effect；CI=0.1~0.3 indicates exist very
Strong synergistic effect；CI=0.3~0.7 indicates there is synergistic effect；CI=0.7~0.85 indicates that the collaboration of moderate strength is made
With；CI=0.85~0.90 indicates there is weaker synergistic effect；It is of the invention the results show that the Anti-N63 of exclusive use
IgG does not show apparent inhibitory activity under the up to concentration of 3000nM, to different HIV-1 activity strains；But work as itself and T20
To HIV-1 after Combination interventionIIIB(B, X4) and HIV-1Bal(B, R5) shows stronger inhibitory activity, especially to T20 drug
Resistant strain inhibitory activity significantly improve, IC50It respectively may be about 73,89 and 140nM, coefficient of concordance CI is 0.16-0.26 (such as table
Shown in 1)；The result shows that the two Combination intervention shows to cooperate with depression effect by force: not only making N63 as caused by immunogene
Neutralization activity is provided with (with inhibition HIV-1 infection energy for the nonneutralizing antibody (not inhibiting HIV-1 infection ability) of gp41
Power), while the antiviral effect (improving 3-8 times) for significantly improving T20 drug itself；Meanwhile it also being had detected in the present invention
A series of HIV clinical strain of different subtypes, the results show that HIV different subtype after Anti-N63 IgG and T20 Combination intervention
The strain of (A, B, C, D, A/E, F and O) shows significantly to cooperate with depression effect (as shown in table 2), and coefficient of concordance CI is
0.14-0.26。
Table 1 is Anti-N63 IgG and its antiviral activity with T20 Combination intervention, including the laboratory HIV-1 adapted strain
And clinical drug resistance strain, wherein IC50That is half-inhibitory concentration refers to the drug concentration for inhibiting 50%HIV-1 infection；CI is
Coefficient of concordance.
Table 1
Wherein, IC50, that is, half-inhibitory concentration refers to the drug concentration for inhibiting 50%HIV-1 infection；CI, that is, coefficient of concordance.
Table 2 is Anti-N63 IgG and its inhibitory activity with T20 Combination intervention to HIV-1 clinical strain, including HIV-1
A, B, C, D, A/E, F and O hypotype.
Table 2
The therapeutic vaccine for being directed to human immunodeficiency virus persistent infection and its AIDS induced of the invention
Composition, there is significant collaboration depression effect, the antiviral effect of T20 drug can be significantly improved, can be further applied
The intervention of AIDS patient, or, related application can be specifically expressed as in the AIDS patients body using T20 drug.
The present invention has the advantages that
Using the immunogene (such as N63) from the functional areas NHR on HIV-1 gp41 as vaccine, induces and be easy to produce
The specific antibody for immunogene, then act synergistically with T20 drug, so that nonneutralizing antibody is provided with neutralization and live
Property, while enhancing the curative effect of T20 drug；It is particularly due to action target spot difference, which will also have T20 resistant strain
Preferable curative effect.
The present invention provides a kind of new Intervention Strategy for design treating AIDS vaccine.
Detailed description of the invention
Critical function area NHR, CHR sequence and T20 and N63 polypeptide sequence on Fig. 1 .HIV-1 gp41.
The cell fusion that Fig. 2 .T20, Anti-N63 IgG and the two Combination intervention inhibit HIV-1 Env to mediate tests knot
Fruit.
To HIV-1 when the serum Combination intervention of Fig. 3 .T20 and rabbit-anti N63IIIBThe suppression result of virus.
Specific embodiment
Embodiment 1 prepares vaccine and targeting caused by immunogene (N63) of the origin derived from HIV-1 transmembrane protein gp41
The composition of the fusion inhibitor composition of HIV-1 gp41 and Combination intervention experiment
1, N63 expression and purifying
The expression vector pGEX-6p-N63His-pp-PDI of building is converted into BL21 competent cell, picking Dan Ke
Grand bacterium colony is in LB culture solution, in 37 degree of cultures to OD600=0.4, then with the IPTG of 0.4mM in 16 degree of overnight inductions；Second
It is collected cell and with sonicated cells, is then centrifuged for and collects the supernatant containing fusion protein；Pass through nickel affinity chromatography
Method purifies the fusion protein in supernatant, the method specifically purified it is following (bibliography Lu, L., Pan, C., Li,
Y.,Lu,H.,Wu,H.,Jiang,S.A bivalent recombinant protein inactivates HIV-1by
targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2
Domains.Retrovirology.2012,9:104):
(1) it balances Ni column: using binding buffer (50mM NaH2P04, pH 8.0,300mM NaCl, 15mM imidazoles)
The pH for washing column to efflux is 8.0；
(2) supernatant of bacteria solution after taking centrifugal breaking is filtered using 0.45 μM of filter membrane；
(3) filtered supernatant of bacteria solution is crossed into column repeatedly, combines albumen sufficiently with affinity purification column；
(4) it is washed using washing buffer (50mM NaH2P04, pH 8.0,300mM NaCl, 60mM imidazoles) solution
Removing impurities albumen, elution volume are about 40ml.；
(5) mesh is eluted using striping buffer (50mM NaH2PO4, pH8.0,300mM NaCl, 300mM imidazoles)
Albumen.Collect each component eluted；
(6) albumen on column, binding buffer are stripped off using the Ni purification column 5ml 6M guanidine hydrochloride processing finished
After balance, 20% ethanol solution is added and is stored in 4 DEG C；
2, prepare animal immune and rabbit polyclonal antibody serum
Rabbit polyclonal antibody serum is prepared, takes 100 μ g N63 albumen to mix with equivalent complete Freund's adjuvant, uses threeway
As intermediate junction device, connects two proper volume syringes and inject repeatedly, emulsify it completely；Using 5 points of dorsal sc
N63 albumen is subcutaneously injected in new zealand white rabbit in injection method；14th, 37,51,65 day after immune, need to take 100 μ gN63 albumen with
Equivalent incomplete Freund's adjuvant mixes, and injects in the same way；It takes a blood sample before being immunized every time, is surveyed with indirect elisa method
Determine immunizing potency；Blood sample after rabbit blood sampling stands 2h at room temperature, when serum is slightly precipitated, 3000rpm centrifugation
15min takes out upper layer antiserum, makes marks, and a part is frozen in -80 DEG C of refrigerators, and another part is directly used in purifying, (with reference to text
Offer Wang, J., Tong, P., Lu, L., Zhou, L., Xu, L., Jiang, S., Chen, Y.H. (2010) .HIV-1 gp41
core with exposed membrane-proximal external region inducing broad HIV-1
neutralizing antibodies.PloS One.6(3):e18233.)
3, the purifying of rabbit polyvalent antibody (bibliography Wang, J., Tong, P., Lu, L., Zhou, L., Xu, L., Jiang,
S.,Chen,Y.H.(2010).HIV-1 gp41 core with exposed membrane-proximal external
region inducing broad HIV-1 neutralizing antibodies.PloS One.6(3):e18233.)
The IgG that specificity is good in antiserum, specific method are quickly extracted with the protein G pillar of commercialization first
It is as follows:
(1) balance commercialization protein G column, the Ph=7.2 of column to efflux is washed with the PBS of Ph=7.2；
(2) serum 1ml is diluted to 5ml with the PBS of Ph=7.2, and is filtered with 045 μM of filter membrane；
(3) serum is crossed into column: 3ml/10min, at least 3 times repeatedly；
(4) PBS of 2ml Ph=7.2 washes column, at least 3 times；
(5) it is eluted on FPLC with the gly of the 0.1M of Ph=2.5, and with the Tris-Hcl of 1.5M Ph=8.8 by Ph tune
Return 7.2；
(6) pillar is washed 3 times with 5ml PBS；
(7) with 20% ethanol elution column material, and 4 DEG C are stored in；
Rabbit igg obtained above is passed through affinity chromatography again to purify anti-N63 IgG, the specific method is as follows:
(1) affinity column material is coupled: N63 protein coupling to the Sepharose 4Fast Flow for having active group NHS-
On；
(2) affinity column material is balanced with the PBS of PH7.2；
(3) by loading after 0.45 μM of membrane filtration of IgG obtained above；
(4) it collects efflux and loading is multiple repeatedly；
(5) the PBS liquid of 2ml Ph=7.2 washes column, at least 3 times；
(6) it is eluted on FPLC with the gly of the 0.1M of Ph=2.5, and with the Tris-Hcl of 1.5M Ph=8.8 by Ph tune
Return 7.2；
(7) pillar is washed 3 times with 5ml PBS；
(8) with 20% ethanol elution column material, and 4 DEG C are stored in；
4, Anti-N63 IgG and its with T20 Combination intervention to HIV-1 cell fusion Inhibition test
The antiviral activity of anti-N63IgG, tool are detected by the cell-cell fusion experiment that HIV-1 Env is mediated
Body method is as follows: every milliliter of H9/HIV-1IIIB(2×105/ ml) with 2.5 μ l 1mM Calcein-AM in 37 degree of incubation half an hour
Afterwards, it is washed 3 times with PBS；In 96 orifice plates every hole be separately added into 50 μ l T20 (10nM), normal rabbit IgG (NR-IgG, 200nM),
After the mixture of anti-N63IgG (200nM) and T20 (10nM) and IgG (200nM), 50 μ l are added through above-mentioned processing in every hole
The H9/HIV-1 crossedIIIBCell is in 37 degree of incubation half an hour；Then 100 μ lMT-2 (1T-2 are added in every hole6/ ml) in 37 degree of incubations 2
In fluorescence microscopy microscopic observation cell fusion situation after hour, (bibliography Xu W., Wang Q., Yu F., Lu L.*,
Jiang S.*.Synergistic Effect Resulting From Combinations of a Bifunctional
HIV-1 Antagonist With Antiretroviral Drugs.J Acquir Immune Defic Syndr.2014
Sep 1；67 (1): 1-6. or Tong, P., Lu, Z., Chen, X., Wang, Q., Yu, F., Zou, P., Yu, X., Li, Y., Lu,
L.,Chen,Y.H.,Jiang,S.An engineered HIV-1 gp41 trimeric coiled coil with
increased stability and anti-HIV-1 activity:implication for developing anti-
HIV microbicides.J Antimicrob Chemother.2013,68(11):2533-44.)；
5, HIV-1 laboratory adapted strains, resistant strain and primary viral strain HIV suppression experiment (bibliography Xu W.,
Wang Q.,Yu F.,Lu L.,Jiang S..Synergistic Effect Resulting From Combinations
of a Bifunctional HIV-1Antagonist With Antiretroviral Drugs.J Acquir Immune
Defic Syndr.2014Sep 1；67 (1): 1-6. or Tong, P., Lu, Z., Chen, X., Wang, Q., Yu, F., Zou, P.,
Yu,X.,Li,Y.,Lu,L.,Chen,Y.H.,Jiang,S.An engineered HIV-1 gp41 trimeric coiled
coil with increased stability and anti-HIV-1 activity:implication for
developing anti-HIV microbicides.J Antimicrob Chemother.2013,68(11):2533-44.)
(1) drug gradient dilution: being added the 1640 50 μ l for being free of serum in 96 orifice plates, and the T20 calculated is added the
After a line carries out gradient dilution, being added in 96 orifice plates with 1:20 or 1:50 times of diluted rabbit anteserum or antibody, sun is concurrently set
Property control and negative control, with 20% ethanol elution column material, and be stored in 4 DEG C；
(2) Strain that -80 DEG C thaw is mixed well, according to 100 times of TCID50 values, (i.e. 50% tissue infection dosage adds
Enter in hole), every 50 μ l of hole, 37 DEG C of CO2 incubators place 30min；
(3) it after MT-2 or M7 cell 1000rpm being centrifuged 3min, being suspended with fresh growth medium, piping and druming mixes,
MT-2 or M7 cell is adjusted to 1x10 by cell count5100 μ l cells are added in a/ml concentration, every hole.37 DEG C of 5%CO2 were cultivated
Night；
(4) culture medium of 150 μ l is drawn in next day every hole, is filled into the fresh 1640+10%FBS culture medium of 150 μ l, is continued to train
It supports 4 days or 7 days, the cell conditioned medium of 50 μ l is drawn into 96 orifice plates in the 5th day after MT-2 cell infection, is added: 5%Triton
X-100-PBS lytic cell, 4 DEG C overnight；The culture medium for drawing 100 holes μ l/ on the 5th day after M7 cell infection, fills into 100 μ l
Fresh 1640+10%FBS culture medium.The 8th day after infection, the cell conditioned medium of 50 μ l is drawn into 96 orifice plates, is added: 5%
Triton X-100-PBS lytic cell, 4 DEG C overnight；
(5) ELISA detects the P24 content in cell conditioned medium.Half area's elisa plate (people HIV- is coated with using coating buffer
IgG5 μ g/ml), 4 DEG C are overnight.PBST board-washing 3 times, impregnate 3min.2%milk PBS closes elisa plate, 37 DEG C of 2h.PBST is washed
Plate 3 times, impregnate 3min.Cells and supernatant after 5 μ l are cracked, after mixing, 37 DEG C of 1h is added.PBST board-washing 3 times, impregnate 3min.
1.5 μ l/ml, 183 source of mouse monoclonal antibody, 37 DEG C of 1h are added.PBST board-washing 3 times, impregnate 3min.Addition sheep anti mouse HRP (1:
3000 dilutions), 37 DEG C of 1h.PBST board-washing 5 times, impregnate 3min.TMB colour developing, Ultra386 (Tecan) detect OD450Absorbance
Value.
Claims (2)
1. a kind of composition for the treatment of AIDS type vaccine, which is characterized in that its origin is exempted from derived from HIV-1 transmembrane protein gp41's
Epidemic focus N63 and the fusion inhibitor Enfuvirtide T20 for targeting HIV-1 gp41 are formed, wherein the amino of immunogene N63
Acid sequence is specially N-terminal-STMGAASMTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAV ERYL
The end KDQ-C；The fusion inhibitor Enfuvirtide T20 of HIV-1 gp41 is targeted from HIV-1 transmembrane protein gp41
The area CHR.
2. the composition for the treatment of AIDS type vaccine as described in claim 1 is preparing answering in treating AIDS vaccine
With, wherein the immunogene and the fusion inhibitor Enfuvirtide T20 are used in combination in HIV-1, as treatment
Property vaccine therapy AIDS.
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| WO2000000223A2 (en) * | 1998-06-29 | 2000-01-06 | Wolfgang Bergter | ANTIVIRAL AND ANTIRETROVIRAL RADIOIMMUNOMEDICAMENTS BASED ON α-EMITTERS AND β-EMITTERS |
| CN1685064A (en) * | 2002-09-27 | 2005-10-19 | 唐纳士公司 | Synergistic compositions for the prevention and treatment of acquired immunodeficiency syndrome |
| CN100341573C (en) * | 2002-09-27 | 2007-10-10 | 唐纳士公司 | Synergistic compositions for the prevention and treatment of acquired immunodeficiency syndrome |
| CN102665755A (en) * | 2009-10-09 | 2012-09-12 | 纽约血库公司 | Immunopotentiator-linked oligomeric influenza immunogenic compositions |
| CN102311487A (en) * | 2010-07-02 | 2012-01-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Anti-HIV (Human Immunodeficiency Virus) infection polypeptide, composition and application |
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| Title |
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| 基于HIV-1 gp41 NHR结构域的亚单位疫苗及融合抑制剂研究;邵继平;《万方数据库》;20130426;摘要第I-V页、第39-41页 * |
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