CN1683019A - Method and use for constructing AIDS primate model - Google Patents
Method and use for constructing AIDS primate model Download PDFInfo
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- CN1683019A CN1683019A CN 200510008575 CN200510008575A CN1683019A CN 1683019 A CN1683019 A CN 1683019A CN 200510008575 CN200510008575 CN 200510008575 CN 200510008575 A CN200510008575 A CN 200510008575A CN 1683019 A CN1683019 A CN 1683019A
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Abstract
The present invention discloses a kind of HIV infection model of Chinese macaque as one kind of primate animal. HIV is inoculated to Chinese macaque via intravenous injection to constitute the HIV infection model of Chinese macaque successively. By means of understanding the infecting course, pathological characteristic, pathogenesis and body's resistance of HIV inside the model, are researched the infected target organ, target tissue and target cell, the attack to the immunity system, the reaction of the immunity system cell, etc. The HIV infection model has non-replaceable effect in AIDS research, anti-AIDS medicine screening, vaccine evaluation, etc.
Description
Technical field
The present invention relates to a kind of AIDS primate model, especially the construction method and the purposes of the acute and chronic HIV (human immunodeficiency virus) infection model of macaque.
Background technology
China since first report acquired immune deficiency syndrome (AIDS) case in 1985, the popular fast rise trend that is of acquired immune deficiency syndrome (AIDS).2003, health ministry carried out nationwide acquired immune deficiency syndrome (AIDS) Epidemiological study together with relevant international organization, and preliminary analysis is the result show, China existing about 840,000 people of AIDSinfected patient, wherein about 80,000 examples of acquired immune deficiency syndrome (AIDS) patient.By 2003, only AIDSinfected patient 1648 examples were totally found in Beijing, ranked the 7th in the whole nation.Have the expert to give a warning, if acquired immune deficiency syndrome (AIDS) is not added a containment, by 2010, China's AIDSinfected patient will be increased sharply to 1,000 ten thousand people, and this type of patient of Beijing will be near 20,000 people, after 2010, grew the disease rate of increase and continued to be the radioactivity growth.
The Chinese government pays much attention to AIDS preventing and controlling work, has established the AIDS preventing and controlling elementary tactics of " put prevention first, communication and education is main, control combination, treating both the principal and secondary aspects of a disease, comprehensive control ".From calendar year 2001, state revenue AIDS preventing and controlling specific project expenditure is invested 12.5 hundred million yuan of national debts by being increased to 100,000,000 yuan original every year 1500 ten thousand, local supporting 1,000,000,000 yuan of blood station capital construction and corollary equipments that are used to strengthen central and west regions.2003, country increased input again 2.7 hundred million yuan and is used for the AIDS preventing and controlling work of key area.
Avoid acquired immune deficiency syndrome (AIDS) to have only two approach being widely current of China: the one, at the medicine of inventing out in recent years AIDS vaccine or radical cure acquired immune deficiency syndrome (AIDS); The 2nd, effectively suppress its route of transmission.For the latter, control is taken drugs, is spread through sex intercourse and the medical science infection is main means, but some present present situations of China make us very worrying.And for the former, need whole world scientific research personnel's arduous effort, for solving HIV sufferers treatment problem, relevant department of Chinese Government has set up treatment acquired immune deficiency syndrome (AIDS) import of drugs registration and development declaration express passway, ratified the tax-free of import treating AIDS medicine, 2002, realized the production domesticization of part antiviral therapy medicine.
Though China has all obtained certain progress to the research of aspects such as acquired immune deficiency syndrome (AIDS) cause of disease, diagnosis, source at present, still lacks suitable HIV (human immunodeficiency virus) infection animal model, especially primate model.Therefore, lack the research bottleneck problem that the acquired immune deficiency syndrome (AIDS) animal model has become restriction prevention or the screening of treatment AIDS-treating medicine, vaccine evaluation and pathogenesis etc.Under these circumstances, the monkey model of AIDS is important step in the R﹠D work.
Though, the known primate infection model of having set up numerous at different pathogens, but set up the primate infection model at acquired immune deficiency syndrome (AIDS), link such as detect, immunoserology is determined in processing, dosage, approach and the metainfective virus of the selection of animal product section, health status, infective virus and exist a large amount of technical problems to need to be resolved hurrily.External aids related infection primate infection model document does not wherein disclose concrete construction method, and the effect of gained animal infection modal is very unclear yet.
(SimianImmunodeficiency Virus SIV) can bring out and sets up the acute or chronic model of monkey SIV macaque (Rhesus Macacus, machin) inoculation simian immunodeficiency virus.This animal model is a best animal model of estimating anti-AIDS drug, AIDS vaccine and immunomodulator.Thereby it is anti-AIDS drug vaccine and the requisite model of immunomodulator therapeutic evaluation, also is the pathogenetic best model of research acquired immune deficiency syndrome (AIDS).Why claim that it is best animal model, be because the variation of clinical symptoms, sign and the hematology of its pathogenic process, immunology, pathology, pathophysiology is very similar with aids patient to people HIV the infected, just becoming the object of study of removing to carry out Medical Biology, materia medica for people's scapegoat, also is that the newspaper medicine inspection office approval of existing anti-AIDS drug is carried out the necessary zoopery that the human body examination obeys and proved.
The inventor has effectively overcome existing many technical problems, successful structure the acute and chronic HIV (human immunodeficiency virus) infection model of Chinese macaque.The repeatability that infects in described animal, good stability are for important foundation has been established in the research of further studying aspects such as this viral pathogenic characteristic, pathogeny, drug screening, vaccine evaluation.
Summary of the invention
One aspect of the present invention relates to the acute and chronic HIV (human immunodeficiency virus) infection model of a kind of HIV (human immunodeficiency virus) primate infection model, especially acquired immune deficiency syndrome (AIDS) macaque.
After the macaque aids infection virus, show very similar with aids patient, PD has 3 stages behind the monkey taint with SIV: the early stage and chronic infection middle and late stage of actute infection, chronic infection, produce AIDS virus resisting antibody IgM and IgG, the body fluid isolated viral positive detects virus-positive, the foundation of this model, on virusology and amynologic index, nosetiology, hematology, immunology, pathogenetic research to HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) comprise virus load, CD4
+T cell and CD8
+The research of the variation of T cell quantity and ratio thereof, the pathomorphology of lymph node and their reverse, alleviation and immunologic reconstitution process, and application facet such as drug screening, vaccine evaluation has irreplaceable effect, selects representational meaning aspect the responsive infection animal research in HIV (human immunodeficiency virus) (Human Immunodeficiency Virus).
The principle of simian acquired immunodeficiency syndrome modelling is after simian immunodeficiency virus (SIV) infects monkey, to duplicate breeding in vivo, directly destroys CD4 on the one hand
+T lymphocyte and immune system stimulate the humoral immunization and the cellullar immunologic response of the complexity that body produces on the other hand, cause multi-faceted negative reaction, cause the serious acquired immunodeficiency syndrome of animal and opportunistic infection at last and death.
We use simian immunodeficiency virus infection Rhesus Macacus or machin that cercopithecus aethiops is found on one's body, occur SIV antigen and monkey CD4 on the monkey body
+T lymphocyte and phagocyte combination, virus is at CD4
+The T lymphocyte duplicates, and constantly destroys CD4
+The T lymphocyte causes the model monkeys morbidity, produces antibody simultaneously in the monkey body and clinical symptoms occurs, and as heating, appetite is not good enough, weight loss and the enlargement of body surface superficial popliteal lymph nodes etc., body fluid and cellular immunization also change in the body, as CD4
+The T lymphocyte reduces, CD4
+/ CD8
+The T percentage of lymphocyte descends, and circulating immune complex and bulky grain immune complex deposit, autoantibody occur and the final autoimmune response that causes, and form the disease overall process similar to people HIV/AIDS.
Another aspect of the present invention relates to a kind of method that makes up acquired immune deficiency syndrome (AIDS) macaque infection model.
1, animal is selected: Rhesus Macacus, machin, adult, male and female dual-purpose.Detect SIV, monkey reverse transcription D type virus (SRV) and monkey T lymphatic I type virus (STLV-I) negative antibody, tuberculin feminine gender, dysentery bacillus feminine gender through serology.
2, strain: the SIVmac 251 that professor Marx in U.S. Aarond Diamond acquired immune deficiency syndrome (AIDS) research center gifts, through healthy monkey PBMC amplification in vitro, through the vein infected monkey, the titration virus titer, press 3MID100-10MID100 dosage vein and infect, this experiment is finished in Institute of Experimental Animals, Chinese Academy of Medical Sciences.
3, different time points is observed animal clinical manifestation and sign behind the taint with SIV, and detects hematology, immunology, virusology and lymph node pathology morphology.According to the variation of above regularity, can be divided into 3 stages.
3.1 acute infection period: be characterized as and infect the back and reached the peak period for the acute rising of plasma viral load in 10～20 days, drop to thereafter and infect the back and reduced to " set point " in 2～3 months---i.e. viral plateau.CD4
+Go up after slightly descending in 2 weeks behind the T cell infection, continue certain level.The lymph node pathology histology is the hypertrophy type.
3.2 chronic infection is early stage or infect the duration: virus load is steady, the CD4+T cell number steadily or slowly descends, and the lymph node pathology histology engenders regression for hypertrophy is main, the last infecting 4～12 months or longer.
3.3 chronic infection intermediary and later stages or stage of exhaustion: the virus load level is higher, and the CD4+T cell descends, lymph node pathology histology regression or exhaustion, and weight loss infects back 10～24 months or longer.
Long and short or the speed that develops of above chronic infection phase is looked monkey individual diversity XOR environment, and the raising factor can be variant.
4, the concrete application of model
4.1 acute infection period application of model: observe the preventive effect of medicine, vaccine etc., handle animal earlier, postoperative infection is observed preventive effect.Medicine carries out simultaneously with infection, observes the change (being that viral peak is lower than normal infection matched group) on viral peak, but is subjected to the influence of animal individual difference bigger.
4.2 chronic infection early stage (i.e. viral plateau) application of model: observe the effect of curative drug or vaccine, more generally be suitable for.Comparison before and after effective evaluation can be treated with animal itself, also treatment group simultaneously and matched group are compared.Infection animal can make data more reliable through reasonable selection and grouping.
4.3 chronic infection intermediary and later stages application of model: the effect of observing medicines such as immunomodulator, immunologic reconstitution and physical efficiency recovery, use the variation of overall health of patients, the decline of virus load, the improvement of amynologic state, especially the histological improvement of lymph node pathology, making destructive lymphoid tissue recover to reach immunologic reconstitution, is the clearer and more definite index that we use.
4.4 different times lymph node biopsy pathologic finding: be to observe zoosis close friend, bad morphology platform, by treating forward and backward contrast, can know the curative effect of knowing anti-AIDS drug and the length of duration of efficacy, also use immunohistochemical method, can measure inmature lymphocytic regenerated situation, this is very convictive index.
Another aspect of the present invention relates to the purposes that acquired immune deficiency syndrome (AIDS) macaque infection model is used for course of infection in the HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) body, pathogeny, the research of body resistant function.Acquired immune deficiency syndrome (AIDS) has many problems to fail to solve at present, the target organ, target tissue and the target cell that comprise infection, to immune attack, the reaction of immune system cell etc., in human body, can't draw materials, and in model monkeys, can carry out purposes in the collaborative morbific research of the drawing materials of any index of time dynamics, spike and correlated condition cause of disease.
Another aspect of the present invention relates to the purposes that acquired immune deficiency syndrome (AIDS) macaque infection model is used for anti-AIDS drug screening and vaccine evaluation.
Behind the macaque taint with SIV, all can detect virusology and amynologic index, as: produce anti-SIV IgM and IgG antibody within a certain period of time, successful isolated viral in body fluid and the tissue, infect the back and detect virus-positive, these virusology and amynologic index have irreplaceable effect to application facet such as HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) drug screening, vaccine evaluations.Specifically, described animal model can be used in as any AIDS virus resisting medicine, comprises in the effect assessment of Chinese medicine.If medicine to be measured has the effect of AIDS virus resisting, then the effect of described medicine can be by changing above index and evaluate efficacy and toxic and side effects in the monkey body.
In the existing laboratory animal of China, do not have other animals ratios to test, thereby to the evaluation of vaccine, this model have the superiority that can not be substituted with the more approaching mankind of monkey.
The specific embodiment:
The present invention will further specify by embodiment:
Embodiment
1, animal is selected: select each one of adult macaque male and female, recheck with monkey national standard microorganism SPF level by experiment before the inoculation, and the inspection antibody of AIDS virus.Detect SIV, monkey reverse transcription D type virus (SRV) and monkey T lymphatic I type virus (STLV-I) negative antibody through serology;
2, virus inoculation
The SIVmac 251 that professor Marx in U.S. Aarond Diamond acquired immune deficiency syndrome (AIDS) research center gifts, through healthy monkey PBMC amplification in vitro, through the vein infected monkey, the titration virus titer, press 5MID 100 dosage veins and infect, all zooperies are all carried out in Institute of Experimental Animals, Chinese Academy of Medical Sciences's acquired immune deficiency syndrome (AIDS) special use Animal Lab. by " laboratory animal institute laboratory animal use and test rules ".
3, the relevant performance of inoculation back animal
3.1, acute infection period: be characterized as and infect back 10～20 days, drop to thereafter and infect the back and reduced to " set point " in 2～3 months for blood plasma and the acute rising of virus load reach the peak period---i.e. viral plateau.CD4
+Go up after slightly descending in 2 weeks behind the T cell infection, continue certain level.The lymph node pathology histology is the hypertrophy type.
3.2, chronic infection is early stage or infect the duration: virus load is steady, and the CD4+T cell number steadily or slowly descends, and the lymph node pathology histology engenders regression for hypertrophy is main, the last infecting 4～12 months or longer.
3.3, chronic infection intermediary and later stages or stage of exhaustion: the virus load level is higher, and CD4+T descends, lymph node pathology histology regression or exhaustion, weight loss infects back 10～24 months or longer.
4, inoculation back animal specimen virus monitor
Behind macaque inoculation SIV, often 1-2 week makes a collection of specimens, and inoculation CEMX 174 cells carry out virus and separate, and every 3-4 day observation of cell pathological changes and change liquid continues 4 weeks of observation.
5, the detection of the RNA viruses carrying capacity of SIV in the animal model
Behind inoculation SIV, every 1-2 week makes a collection of specimens, and measures the RNA viruses carrying capacity with the RT_PCR method.
The above results confirms: the present invention adopts the SIV inoculation can effectively infect macaque, and described virus is duplicated and toxin expelling in this animal model.
6, the pathology of animal model detect
After animals received SIV inoculation, get lymph node with biopsy method, 10% formalin fixed, paraffin embedding, after the routine pathology tissue slice is handled, dyeing, microscopy.Confirm that the animal model that adopts the inventive method to make up can effectively be simulated the course of infection of SIV in primate.
Use this model, the inventor provides service for domestic Military Medical Science Institute, China Academy of TCM, biotechnology research institute of the Chinese Academy of Medical Sciences, medicine institute, Chinese Academy of Sciences institute of materia medica, Shanghai, Guangzhou Plant Inst., the strong psychological treatment industry in Zhuhai etc., and the research that simian acquired immunodeficiency syndrome dendron shape vaccine therapy has been carried out in the fifth-largest of Paris, FRA and inventor's cooperation also is to use this model.Proving that through these services simian acquired immunodeficiency syndrome models are used for study of pathogenesis, the drug screening of AIDS virus resisting, the vaccine evaluation of AIDS viral infection, is believable, science, valuable.
Claims (8)
1. AIDS primate model is characterized in that:
(A) select the macaque that grows up, detect SIV, monkey reverse transcription D type virus (SRV) and monkey T lymphatic I type virus (STLV-I) negative antibody through serology;
(B) strain is SIVmac251, through healthy monkey PBMC amplification in vitro;
2. a kind of AIDS primate model according to claim 1 is characterized in that: it is Chinese macaque infection model.
3. AIDS primate model construction method, it is characterized in that: vaccination ways is the intravenous injection virus inoculation, inoculum concentration is 3MID100-10MID100.
4. a kind of AIDS primate model construction method according to claim 3 is characterized in that: after the macaque inoculation HIV (human immunodeficiency virus) (Human Immunodeficiency Virus), every 1-2 week makes a collection of specimens, and inoculation CEMX174 cell carries out virus and separates.
5. a kind of AIDS primate model construction method according to claim 3 is characterized in that: measure body fluid and in-house virus load with the RT_PCR method.
6. a kind of AIDS primate model construction method according to claim 3 is characterized in that: after accepting virus inoculation, get lymph node with biopsy method, and formalin fixed, paraffin embedding, after the routine pathology tissue slice is handled, dyeing, microscopy.
7. an AIDS primate model is characterized in that described acquired immune deficiency syndrome (AIDS) primate infection model is used for the purposes of anti-AIDS drug screening.
8. an AIDS primate model is characterized in that described acquired immune deficiency syndrome (AIDS) primate infection model is used for the purposes that anti-AIDS vaccine is estimated.
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| CN 200510008575 CN1683019A (en) | 2005-02-23 | 2005-02-23 | Method and use for constructing AIDS primate model |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102154356A (en) * | 2011-01-07 | 2011-08-17 | 中国医学科学院医学实验动物研究所 | Hybrid immunodeficiency plasmid containing human immunodeficiency virus (HIV)-1 circulating recombinant form (CRF) 01-AE subtype reverse transcriptase (RT) gene, virus and use |
| CN102465117A (en) * | 2010-11-17 | 2012-05-23 | 南开大学 | Chimeric simian/human immunodeficency virus strain and application thereof |
| CN104077948A (en) * | 2014-07-23 | 2014-10-01 | 首都医科大学附属北京佑安医院 | AIDS based preparation method of three-dimensional faulting specimens for researching and teaching |
| CN106636461A (en) * | 2016-09-21 | 2017-05-10 | 广东省实验动物监测所 | Detection primer set and method capable of simultaneously detecting and distinguishing SIV, SRV and STLV |
| CN112056275A (en) * | 2020-09-27 | 2020-12-11 | 澎立生物医药技术（上海）有限公司 | Intestinal mucositis animal model and construction method and application thereof |
| CN113299407A (en) * | 2021-06-16 | 2021-08-24 | 四川省疾病预防控制中心 | Key population AIDS intervention method based on emerging time-space hotspot analysis |
-
2005
- 2005-02-23 CN CN 200510008575 patent/CN1683019A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102465117A (en) * | 2010-11-17 | 2012-05-23 | 南开大学 | Chimeric simian/human immunodeficency virus strain and application thereof |
| CN102465117B (en) * | 2010-11-17 | 2013-01-23 | 南开大学 | Chimeric simian/human immunodeficency virus strain and application thereof |
| CN102154356A (en) * | 2011-01-07 | 2011-08-17 | 中国医学科学院医学实验动物研究所 | Hybrid immunodeficiency plasmid containing human immunodeficiency virus (HIV)-1 circulating recombinant form (CRF) 01-AE subtype reverse transcriptase (RT) gene, virus and use |
| CN102154356B (en) * | 2011-01-07 | 2012-11-14 | 中国医学科学院医学实验动物研究所 | Hybrid immunodeficiency plasmid containing human immunodeficiency virus (HIV)-1 circulating recombinant form (CRF) 01-AE subtype reverse transcriptase (RT) gene, virus and use |
| CN104077948A (en) * | 2014-07-23 | 2014-10-01 | 首都医科大学附属北京佑安医院 | AIDS based preparation method of three-dimensional faulting specimens for researching and teaching |
| CN104077948B (en) * | 2014-07-23 | 2016-07-13 | 首都医科大学附属北京佑安医院 | Three-dimension disclocation scientific research based on acquired immune deficiency syndrome (AIDS) and method for preparing teaching specimen |
| CN106636461A (en) * | 2016-09-21 | 2017-05-10 | 广东省实验动物监测所 | Detection primer set and method capable of simultaneously detecting and distinguishing SIV, SRV and STLV |
| CN106636461B (en) * | 2016-09-21 | 2018-08-14 | 广东省实验动物监测所 | A kind of detection primer group and method that can be detected simultaneously and distinguish SIV, SRV, STLV |
| CN112056275A (en) * | 2020-09-27 | 2020-12-11 | 澎立生物医药技术（上海）有限公司 | Intestinal mucositis animal model and construction method and application thereof |
| CN112056275B (en) * | 2020-09-27 | 2022-05-10 | 澎立生物医药技术（上海）有限公司 | Intestinal mucositis animal model and construction method and application thereof |
| CN113299407A (en) * | 2021-06-16 | 2021-08-24 | 四川省疾病预防控制中心 | Key population AIDS intervention method based on emerging time-space hotspot analysis |
| CN113299407B (en) * | 2021-06-16 | 2023-08-08 | 四川省疾病预防控制中心 | Important crowd AIDS intervention method based on emerging space-time hot spot analysis |
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