DK152517B - PROCEDURE FOR DETECTING INFECTIOUS AIDS VIRUS - Google Patents
PROCEDURE FOR DETECTING INFECTIOUS AIDS VIRUS Download PDFInfo
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- DK152517B DK152517B DK379385A DK379385A DK152517B DK 152517 B DK152517 B DK 152517B DK 379385 A DK379385 A DK 379385A DK 379385 A DK379385 A DK 379385A DK 152517 B DK152517 B DK 152517B
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- 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
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- 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
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- 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
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Description
iin
DK 152517BDK 152517B
Den foreliggende opfindelse angår en fremgangsmåde til påvisning af infektiøs AIDS-virus, LAV/HTLV-III virus, i vævsvæsker, såsom blodserum eller andre vævsvæsker.The present invention relates to a method for detecting infectious AIDS virus, LAV / HTLV-III virus, in tissue fluids such as blood serum or other tissue fluids.
Sygdommen AIDS ("acquired immunodeficiency syndrome") 5 har kun været kendt i ganske få år, men har udviklet sig nærmest eksplosivt siden 1981. Indtil udgangen af 1984 er der i USA registreret mere end 10 000 nye tilfælde, men det ventes, at yderligere 10 000 tilfælde vil opstå i 1985.AIDS ("acquired immunodeficiency syndrome") 5 has only been known for a few years, but has developed almost explosively since 1981. Until the end of 1984, more than 10,000 new cases have been registered in the United States, but it is expected that further 10,000 cases will occur in 1985.
10 AIDS skyldes et virus, der betegnes LAV ("lymphadenopathy- associated virus") eller HTLV-III ("human T-cell lympho-tropic virus type III"). Dette virus inficerer specifikt T-4 lymphocytter, der spiller en central rolle ved kontrol af immunsystemet. Sygdommen er særlig farlig over-15 for personer med svækket immunsystem, idet patienten udsættes for en risiko for at få en lang række sygdomme, som immunsystemet normalt beskytter imod. Eksempler herpå er lungelidelser, som på sådanne patienter udvikler sig dødeligt på kort tid, og Kaposi's sarcom, der hid-20 til har været en overordentlig sjælden sygdom, men som angriber AIDS-ofre med en hyppighed på over 30?ό. Det er også kendt, at mange AIDS-patienter lider af eller har haft hepatitis.AIDS is caused by a virus called LAV ("lymphadenopathy-associated virus") or HTLV-III ("human T-cell lympho-tropic virus type III"). This virus specifically infects T-4 lymphocytes, which play a key role in controlling the immune system. The disease is particularly dangerous for people with a weakened immune system, as the patient is at risk for a variety of diseases that the immune system normally protects against. Examples include lung disease that develops in such patients in a short period of time, and Kaposi's sarcoma, hitherto an extremely rare disease, but which attacks AIDS victims with a frequency of over 30? It is also known that many AIDS patients suffer from or have had hepatitis.
Selv om antallet af patienter med infektiøs AIDS er 25 stærkt stigende, har man konstateret, at et langt større antal personer har udviklet antistoffer mod AIDS, uden at de har udviklet sygdommen. Det har også vist sig, at personer kan være smittet med AIDS og således frembyde en smitterisiko, uden at de endnu har udviklet 30 antistoffer mod AIDS.Although the number of patients with infectious AIDS is 25 greatly increasing, it has been found that a far greater number of people have developed antibodies to AIDS without developing the disease. It has also been found that people can be infected with AIDS and thus present a risk of infection without having yet developed 30 antibodies to AIDS.
For at søge at begrænse sygdommens udbredelse er detTo seek to limit the spread of the disease it is
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2 af stor betydning at påvise alle tilfælde af infektiøs AIDS, således at smitte fra sådanne patienter kan forebygges. Da smitte især sker ved overførsel af blod eller anden vævsvæske fra en smittebærer, er det af stor be-5 tydning at kunne påvise, om bloddonorer har infektiøs AIDS.2 is of great importance to detect all cases of infectious AIDS so that infection from such patients can be prevented. Since infection is especially caused by the transfer of blood or other tissue fluid from an infectious carrier, it is of great importance to be able to detect whether blood donors have infectious AIDS.
Hidtil har man ikke haft nogen metode til at påvise tilstedeværelsen af infektiøs AIDS, hvorimod det har været muligt at påvise antistoffer mod AIDS i vævsvæsker.So far, there has been no method of detecting the presence of infectious AIDS, whereas it has been possible to detect antibodies to AIDS in tissue fluids.
10 I en række lande har man indført kontrol af alle blod donorer for tilstedeværelsen af antistoffer mod AIDS og afvist alle positive. Dette sikrer imidlertid ikke mod risikoen for at tappe blod fra AIDS-smittede personer, som (endnu) ikke har udviklet antistoffer.10 A number of countries have introduced checks on all blood donors for the presence of antibodies against AIDS and have rejected all positive ones. However, this does not safeguard against the risk of drawing blood from AIDS-infected individuals who have (yet) not developed antibodies.
15 Den foreliggende opfindelse har til formål at løse oven nævnte problem ved at anvise en fremgangsmåde til påvisning af infektiøs AIDS i prøver af vævsvæske.The present invention aims to solve the above-mentioned problem by providing a method for detecting infectious AIDS in tissue fluid samples.
Endvidere har opfindelsen til formål at påvise, om der i injektionspræparater findes infektiøse AIDS.Furthermore, the invention aims to demonstrate whether infectious AIDS is present in injection preparations.
20 Fra Nature, vol., 316, 1985, p. 69 - 74 og 262 - 265, er det kendt, at virus fremstillet fra HTLV-III genom er infektiøs og udøver en betydelig cytopatisk effekt in vitro på T4-positive celler. Således har man dyrket humane celler i suspension med T4-markører i et substrat 25 indeholdende HTLV-III virus. Efter dyrkning i nogle dage har der kunnet påvises en cytopatisk effekt på cellerne.20 From Nature, Vol. 316, 1985, pp. 69-74 and 262-265, it is known that viruses produced from HTLV-III genome are infectious and exert a significant cytopathic effect in vitro on T4-positive cells. Thus, human cells have been grown in suspension with T4 markers in a substrate 25 containing HTLV-III virus. After cultivation for a few days, a cytopathic effect on the cells has been demonstrated.
De ovennævnte undersøgelser har imidlertid ikke ført fagmanden på den tanke, at der kan udvikles en sikker 30 metode til påvisning af infektiøs AIDS i prøver af vævs-However, the aforementioned studies have not led the person of skill in the art to develop a safe method of detecting infectious AIDS in tissue samples.
DK 152517BDK 152517B
3 væske ved dyrkning af humane celler med T4-markører i et substrat.3 fluid by culturing human cells with T4 markers in a substrate.
Den foreliggende opfindelse er baseret på den idé, at man kan anvende en cellelinie med høj affinitet til 5 LAV/HTLV-III virus, der dyrkes som monolagskultur under nærmere angivne betingelser. Det har overraskende vist sig, at man derved kan opnå en meget sikker identifikation og en rationel og forenklet procedure. Fremgangsmåden, der er af den i indledningen til krav 1 angiv-10 ne art, er således ejendommelig ved det i den kende tegnende del af krav 1 anførte.The present invention is based on the idea that a high affinity cell line can be used for 5 LAV / HTLV-III virus grown as monolayer culture under specified conditions. Surprisingly, it has been found that a very secure identification and a rational and simplified procedure can be obtained. Thus, the method of the kind set forth in the preamble of claim 1 is peculiar to that of the prior art portion of claim 1.
De til udøvelse af opfindelsen særlig egnede humane celler er af typen lymfocytter, leukæmiceller eller celler fra hjerne-, lunge-, slimhinde-, lever- eller 15 nyrevæv.The human cells particularly suitable for carrying out the invention are of the type of lymphocytes, leukemia cells or cells of the brain, lung, mucosal, liver or kidney tissues.
Ued den omhandlede fremgangsmåde vil der i afhængighed af mængden af tilstedeværende LAV/HTLV-III virus, på kortere eller længere tid kunne påvises en cytopatisk effekt af de dyrkede celler. Påvisningen kan ske mikro-20 skopisk, men enhver anden påvisningsmetode kan dog be nyttes. Eksempler herpå er specifikke farvereaktioner eller 1) fiksering, farvning og mikroskopi 2) elektronmikroskopi 25 3) bestemmelse af viral nucleinsyre ved a) specifik farvning b) specifikke inhibitorer og nucleinsyresyntese 4) plaque-assay metode 5) fluorescens antistof-test 30 a) direkte metode b) indirekte metode 6) Reverse transcriptase-aktivitetsmåling.In the present process, depending on the amount of LAV / HTLV-III virus present, a cytopathic effect of the cultured cells could be detected in a shorter or longer time. The detection can be done microscopically, but any other detection method can be used. Examples are specific color reactions or 1) fixation, staining and microscopy 2) electron microscopy 3) determination of viral nucleic acid by a) specific staining b) specific inhibitors and nucleic acid synthesis 4) plaque assay method 5) fluorescence antibody test 30 a) direct method b) indirect method 6) Reverse transcriptase activity measurement.
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44
De under pkt. 1, 3, 4 og 5 nævnte metoder er beskrevet af Robert J. Kuchler: "Biochemical Methods in Cell Culture and Virology", 1977, Dowdon, Hutchinsom & Ross,Those under cl. Methods 1, 3, 4 and 5 are described by Robert J. Kuchler: "Biochemical Methods in Cell Culture and Virology", 1977, Dowdon, Hutchinsom & Ross,
Juc.Juc.
5 Det er påvist, at visse virus-typer, som er nært beslæg tet med LAV/HTLV-III, forårsager samme eller tilsvarende cytopatiske effekt på humane celler med T4-markører. Eksempler herpå er vira af typen visna, såsom Maedi-vis-na virus, der angriber får, se Nature New Biology, vol.It has been shown that certain virus types closely related to LAV / HTLV-III cause the same or similar cytopathic effect on human cells with T4 markers. Examples of these are viruses of the type virus, such as Maedi viruses that attack sheep, see Nature New Biology, vol.
10 237, May 24, 1972, p. 114-115. LAV/HTLV-III virus er nu klassificeret som tilhørende underfamilien lenti-virus, hvortil også Maedi-visna virus hører, idet RNA-strukturen og de morfologiske egenskaber viser et nært slægtskab.10, 237, May 24, 1972, pp. 114-115. The LAV / HTLV-III virus is now classified as belonging to the subfamily lenti virus, to which also the Maedi-visna virus belongs, in that the RNA structure and morphological characteristics show a close relationship.
15 Ved den omhandlede fremgangsmåde til påvisning af AIDS-virus kan som positiv kontrol benyttes en prøve med et kendt indhold af AIDS-virus. I stedet kan man dog anvende et virus med tilsvarende egenskaber, såsom Maedi-visna. Derved undgås risikoen for smitte af laboratorie- 20 personalet med AIDS-virus fra de benyttede reagenser og hjælpemidler.In the present method for the detection of AIDS virus, a test with a known content of AIDS virus can be used as a positive control. However, a virus with similar properties, such as Maedi-visna, can be used instead. This avoids the risk of infection by the laboratory staff with AIDS virus from the reagents and aids used.
Fremgangsmåden ifølge opfindelsen skal i det efterfølgende illustreres nærmere ved hjælp af eksempler.The method according to the invention will be illustrated in the following by way of example.
EKSEMPEL 1 25 Den udvalgte cellelinie podes i en vævsdyrkningsbakke med 24 huller, idet der i hvert hul podes samme antal celler, så der på 2 dage opnås 2/3 konfluent, idet der anvendes et serumholdigt vækstmedium. Efter opnåelse af en tilpas vækst (2/3 konfluent) skylles hvert hul 30 tre gange med vækstmedium indeholdende penicillin og streptomycin, men uden indhold af serum.EXAMPLE 1 The selected cell line is seeded in a 24-hole tissue culture tray, grafting in each hole the same number of cells to obtain 2/3 confluent in 2 days using a serum-containing growth medium. After achieving a suitable growth (2/3 confluent), each hole is rinsed three times with growth medium containing penicillin and streptomycin, but without serum.
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55
Kulturen inkuberes med den tredie portion skyllevaske i 10 minutter ved 37 °C, hvorefter vækstmediet fjernes. Derefter behandles hullerne individuelt på følgende måde: 5 1. række huller (fire huller til positiv kontrol) tilsæt tes 1 ml vækstmedium uden indhold af serum, men med fortyndinger af LAV/HTLV-III virus til det dobbelte rumfang.The culture is incubated with the third portion of rinsing for 10 minutes at 37 ° C, after which the growth medium is removed. Thereafter, the holes are individually treated as follows: 1st row of holes (four holes for positive control) add 1 ml of growth medium without serum content but with dilutions of LAV / HTLV-III double volume.
2. række huller (fire huller til negativ kontrol). Til 10 hvert hul sættes 0,5 ml standardiseret prøvemateriale, der er fundet fri for virus, og 0,5 ml vækstmedium uden serum.2nd row of holes (four holes for negative control). To each 10 holes is added 0.5 ml of standard virus-free sample material and 0.5 ml of serum-free growth medium.
3-6. rækker (testrækker). I hver række til fire test-huller tilsættes 0,5 ml af samme prøvemateriale i de 15 fire huller og 0,5 ml vækstmedium uden serum.3-6. rows (test rows). In each row of four test holes, 0.5 ml of the same sample material is added into the 15 four holes and 0.5 ml of growth medium without serum.
Dyrkningsskålene inkuberes ved 37 °C i 4 timer. Derefter suges al væske fra samtlige huller. Til hvert hul sættes dernæst 3 ml vækstmedium med antibiotica (penicillin og streptomycin) og 2% føtal kalveserum. Dyrkningsskå-20 lene inkuberes derefter ved 37 °C i op til 30 dage.The culture dishes are incubated at 37 ° C for 4 hours. Then all liquid from all holes is sucked. Next, 3 ml of growth medium with antibiotics (penicillin and streptomycin) and 2% fetal calf serum are added to each hole. The culture dishes are then incubated at 37 ° C for up to 30 days.
Der foretages medieskift med vækstmedium indeholdende antibiotica og 2% føtal kalveserum 3 gange ugentlig.Media changes are made with growth medium containing antibiotics and 2% fetal calf serum 3 times weekly.
Hver dag foretages mikroskopisk iagttagelse for cytopa-tisk effekt (CPE), som vurderes efter følgende skala: 25 0 - konfluent, normale sunde celler, ingen CPE, 0 - 30¾ PFU (plaque forming unit).Each day, microscopic observation for cytopathic effect (CPE) is made, which is evaluated on the following scale: 25 0 - confluent, normal healthy cells, no CPE, 0 - 30¾ plaque forming unit.
1+ - Isolerede "foci" og celler med CPE, PFU = ca. 50¾.1+ - Isolated "foci" and cells with CPE, PFU = ca. 50¾.
2+ - Omkring 50¾ af cellerne viser CPE, PFU = ca. 80¾.2+ - About 50¾ of cells show CPE, PFU = approx. 80¾.
3+ - komplet destruktion af cellelag, PFU = ca. 100¾.3+ - complete cell layer destruction, PFU = approx. 100¾.
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6 EKSEMPEL 2EXAMPLE 2
Den i eksempel 1 beskrevne procedure gentages med den ændring, at der til positiv kontrol anvendes Maedi-visna virus i stedet for LAV/HTLV-III virus.The procedure described in Example 1 is repeated with the change that Maedi-visna virus is used instead of LAV / HTLV-III virus for positive control.
5 Undersøgelser af en række væskeprøver fra blodserum ved de i eksempel 1 og 2 beskrevne metoder gav samme resultater.5 Studies on a series of blood samples from blood serum by the methods described in Examples 1 and 2 gave the same results.
Claims (4)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK379385A DK152517B (en) | 1985-08-21 | 1985-08-21 | PROCEDURE FOR DETECTING INFECTIOUS AIDS VIRUS |
| PCT/DK1986/000093 WO1987001135A1 (en) | 1985-08-21 | 1986-08-20 | A method of detecting infectious aids virus |
| AU63322/86A AU6332286A (en) | 1985-08-21 | 1986-08-20 | A method of detecting infectious aids virus |
| EP19860905238 EP0233264A1 (en) | 1985-08-21 | 1986-08-20 | A method of detecting infectious aids virus |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK379385A DK152517B (en) | 1985-08-21 | 1985-08-21 | PROCEDURE FOR DETECTING INFECTIOUS AIDS VIRUS |
| DK379385 | 1985-08-21 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK379385D0 DK379385D0 (en) | 1985-08-21 |
| DK379385A DK379385A (en) | 1987-03-23 |
| DK152517B true DK152517B (en) | 1988-03-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK379385A DK152517B (en) | 1985-08-21 | 1985-08-21 | PROCEDURE FOR DETECTING INFECTIOUS AIDS VIRUS |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0233264A1 (en) |
| AU (1) | AU6332286A (en) |
| DK (1) | DK152517B (en) |
| WO (1) | WO1987001135A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU609447B2 (en) * | 1987-02-19 | 1991-05-02 | Nissin Shokuhin Kabushiki Kaisha | Methods and materials for hiv detection and therapy |
-
1985
- 1985-08-21 DK DK379385A patent/DK152517B/en not_active Application Discontinuation
-
1986
- 1986-08-20 EP EP19860905238 patent/EP0233264A1/en not_active Ceased
- 1986-08-20 AU AU63322/86A patent/AU6332286A/en not_active Abandoned
- 1986-08-20 WO PCT/DK1986/000093 patent/WO1987001135A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK379385A (en) | 1987-03-23 |
| WO1987001135A1 (en) | 1987-02-26 |
| DK379385D0 (en) | 1985-08-21 |
| AU6332286A (en) | 1987-03-10 |
| EP0233264A1 (en) | 1987-08-26 |
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