US5212084A - Retrovirus and related method used for producing a model for evaluating the antiretroviral effects of drugs and vaccines - Google Patents
Retrovirus and related method used for producing a model for evaluating the antiretroviral effects of drugs and vaccines Download PDFInfo
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- US5212084A US5212084A US07/200,843 US20084388A US5212084A US 5212084 A US5212084 A US 5212084A US 20084388 A US20084388 A US 20084388A US 5212084 A US5212084 A US 5212084A
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/14011—Deltaretrovirus, e.g. bovine leukeamia virus
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- the present invention relates to the health research industry, and more particularly to a method for providing a model in which the efficacy of antiretroviral drugs and vaccines can be determined in a relatively short time, as well as a retrovirus used therein.
- HIV human immunodeficiency virus
- AIDS acquired immunodeficiency syndrome
- the major requirements for an animal model to be useful in vaccine efficacy studies are that (i) essentially all animals become infected following innoculation of virus; (ii) infection be easily detected by isolation of virus, which can be quantitated; (iii) seroconversion occurs; and (iv) infection elicits disease, preferably analogous to disease induced by the same virus in humans.
- the latter is important if the vaccine does not provide absolute protection against infection, in which case one could monitor and assess the effects of the putative vaccine on prevention or the severity of the ensuing disease.
- a major obstacle to researchers has been the lack of a model which provides a means to quickly determine the efficacy of newly developed antiretroviral drugs and vaccines, and particularly those associated with AIDS. This is primarily because there exists no previously identified immunodeficiency virus capable of causing acute disease and death within a few days after infection.
- the present invention relates to a model for rapidly evaluating the antiretroviral effects of drugs and vaccines.
- SIV/SMM/PBg14 A highly virulent strain of a simian immunodeficiency virus (a T-lymphotropic retrovirus), herein termed "SIV/SMM/PBg14", was obtained from the tissues of a first pig-tailed macaque that had been inoculated with the virus approximately 14 months earlier. The macaque developed chronic diarrhea, lymphadenopathy, splenomegaly, lymphopenia and thrombocytopenia, and also became terminally anemic and ataxic. Blood was taken from the first infected macaque and transfused to second macaques. The majority of these second macaques died in about 7 to 9 days after transfusion.
- SIV/SMM/PBg14 a highly virulent strain of a simian immunodeficiency virus
- lymphoid tissues Prior to death, i.e., about 5 days after transfusion, the second macaques developed acute disease with symptoms that included lymphadenopathy, splenomegaly and hyperplasia, and hemorrhage and necrosis of lymphoid tissue. Histologically, the lymphoid tissues became reactive and contained foci of necrosis and multinucleated giant cells. Moreover, virus could be isolated from multiple tissues, including the brain. Similar results were obtained by repeating the inoculation step with a retrovirus isolated from tissues of either the initial macaque or the transfusion recipients.
- FIG. 1 is a gel showing a comparison of SIV/SMM and HIV gene products by RIP assay. Proteins from PHA-AWBC infected with SIV/SMM (lane 1) or HIV (lane 2) were immunoprecipitated with rabbit antiserum to HIV (CDC isolate 451). Lane 3: 14 C-labeled molecular weight markers.
- FIG. 2 is a graph illustrating the results of neutralization of SIV/SMM of the present invention and LAV by antiserum elicited by LAV; SIV/SMM (-) and LAV (---) were incubated with serum from a LAV-infected chimpanzee (o) or with serum from mangabey 14 (•) prior to infection of PHA-AWBC.
- FIG. 3 is a graph illustrating the cytopathic effect of SIV/SMM of the present invention on helper T-lymphocytes; samples of PHA-AWBC that were either uninfected (O---O) or infected O-O) with SIV/SMM from mangabey 7 were taken at 2- to 3-day intervals and assayed for numbers of helper (T4) and suppressor (T8) T cells and for reverse transcriptase activity (x) present in the culture.
- T4 helper
- T8 suppressor
- SIV/SMM simian immunodeficiency virus/sooty mangabey monkey
- Virus was isolated from PBMC of mangabeys by coculturing PBMC with phytohemagglutinin P-stimulated adult human leukocytes (PHA-AWBC). All of the viruses identified herein are deposited at the Yerkes Regional Primate Research Center, Atlanta, Georgia. Cell-free supernatants from cocultures were monitored for Mg 2+ -dependent reverse transcriptase activity. Culture supernatants with positive reverse transcriptase were tested for their ability to transfer infectivity to fresh PHA-AWBC or to established cell lines; some of the initial cocultures were tested by electron microscopy for the presence of virus.
- PHA-AWBC phytohemagglutinin P-stimulated adult human leukocytes
- the cellular tropism of SIV/SMM was determined in two ways. First, PHA-AWBC were infected with an isolate of SIV/SMM and, periodically, the number of T-helper (T4) and T-cytotoxic/suppressor cells (T8) in the infected culture and in an uninfected control culture were determined by indirect immunofluorescence assay (IFA) using a T-helper/suppressor ratio test kit (Becton Dickinson). At least 500 cells were counted for each determination. Reverse transcriptase activity in both cultures was also assayed and, in the infected culture, peaked at >10 6 cpm per reaction, while that in the control culture never exceeded 1400 cpm.
- IFA indirect immunofluorescence assay
- Mangabey serum samples were tested at a 1:50 dilution by enzyme immunoassay (EIA) using Abbott Laboratories HTLV-III EIA kit, at a 1:100 dilution by immunoblot using H9/HTLV-III antigen, and at a 1:20 dilution for SIV/SMM-specific antibodies by indirect IFA using acetone-fixed, virus-infected PHA-AWBC.
- the second antibody was a fluorescein-labeled goat anti-monkey IgG (Cooper Biomedical, Malvern, Pa).
- the virus/antibody mixture was then used to infect 10 7 PHA-AWBC in 2.5 ml of medium B (RPMI containing 10% fetal bovine serum, interleukin 2, and DEAE-dextran). After overnight adsorption, the cells were washed and resuspended in 15 ml of medium B. Culture supernatants were monitored for extracellular reverse transcriptase activity on days 6, 9, 12, and 16. Neutralizing antibody activity was considered to be present if there was at least 80% inhibition of reverse transcriptase activity compared to reverse transcriptase activity in control cultures.
- medium B RPMI containing 10% fetal bovine serum, interleukin 2, and DEAE-dextran
- Virus was detected in cocultures of PHA-AWBC and PBMC from 14 of 15 randomly selected mangabeys, as seen in Table 1
- Reverse transcriptase activity was detected in initial cultures as early as 6 days and as late as 23 days after establishing the cocultures, and peak reverse transcriptase activity reached >3 ⁇ 10 6 cpm/ml
- Cell-free supernatants of positive cultures transferred infectivity to fresh PHA-AWBC
- Examination of cultures by thin-section electron microscopy showed retrovirus particles with eccentric nucleoids that were morphologically indistinguishable from HIV, STLV-III, and STLV-III AGM .
- a chimpanzee (C-560) serum sample that had a neutralizing titer of approximately 300 against LAV (P.N.F., unpublished work) was used.
- a 1:10 dilution of the anti-LAV serum from chimpanzee C-560 completely neutralized LAV and showed some neutralizing activity against SIV/SMM (FIG. 2).
- reverse transcriptase activity in the culture determined as cpm
- SIV/SMM with LAV-specific antiserum was decreased by 98% compared to that in the culture established after incubation of SIV/SMM with mangabey serum.
- Serum from mangabey 14 had a slight effect on the replication of SIV/SMM but no effect on the replication of LAV. Serum obtained from C-560 prior to LAV infection did not neutralize either LAV or SIV/SMM and resulted in virus growth curves similar to those obtained with serum from mangabey 14 (FIG. 2).
- Antibodies from some mangabeys were cross-reactive with HIV p24 by immunoblot and immunoprecipitated HIV p24, which is encoded in the gag region of the viral genome, in RIP assays. It is also of interest that the cross-reactivity of antibodies to HIV for SIV/SMM included neutralizing antibodies.
- lymphoid foci in the mucosa of the colon were also very prominent. Histologic examination of tissue sections from these two cases revealed prominent hyperplasia of virtually all lymphoid-associated tissues throughout the body. Prominent paracortical expansion of lymph nodes was the consistent feature with germinal centers usually indistinct or consisting only of poorly defined pale hyalinized areas.
- the third blood transfusion recipient (animal PWi) developed a similar acute clinical disease syndrome, but appeared to respond slowly to intense broad spectrum antibiotic therapy. This animal also showed epistaxis of varying degrees from day 12 to day 18 post-transfusion. Animal PWi developed severe oral candidiasis and showed a 14.1% weight loss during the 21 day period following receipt of the blood transfusion. A hemogram evaluation 3 weeks after the blood transfusion revealed anemia (Hcrt. of 25.3), a WBC count of 13,200 with 3% band neutrophils and 15% monocytes, and mild thrombocytopenia (platelet count of 133,000). At sixty-six days post-transfusion, this animal became lethargic and developed a watery diarrhea.
- the animal showed severe generalized lymphadenopathy, splenomegaly and oroesophageal candidiasis. Histologic examination of tissue sections from this animal revealed mild to moderate lymphoid depletion with prominent numbers of syncytial and Langhan's type giant cells, similar to those seen in PBj, throughout all the lymph nodes with infiltration of similar cells throughout the liver, within the lamina intestinal and submucosa of the colon and small intestine, predominantly in gut-associated lymphoid tissue, and within adipose tissue surrounding many organs and tissues. Fewer giant cells were within the spleen, tonsil and stomach. Examination of multiple brain sections revealed moderate numbers of giant cells throughout meningeal tissues. Lesions within brain parenchyma were minimal.
- Virus isolated from animals that died acutely was inoculated intravenously into 6 pig-tailed macaques, 3 rhesus monkeys and 3 young, seronegative mangabeys. Diarrheal material from the animals dying acute deaths was also administered by nasogastric intubation to 3 young pig-tailed macaques. All of the pig-tailed macaques and mangabeys, and one of three rhesus monkeys that received virus by intravenous inoculation, developed acute clinical disease and died within 2 weeks or less. One of three pig-tailed macaques that received diarrheal material by nasogastric intubation developed acute clinical disease and died 12 days post-exposure. All of these animals had clinical disease and gross and microscopic lesions that were essentially identical to those described above for the blood transfusion recipients. Retrovirus was isolated from blood and multiple tissues of all animals that died acutely.
- the lethal variant appears to replicate more efficiently in vitro than the original SIV/SMM isolate and also appears to have escaped immune surveillance by alteration of neutralizing epitopes.
- the latter conclusion is based on the fact that SIV/SMM, but not SIV/SMM/PBMj14 is neutralized by serum from PBJ obtained at the time of death.
- a biological deposit of the virus SIV/SMM/PBj14 was made with the Patent Culture Depository of the American Type Culture Collection (ATCC), 12301 parklawn Drive, Rockville, Md. 20852 U.S.A., on Jul. 2, 1991. viability was established by the ATCC as of Sep. 25, 1991.
- the ATCC accession number of the deposit of SIV/SMM/PBj14 is VR 2331.
- the present invention provides an effective model for evaluating the antiretroviral effects of newly developed drugs and vaccines. Furthermore, the lethal HIV-like virus isolated by the present inventors is a great asset for studies designed to evaluate newly developed antiretroviral drugs and vaccines.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995026405A1 (en) * | 1994-03-25 | 1995-10-05 | Stichting Rega Vzw | T-lymphotropic primate virus l (ptlv-l) and its applications |
NL9400932A (en) * | 1994-03-25 | 1995-11-01 | Stichting Rega V Z W | T-Lymphotropic primate virus L (PTLV-L) and uses thereof |
WO2003085116A1 (en) * | 2002-04-05 | 2003-10-16 | Klaus Cichutek | Lentiviral vectors derived from sivsmm/pbj14, method for their production and uses thereof |
US20040234953A1 (en) * | 2000-05-18 | 2004-11-25 | Oregon Health & Science University | Japanese macaque herpesvirus nucleic acid and polypeptide sequences and their use |
WO2012170765A2 (en) | 2011-06-10 | 2012-12-13 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
-
1988
- 1988-06-01 US US07/200,843 patent/US5212084A/en not_active Expired - Fee Related
Non-Patent Citations (27)
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995026405A1 (en) * | 1994-03-25 | 1995-10-05 | Stichting Rega Vzw | T-lymphotropic primate virus l (ptlv-l) and its applications |
NL9400932A (en) * | 1994-03-25 | 1995-11-01 | Stichting Rega V Z W | T-Lymphotropic primate virus L (PTLV-L) and uses thereof |
US20040234953A1 (en) * | 2000-05-18 | 2004-11-25 | Oregon Health & Science University | Japanese macaque herpesvirus nucleic acid and polypeptide sequences and their use |
US20050239052A1 (en) * | 2000-05-18 | 2005-10-27 | Wong Scott W | Cloning of rhadinovirus genome and methods for its use |
WO2003085116A1 (en) * | 2002-04-05 | 2003-10-16 | Klaus Cichutek | Lentiviral vectors derived from sivsmm/pbj14, method for their production and uses thereof |
US20050202560A1 (en) * | 2002-04-05 | 2005-09-15 | Klaus Cichutek | Lentiviral vectors derived from sivsmm/pbj14, method for their production and uses thereof |
US7727522B2 (en) * | 2002-04-05 | 2010-06-01 | Klaus Cichutek | Lentiviral vectors derived from SIVsmm/PBj14, method for their production and uses thereof |
WO2012170765A2 (en) | 2011-06-10 | 2012-12-13 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
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