Immunogenetics of murine and feline retroviruses.
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Animals↗
Biomedical subjects
W D Hardy
Publications and source records attributed to W D Hardy.
Infection with human T-cell leukemia virus type I in patients with leukemia.
Among 211 adults with leukemia who received multiple transfusions, 6 were found to be seropositive for human T-cell leukemia virus Type I (HTLV-I). Before the positive serum specimens were obtained, these patients received a mean of 14 units of red cells and 78 units of platelets. Seroconversion could be documented in three patients. None of the 6 patients seropositive for HTLV-I had a T-cell leukemia, other illnesses attributable to HTLV-I infection, or risk factors for HTLV-I infection other than transfusion: none were seropositive for human immunodeficiency virus. Patients with leukemia who receive multiple transfusions appear to be at risk for HTLV-I infection.
Antibodies, Viral↗
Peptide T does not inhibit HIV-1 infection in an in vitro serum-free system.
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Cell Line↗
Structure and origins of the HZ2-feline sarcoma virus.
The HZ2-feline sarcoma virus (HZ2-FeSV) is a replication-defective acute transforming feline retrovirus with oncogene homology to Abelson murine leukemia virus (A-MuLV) (P. Besmer, W.D. Hardy,Jr., E. E. Zuckerman, P. J. Bergold, L. Lederman, and H. W. Snyder, Jr. (1983) Nature (London) 303, 825-828). In contrast to A-MuLV which was isolated from a hematopoietic tumor, the HZ2-FeSV derives from a multicentric fibrosarcoma. We have molecularly cloned the HZ2-FeSV provirus from mink HZ2-FeSV nonproducer cells. The molecularly cloned HZ2-FeSV provirus is biologically active upon transfection of NIH 3T3 indicator cells. The genetic structure of the HZ2-FeSV provirus was determined by EM heteroduplex and Southern blot analysis. The HZ2-FeSV has a 6.8 kb-viral genome with the structure: 5' delta gag-abl-delta pol-delta env 3'. The abl insert, which is 1.4 kb, is located 1.9 kb from the 5' end and 3.5 kb from the 3' end of the viral genome. The 5' 1.9 kb in the HZ2-FeSV are colinear with 5' FeLV sequences, and the 3' 3.5 kb are colinear with 3' FeLV sequences, with the exception of a 0.85-kb deletion in the env gene. HZ2-FeSV v-abl and A-MuLV v-abl share 1.2 kb of abl sequences which are known to specify the protein kinase domain of the abl gene product and are necessary for fibroblast transformation in vitro. The DNA from several tumor tissues of cat 3590 from which the HZ2-FeSV was obtained was found to contain several HZ2-FeSV-related proviruses including the HZ2-FeSV. The variant HZ2-FeSVs have indistinguishable 5' gag-abl sequences; however, they differ in 3' sequences which likely do not include any abl sequences. The DNAs from fibrosarcomas obtained by inoculation of kittens with tumor extract were found to contain variant HZ2-FeSV proviruses as well. Taken together these results indicate a role for the HZ2-FeSVs in sarcomagenesis.
Abelson murine leukemia virus↗
Prevalence of feline leukemia virus infection in random source laboratory cats.
Three years of quarantine data involving the prevalence of Feline Leukemia Virus (FeLV) in laboratory cats (Felis catus) was evaluated. Testing was performed using a commercially available ELISA system. Annual prevalence of infection ranged from 5.4 to 10.7% of the 937 cats tested. Results obtained with the enzyme linked immunosorbent assay (ELISA) system compared well with tests performed using an immunofluorescent antibody assay system (IFA). Seasonal periodicity was noted with higher infection rates among animals received in April. Holding period at the supplier and gender did not influence disease prevalence. The availability of a simple test system, the unacceptability of FeLV infected cats for research, the danger of transmission and a higher prevalence of infection than earlier reports indicated that supplier and user evaluation of research cats for FeLV would be prudent.
Animals↗
Nucleotide sequence of the 1.2-kb 3'-region and genotype distribution of two common c-myc alleles of the domestic cat.
Nucleotide (nt) sequence analyses of the 1.2-kb BamHI-EcoRI cloned 3'-fragment encompassing the polymorphic SmaI restriction site of the feline c-myc gene reveal that the SmaI site, present in CM2 allele but absent from CM3 allele, is located in intron 2, 134 nt 5' of the exon 3. A G-to-C transversion in CM2 results in the creation of the SmaI site. Additionally, the alleles differ at four other nt positions in intron 2, three of these changes being in a region of the intron which exhibits 80% homology between the feline and human c-myc. The alleles also differ in two nt positions in exon 3 in the third position of the codon resulting, however, in no amino acid alteration. Genotype distribution analysis based on the SmaI polymorphism shows that CM2 homozygosity is rare and its frequency deviates significantly from the expected distribution patterns for independently segregating alleles.
Alleles↗
A new acute transforming feline retrovirus with fms homology specifies a C-terminally truncated version of the c-fms protein that is different from SM-feline sarcoma virus v-fms protein.
The HZ5-feline sarcoma virus (FeSV) is a new acute transforming feline retrovirus which was isolated from a multicentric fibrosarcoma of a domestic cat. The HZ5-FeSV transforms fibroblasts in vitro and is replication defective. A biologically active integrated HZ5-FeSV provirus was molecularly cloned from cellular DNA of HZ5-FeSV-infected FRE-3A rat cells. The HZ5-FeSV has oncogene homology with the fms sequences of the SM-FeSV. The genome organization of the 8.6-kilobase HZ5-FeSV provirus is 5' delta gag-fms-delta pol-delta env 3'. The HZ5-and SM-FeSVs display indistinguishable in vitro transformation characteristics, and the structures of the gag-fms transforming genes in the two viruses are very similar. In the HZ5-FeSV and the SM-FeSV, identical c-fms and feline leukemia virus p10 sequences form the 5' gag-fms junction. With regard to v-fms the two viruses are homologous up to 11 amino acids before the C terminus of the SM-FeSV v-fms protein. In HZ5-FeSV a segment of 362 nucleotides then follows before the 3' recombination site with feline leukemia virus pol. The new 3' v-fms sequence encodes 27 amino acids before reaching a TGA termination signal. The relationship of this sequence with the recently characterized human c-fms sequence has been examined. The 3' HZ5-FeSV v-fms sequence is homologous with 3' c-fms sequences. A frameshift mutation (11-base-pair deletion) was found in the C-terminal fms coding sequence of the HZ5-FeSV. As a result, the HZ5-FeSV v-fms protein is predicted to be a C-terminally truncated version of c-fms. This frameshift mutation may determine the oncogenic properties of v-fms in the HZ5-FeSV.
Animals↗
FeLV-induced feline acquired immune deficiency syndrome. A model for human AIDS.
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Acquired Immunodeficiency Syndrome↗
Veterinary oncology: what does the future hold?
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Animals↗
Antitumor activity of protein A administered intravenously to pet cats with leukemia or lymphosarcoma.
Extracorporeal immunoadsorption with protein A (SpA) containing Staphylococcus aureus Cowan I (SAC) has previously been shown to induce an antitumor and antiviral response in some feline leukemia virus (FeLV)-infected, lymphosarcoma (LSA) cats. However, the mechanism by which this response is induced is unknown. Since it is possible that SpA dissociates from the SAC column during treatment, and that intravenous infusion of SpA could be a more efficacious form of treatment than extracorporeal immunoadsorption therapy, 6 normal cats and 15 FeLV-infected pet cats with naturally occurring leukemia or LSA were infused with SpA. No toxic effects resulting from SpA infusion were observed in the normal cats. Antitumor effects were observed in one of the eight cats with LSA and in three of the six cats with leukemia, but there were no antiviral responses. The antitumor responses were objective regressions; however, all tumors recurred. These results demonstrate that infusion of SpA into FeLV-infected LSA or leukemic cats can result in an antitumor but apparently not in an antiviral response.
Animals↗
Immunological and biochemical characterization of HZ2 feline sarcoma virus and Abelson murine leukaemia virus translation products.
The extent of homology between the translation products of the HZ2 strain of feline sarcoma virus (HZ2-FeSV) and the Abelson murine leukaemia virus (A-MuLV) was examined immunologically and biochemically. Antiserum prepared against the v-abl-encoded determinants of the A-MuLV polyprotein P120gag-abl was also found to precipitate specifically the 98K mol. wt. HZ2-FeSV protein (P98gag-abl). The basis for this immunological crossreactivity was indicated by the findings that the two proteins had at least six [35S]methionine-containing tryptic peptides and at least eight [35S]methionine-containing chymotryptic peptides in common. Each of the two proteins also had tryptic and chymotryptic peptides which were unique. Both proteins were associated with tyrosyl kinase activities which exhibited some similar biochemical properties in vitro. However, the HZ2-FeSV-associated activity was much more sensitive to competitive inhibition by nucleoside and deoxynucleoside diphosphates than was the A-MuLV-associated activity. These results suggest that, while the gag-abl translation products of these two independent isolates of transforming retrovirus are highly related structurally and functionally, the differences in structure contribute to differences in enzyme activity. Further comparative studies of these two proteins should play an important role in determining their roles in induction of two different types of malignancy: lymphosarcoma in the case of the A-MuLV protein and fibrosarcoma in the case of the HZ2-FeSV protein.
Abelson murine leukemia virus↗
Levamisole as adjuvant to chemotherapy for canine lymphosarcoma.
Ninety-eight dogs with previously untreated lymphosarcoma were selected for study. All dogs were clinically staged and stratified on the basis of stage. All dogs were treated with combination chemotherapy (vincristine, L-asparaginase, cyclophosphamide, and methotrexate) and randomized to either a levamisole or placebo group. There was no significant difference in either remission time or survival time between the levamisole and placebo groups. Clinical stage, age, and body weight had no influence on remission or survival time. The most significant prognostic factor was sex: Female dogs had significantly enhanced remission time (p = 0.004) and survival time (p = less than 0.001).
Animals↗
Evaluation of effects of levamisole and surgery on canine mammary cancer.
Three hundred and forty-five dogs with mammary tumors were initially evaluated for study. One hundred and forty-four dogs with untreated malignant mammary tumors (136 adenocarcinomas, 5 malignant mixed, 3 sarcomas) were selected for study. All dogs were clinically staged and stratified on the basis of tumor volume and body weight. Dogs were randomized to either a radical mastectomy or simple mastectomy group, and then further randomized to a levamisole or placebo group. There was no significant difference in either survival time or cancer-free survival time between the surgery groups or between the levamisole and placebo groups. The most significant prognostic factor was tumor volume; dogs with tumors less than 41 cc had significantly enhanced survival time (p = 0.0007) and cancer-free survival time (p = 0.0005).
Animals↗
Isolation of a new feline sarcoma virus (HZ1-FeSV): biochemical and immunological characterization of its translation product.
A new strain of feline sarcoma virus, designated HZ1-FeSV, was isolated from a 4-year-old domestic cat with multicentric fibrosarcoma. A primary tumor cell line was established and virus produced from that line was found to induce foci in feline embryonic lung fibroblasts (FLF3) and mink lung fibroblasts (CCL64) in tissue culture and fibrosarcomas in inoculated 10-week-old kittens. The derivation of transformed nonproducer clones of FLF3 and CCL64 cells containing helper virus-rescuable, focus-forming activity indicated that HZ1-FeSV was defective for replication. The only discernible translation product of the HZ1-FeSV genome in cultured cells was a 100,000-Da polyprotein (P100) which contained amino-terminal sequences of the FeLV gag gene precursor protein covalently linked to a sarcoma virus-specific domain. Immunoprecipitates containing P100 exhibited a protein kinase activity capable of phosphorylating tyrosine residues of P100. Immunologically, P100 was highly cross-reactive with gag-fes polyproteins encoded by two previously characterized strains of FeSV, the GA- and the ST-FeSV. By comparison of methionine-containing tryptic peptides, the HZ1-FeSV protein was shown to be more closely related to the GA-FeSV protein than to the ST-FeSV protein, but to be distinguishable from both other proteins.
Animals↗
Clearance of feline leukemia virus from persistently infected pet cats treated by extracorporeal immunoadsorption is correlated with an enhanced antibody response to FeLV gp 70.
Six persistently feline leukemia virus (FeLV)-infected pet cats were treated by extracorporeal immunoadsorption with Staphylococcus aureus Cowan I (SAC) to remove circulating immune complexes and immunoglobulin G (IgG) from plasma. In three of these cats, the FeLV infection was eliminated, whereas in the other three cats the infection persisted. The amounts of peripheral blood leukocyte (PBL)-associated FeLV, soluble FeLV envelope glycoprotein (gp70) antigens in serum, and FeLV-gp70-specific antibodies were determined in all six cats at different times during treatment. In all of the cats, there were fluctuations in the amounts of FeLV-positive PBL and of serum antigen related to FeLV gp70. The one serologic parameter that always correlated with complete clearance of FeLV in the responder cats was the development of free antibodies to gp70. These results suggest that extracorporeal immunoadsorption treatment stimulates an existing low level antibody response to FeLV in some cats, and that these antibodies mediate the clearance of FeLV. The results also suggest that determination of antibody titer to FeLV is of value in predicting the outcome of extracorporeal immunoadsorption treatments as well as when treatment may be terminated.
Animals↗
Evaluation of effect of levamisole on feline mammary cancer.
Seventy-three cats with untreated malignant mammary tumors (64 with adenocarcinoma, 9 with carcinoma in situ) were selected for study. All cats were clinically staged and stratified on the basis of tumor volume. Following radical mastectomy, the cats were randomized for treatment with either levamisole or placebo. There was no significant difference in either survival time or recurrence rate between the levamisole and placebo groups. The most significant prognostic factor was tumor volume: Cats with small tumors had a significantly enhanced survival time (p = 0.00006) and lower recurrence rate (p = 0.00004). Breed of cat was also an important prognostic factor; the domestic short-haired cats had a significantly (p = 0.038) longer survival time than the cats of other breeds.
Adenocarcinoma↗
The Hardy-Zuckerman 2-FeSV, a new feline retrovirus with oncogene homology to Abelson-MuLV.
There is substantial evidence that oncogenes (v-onc) of acute transforming retroviruses have been acquired by transduction of cellular genes (c-onc) with retroviruses. Feline leukaemia virus (FeLV)-associated feline fibrosarcomas have proven to be extremely useful for the isolation of acute transforming retroviruses of a mammalian species. Three different v-onc genes have been identified in five acute transforming feline retroviruses. The Susan McDonough feline sarcoma virus (SMFeSV) contains the oncogene fms (ref. 4). The Snyder-Theilen (ST) and Gardner-Arnstein (GA) FeSVs contain the oncogene fes (ref. 4), which is homologous to the oncogene fps of the avian sarcoma viruses FSV, RRCII, PRCIV and 16L (refs 7, 8). The v-onc sequences of the Parodi-Irgens (PI) FeSV have recently been found to be homologous with the v-sis sequences of the simian sarcoma virus. We report here the isolation of another acute transforming feline retrovirus from a naturally occurring feline fibrosarcoma, designated the Hardy-Zuckerman 2 feline sarcoma virus (HZ2-FeSV) and demonstrate that the HZ2-FeSV and Abelson murine leukaemia virus (A-MuLV) have homologous oncogenes.
Abelson murine leukemia virus↗
The feline oncornavirus-associated cell membrane antigen (FOCMA) is related to, but distinguishable from, FeLV-C gp70.
The feline oncornavirus-associated cell membrane antigen (FOCMA) on the surface of feline lymphosarcoma (LSA) cells is defined as the target(s) recognized in immunofluorescence (IFA) tests by antibody in sera of cats relatively resistant to development of FeLV (feline leukemia virus) LSA and FeSV (feline sarcoma virus) fibrosarcoma. The specificities of antibodies in cat FOCMA-typing sera and the nature of the LSA antigens recognized were investigated in the present study. FOCMA sera obtained from viremic cats were separable into at least two classes : those which contained antibodies against the envelope glycoprotein (gp70) of subgroup C FeLV and those which did not contain antibodies against any subgroup of FeLV. The first class of sera could be further subdivided into three groups: those whose FOCMA reactivity could be completely absorbed, partially absorbed, or not absorbed by FeLV-C antigens. The second class of sera could be further subdivided into two groups: those whose FOCMA reactivity could be partially absorbed and those whose activity could not be absorbed by FeLV-C. The results indicate that the FOCMA reactivity exhibited by some viremic cat sera can be partially, if not entirely, attributed to antibodies not crossreactive with FeLV virion antigens. A consistent property of all FOCMA sera in this study is the ability to bind to 70-kDa proteins on the surface of LSA cells. Staphylococcus aureus V8 protease partial digest maps of 70-kDa proteins purified from 12 primary feline LSAs (five FeLV positive and seven FeLV negative) all showed 18-, 14-, and 10-kDa fragments. V8 maps of FeLV-C gp70 showed similarly sized fragments while the maps of the RD114, FeLV-A, and FeLV-B gp70s were distinct. However, in a subgroup-specific radioimmunoassay for FeLV-C gp70-related antigens, the LSA 70-kDa proteins were found to be serologically related to, but distinct from, FeLV-C gp70. The results on the antigenic variations among LSA 70-kDa proteins and the antibodies which bind them are entirely consistent with previous studies indicating heterogeneity among FOCMA determinants.
Animals↗