Nucleotide sequence of SRV-1, a type D simian acquired immune deficiency syndrome retrovirus.

Simian acquired immune deficiency syndrome (SAIDS) in the macaque genus of monkeys at the California Primate Research Center is apparently caused by infection by a type D retrovirus. The complete nucleotide sequence (8173 base pairs) of a molecular clone of the prototype SAIDS virus isolate, SRV-1, reveals a typical retrovirus structure with long terminal repeats (346 base pairs) and open reading frames for the gag (663 codons), pol (867 codons), and env (605 codons) genes. SRV-1 also has a separate open reading frame of 314 codons between the gag and pol genes that defines the viral protease gene (prt) and a short open reading frame of unknown significance downstream from the env gene. The SRV-1 protease region shows a high degree of homology to its counterpart in the hamster intracisternal A-type particle genome; both these protease genes are about twice as long as the analogous region of other retroviruses. SRV-1 has no notable similarity in either genetic organization or sequence to the human AIDS retroviruses.

Isolation of a neurotropic type C virus.

A neurogenic paralysis of the lower limb can be induced and serially transmitted in mice by a nontransforming type C virus strain that originated in an embryo of a wild mouse. The virus exerted a neurotropic effect on the anterior horn neurons.

Establishment of a cell line with associated Epstein-Barr-like virus from a leukemic orangutan.

An Epstein-Barr virus like herpesvirus has been isolated from a lymphoid cell line derived from an orangutan with spontaneous myelomonocytic leukemia. Herpesvirus has not previously been isolated from this species of higher ape.

The Lake Casitas wild mouse: evolving genetic resistance to retroviral disease.

A small colony of feral mice from California continues to flourish in spite of a virulent epizootic of pathological retrovirus. Epidemiological and genetic studies revealed that the viral infection is strongly balanced by the polymorphic resistance locus, Fv-4, a transcriptionally active but truncated provirus that originated in the East Asian ancestors of the Californian mice. The natural history of these populations represents a graphic example of genomic adaptation in free-ranging populations to regulate and delimit infectious disease.

Growth properties and susceptibility to viral transformation of skin fibroblasts from individuals at high genetic risk for colorectal cancer.

Growth characteristics and susceptibility to viral transformation were compared in cultured skin fibroblasts from patients with Gardner's syndrome (GS), those with familial polyposis coli (FP), asymptomatic family members, and unrelated controls. Compared to cells from unrelated controls, cells from 4 of 5 GS patients were transformed by Kirsten murine sarcoma virus at 100- to 1,000-fold increased efficiency. The transformation efficiencies of fibroblasts from 2 of 3 FP patients were 10- to 100-fold greater than those of unrelated controls. However, because the fibroblasts from some of the young asymptomatic GS and FP family members also transformed at higher efficiency than did cells from unrelated controls, long-term observation of these families is required. This would determine whether or not these members develop clinical manifestations of GS or FP and thus establish the specificitiy of this assay for detection of individuals bearing the mutant gene. Compared to fibroblasts from unrelated controls, GS and FP fibroblasts showed a twofold to threefold increased saturation density and plating efficiency, but this difference was not noted with fibroblasts from most of the asymptomatic family members.

Isolation of feline leukemia virus from a leopard cat cell line and search for retrovirus in wild felidae.

A strain of feline leukemia virus (FeLV), subgroup A, was isolated in early subpassage of a testicular fibroblast culture obtained from a captive Asian leopard cat. Neither FeLV nor RD-114 virus was recovered from cultured tissues of 15 other animals, representing eight species of wild Felidae.

Prevalence and distribution of murine mammary tumor virus antigen detectable by immunocytochemistry in spontaneous breast tumors of wild mice.

Mouse mammary tumor virus (MuMTV) antigens were detected by immunoperoxidase cytochemistry in spontaneous breast tumors of wild mice from two widely separated areas of southern California. Eleven of 25 (44%) tumors from Lake Casitas (LC) mice and 4 of 5 tumors from Bouquet Canyon mice were positive. Included among the tumors lacking detectable MuMTV antigen were well-differentiated type A and type B carcinomas as well as tumors with an atypical pattern. In the antigen-positive tumors the distribution of staining was patchy and extremely variable in extent (less than 1-70% stained cells). The intensity and extent of staining were generally greater in breast tumors from hybrids of LC wild mice and C5LBL/10Sn or AKR inbred mice. A good correlation was found in the same tumors between immunoperoxidase staining, detection of MuMTV gp52 antigen by radioimmunoassay, and detection of type B particles by electron microscopy. All of the breast tumors in LC mice were positive for type C virus particles.

Immunogenetics of a thymus antigen in lymphoma-prone and lymphoma-resistant colonies of wild mice.

The Thy-1 (theta) antigen was identified in wild mice (Mus musculus), the frequency of its alleles was determined in two natural populations of wild mice, and the possible T-cell origin of spontaneous lymphomas was investigated in one of these populations. Reaction patterns for Thy-1 antigen with the use of direct cytoxicity and indirect absorption assays were identical in wild mice and inbred strains. Between 15 and 55 percent of viable spleen cells from healthy young or old wild mice were Thy-1 positive. Spleen, but not brain, cells from older wild mice were less strongly positive. Wild mice from the lymphoma-prone population were polymorphic for Thy-1alpha and Thy-1beta alleles, whereas wild mice from the lymphoma-resistant populations were homozygous for the Thy-1beta allele. Contrary to expectation, a higher frequency of the Thy-1beta allele was noted in the mice with lymphomas. Alleles at two other loci on chromosome number 9 (Mod-1alpha and Trfbeta) were fixed in both populations. The absence of detectable Thy-1 antigen on spleen cells (despite its detectability in undiminished titer in brain tissue) in 80 percent of mice with lymphomas, along with the absence of thymus involvement in the lymphomatous proliferations, suggested that these tumors are derived from an expansion of non-thymus-derived cells.

Inhibition of spontaneous transformation of rat embryo cells releasing endogenous type C virus by virus-specific antiserum.

Noninbred Sprague-Dawley rat embryo cell clones predictably undergo transformation after 20-30 in vitro passages following spontaneous release of endogenous rat leukemia virus (RaLV). In the presence of RaLV-specific antiserum, virus production and infectivity were reduced and transformation was delayed from 6 to 25 weeks. Transformation was not associated with an increased expression of Kirsten murine sarcoma virus-related src gene RNA.

Prevalence of murine mammary tumor virus antibody and antigens in normal and tumor-bearing feral mice.

Approximately 20% of normal male and female feral mice (Mus musculus) from areas with populations having either high [Lake Casitas (LC) and La Puente] or low (Bouquet Canyon) spontaneous lymphoma incidence expressed murine mammary tumor virus (MuMTV) gp52 in specific tissues. Sera from a low percentage (6%) of mice from the same trapping areas contained precipitating antibody specific for MuMTV. Although moderate to high levels of MuMTV gp52 were expressed in mammary tumor tissues of 3 of 7 LC mice and 3 of 3 (C57BL/10ScSn X LC)F1 mice, the same animals showed no detectable MuMTV-precipitating antibody. Neither MuMTV antibody nor tumor-associated MuMTV gp52 was defected in 10 LC mice bearing lymphomas or in 5 LC mice bearing hepatomas. Low levels of MuMTV gp52 expression and MuMTV antibody were also detected in subspecies of M. musculus and in the more distantly related species M. cervicolar. Compared with normal and tumor-bearing inbred mice of high (C3H/HeN) and low (C3H/HeN foster-nursed on NIH Swiss) mammary tumor strains, normal and tumor-bearing feral mice express MuMTV gp52 and MuMTV-precipitating antibodies at low frequency.

Prevention of paralysis and suppression of lymphoma in wild mice by passive immunization to congenitally transmitted murine leukemia virus.

Lake Casitas wild mice were passively immunized as newborns with antiserum to congenitally transmitted murine leukemia virus. Immunization with immunoglobulin having a high neutralizing titer to ecotropic virus and a low titer to amphotropic virus correlated with the complete prevention of paralysis and a slight (25%), but statistically insignificant, reduction in the incidence of lymphoma. Occurrence of other tumor types and total mortality rate were not affected by immunization.

Mammary tumor virus particles in the submaxillary gland, seminal vesicle, and nonmammary tumors of wild mice.

Type-B mammary tumor virus particles were detected by electron microscopy in the submaxillary glands of 6 of 27 freshly trapped, pregnant wild mice (Mus musculus). Type-B particles were also detected in 3 9f 24 seminal vesicles and 2 pulmonary adenomas from wild mice. Intracytoplasmic type-A virus particles were found in 7 spontaneous nonmammary tumors (lymphoma, hepatoma, lung adenoma) of aging wild mice. Type-C virus particles were also detected in many of these tissues.

Type C virus expression in lymphoma-paralysis-prone wild mice.

Wild mice trapped near Lake Casitas (LC) in southern California showed a high prevalence of infectious type C virus in the liver, spleen, and thymus within the first few weeks of life. By young adulthood about 80% of LC mice (including their genital tissues) were infected. Virus isolates from these mice cause lymphoma and lower limb paralysis under both natural and experimental conditions. Mice destined to develop paralysis showed higher levels of serum gs antigen early in life, whereas mice destined to develop lymphoma or remain free of these diseases could not be distinguished by this test. The individual variation in virus expression suggested that differences in virus type or in the immune or other host defense mechanisms greatly influenced susceptibility or resistance to indigenous type C virus-caused disease in LC wild mice.

Congenital transmission of murine leukemia virus from wild mice prone to the development of lymphoma and paralysis.

Maternal congenital transmission of infectious murine leukemia virus, primarily via milk, was the major route of virus spread in Lake Casitas (LC) wild mice and in crosses of LC mice with uninfected wild and laboratory mice. An indirect extrachromosomal male transmission in utero of LC virus also readily occurred in matings of viremic LC males with C57L females but apparently not with other uninfected wild or NIH Swiss females. Both amphotropic and ecotropic classes of LC murine leukemia viruses were potentially transmissible by congenital and venereal epigenetic means and could induce the same two diseases, lymphoma and paralysis, that occurred naturally in LC wild mice. Lymphoma and paralysis both failed to occur in uninfected LC mice or their hybrid progeny that escaped congenital infection.

Suppression of infectious murine leukemia virus in wild mice (Mus musculus) by passive immunization.

Passive immunization with heterologous antivirus antiserum beginning at birth successfully suppressed infectious murine leukemia virus expression in Lake Casitas wild mice (Musmusculus) at 5-7 weeks of age.

Human bladder carcinoma: characterization of two new tumor cell lines and search for tumor viruses.

Two newly established human bladder carcinoma cell lines, designated HT-1197 and HT-1376, were characterized. Cells of both cultures exhibited fine structural microvilli and tonofibrils indicative of their epithelial origin. In addition, desmosomes were also present in HT-1197. Marker chromosomes present in HT-1197 and HT-1376 distinguished these from each other and from other known human tumor cell lines. Both cultures grew in soft agar, induced fibrinolytic activity, and were tumorigenic in mice and hamsters. No type C or other virus expression was detected in these cell lines nor in other human urothelial tumors tested.

Two syngeneic cell lines from human breast tissue: the aneuploid mammary epithelial (Hs578T) and the diploid myoepithelial (Hs578Bst) cell lines.

We characterized two human cell lines (Hs578T and Hs578Bst), which provide several unique features that should be useful in the study of breast disease. Hs578T, derived from a carcinosarcoma, is epithelial in origin. Hs578Bst, established from normal tissue peripheral to the tumor, is myoepithelial in origin. This is the first report of companion cell lines, one malignant and one normal, established from the same organ.

Inefficient humoral immune response of lymphoma-prone wild mice to persistent leukemia virus infection.

Adult wild mice (LC) from a natural colony with a high incidence of spontaneous lymphomas had free infectious virus in their seara (average 10(3.5) infectious units/ml) and parenchymal organs (average 10(5.2) infectious units/g tissue). They did not have detectable levels of free virus-specific antibodies that could be demonstrated by virus neutralization or immunofluorescence at higher than a 1:10 dilution. Only 5 of 28 animals had free antibodies detectable by radioimmunoprecipitation assay, and tissues of 4 mice also had nondetectable levels of virus determined by infectivity assay. Formalized vaccine from the indigenous virus did not induce production of virus-neutralizing antibodies or protect against naturally occurring disease. The animals with persistent leukemia virus infection, however, elicited good humoral immune responses to virus-unrelated antigen.

Natural history of endemic type D retrovirus infection and acquired immune deficiency syndrome in group-housed rhesus monkeys.

A 2.5-year epidemiologic study of a breeding group of rhesus monkeys (Macaca mulatta), which is a focus of endemic simian acquired immunodeficiency syndrome (SAIDS), demonstrated a strong association between the occurrence of SAIDS and infection with a type D retrovirus, SAIDS retrovirus serotype 1 (SRV-1). Of 23 healthy "tracer" juvenile rhesus monkeys, 19 (83%) died with SAIDS within 9 months of introduction into the resident SAIDS-endemic population. In contrast, 21 healthy "sentinel" juvenile rhesus monkeys placed in the same outdoor enclosure but denied physical contact with the SAIDS-affected group by a 10-foot-wide "buffer zone" remained free of SRV-1, SRV-1 antibody, and disease for 2.5 years. The SAIDS-specific mortality rate was significantly higher in juveniles than in adults. In repeated serologic testing, the overall prevalence of SRV-1 antibody ranged from 68 to 85%. Antibody prevalence increased with age. Seroconversion was found to be a poor indicator of infection rate, as approximately 50% of virus-positive juvenile monkeys had no antibody detectable by enzyme-linked immunosorbent assay. Repeated viral isolations from all animals revealed 1) SRV-1 viremia with clinical SAIDS; 2) persistent viremia and viral shedding in apparently healthy animals; 3) transient viremia and clinical recovery; 4) intermittent viremia, suggesting activation of latent infections; and 5) viremia in a 1-day-old infant, suggesting transplacental transmission. The prevalence of SRV-1 antibody in SAIDS-free breeding groups of rhesus monkeys was 4%. The seroprevalence of antibodies against human T-cell leukemia virus type 1 (HTLV-1), human immunodeficiency virus (HIV), and simian immunodeficiency virus (SIV; formerly STLV-III) was uniformly low or absent in both SAIDS-free and SAIDS-affected groups of rhesus monkeys, demonstrating that these retroviruses are not etiologically linked to SAIDS at the California Primate Research Center.

Hyperplastic and neoplastic changes in the mammary glands of feral mice free of endogenous mouse mammary tumor virus provirus.

Laboratory colonies of feral mice (Mus musculus domesticus) have been established with specific mouse mammary tumor virus (MuMTV) genotype, including colonies lacking any proviral DNA (ev-) or carrying only a single copy of MuMTV DNA (ev+). No evidence of a decline in reproductive capacity has been observed in the first 8 generations. Both the ev- and ev+ mice showed normal mammary gland development and the development of hyperplastic lesions in the older females. The mice were very resistant to spontaneous or chemically induced mammary tumors. However, the occurrence of 1 mammary tumor in an ev- mouse indicates that mammary neoplasias can occur in the absence of MuMTV DNA. The few tumors that do occur in the ev- mice provide a unique opportunity to study the neoplastic process in the absence of proviral DNA.