[CANCER RESEARCH 38, 3123-3139, October 1978] Type D Primate Retroviruses: A Review1 Donald Fine and Gerald Schochetman Viral Oncology Program, Frederick Cancer Research Center. Frederick, Maryland 21701 Abstract The prototype virus of the type D retroviruses is the techniques. The retrovirus associated with the induction of Mason-Pfizer monkey virus (MPMV). MPMV was originally mammary cancer in mice, MMTV,2 is morphologically dis isolated from a breast carcinoma of a female rhesus tinct from the type C viruses and is the prototype of the type monkey (an Old World monkey). MPMV is of obvious B virus group (30). A retrovirus group of primate origin, importance in that it is the only retrovirus thus far isolated which has properties similar to the type C and type B from a mammary tumor of a primate and has been shown viruses but is morphologically distinct from them, has been to have transforming potential for primate cells in vitro. designated genus Oncornavirus D (30). The prototype virus Subsequent to the isolation of MPMV, viruses morpholog of this genus is the MPMV. MPMV was originally isolated ically and ¡mmunologicallyindistinguishable from MPMV from a mammary carcinoma of a female rhesus monkey (an have been isolated from normal placenta and lactating Old World monkey) (19, 60). Because mammary carcinomas mammary glands of other rhesus monkeys in captivity. represent the most prevalent form of neoplasia in humans Recently, viruses morphologically resembling MPMV have and, furthermore, because the incidence of mammary tu been isolated from a langur monkey (another Old World mors in subhuman primates is rare (61, 62, 70, 78), MPMV monkey) and from squirrel monkeys (a New World mon is of obvious potential importance because it is the only key). Based on nucleic acid hybridization studies, the retrovirus thus far isolated from a primate mammary tumor. latter 2 viruses represent endogenous viruses in their Recently, there have been reports that viruses morpho species of origin, whereas MPMV appears to be a horizon logically and immunologically similar to MPMV have been tally transmitted virus containing gene sequences par isolated from certain rhesus monkey and human tissues tially related to the langur monkey isolate. Studies on the and cell lines (6, 8, 10, 44, 49, 55, 57-59, 72, 81, 107-109). immunological relatedness of the type D retroviruses Virus morphologically resembling MPMV have also been have demonstrated interspecies cross-reactivities be isolated from normal tissues of a langur monkey (99) (an tween the major internal and external proteins of the other Old World monkey) and from squirrel monkeys (53, viruses. Furthermore, these viruses also share cross- 99) (a New World monkey). Only the langur isolate shares reactivity of their major external glycoproteins with those significant immunological cross-reactivity and nucleic acid of the type C baboon endogenous virus. These interspe sequence homology with MPMV. The discovery of these 2 cies reactivities can also be demonstrated in natural sera viruses makes it apparent that MPMV is a member of a from both imported and laboratory-bred monkeys. The larger group of viruses of both Old and New World pri demonstration of these interspecies cross-reactivities mates. Furthermore, the large accumulation of information shared by distantly related primate retroviruses provides on MPMV and the new type D primate isolates warrants a a means for detecting determinants that are representa comprehensive review of these viruses. This review will tive of all primate retroviruses presently known and yet to consider the unique characteristics of type D retroviruses be isolated and may provide new assays for detection of as well as their distribution in the primate population and a human retrovirus. their relevance to human cancer. Introduction History Over the past 60 years, a considerable amount of infor MPMV. MPMV was first observed and isolated from a mation has been amassed concerning the role of viruses as tissue biopsy performed on an 8-year-old female rhesus etiological agents of animal neoplasia. In particular, those viruses known as RNA tumor viruses or retroviruses have 2 The abbreviations used are: MMTV, mouse mammary tumor virus; been implicated in a variety of cancers in a wide variety of MPMV, Mason-Pfizer monkey virus; CMMT, cocultivated monkey embryo and mammary tumor; PO-1-Lu, langur virus; SMRV, squirrel monkey retro- animal species. Those associated with the induction of virus; RT, reverse transcriptase; A204, human rhabdomyosarcoma; B-GPV, lymphomas, leukemia, or sarcomas have been termed type guinea pig endogenous virus; BaEV, baboon endogenous virus; AMV, avian C viruses based on their morphology as determined by myeloblastosis virus; BLV, bovine leukemia virus; EIAV, equine infectious anemia virus; oligo(dT)-poly(rA), noncovalent copolymer of oligodeoxythy- electron microscopy (14). They have been isolated from midylate and polyriboadenylate; oligo(dG)-poly(rC), noncovalent copolymer several vertebrate classes and are structurally, biochemi of oligodeoxyguanylate and polyribocytidylate; SDS-PAGE, sodium dodecyl cally, and biologically similar, although they are distin sulfate-polyacrylamide gel electrophoresis; gp, p, followed by 2 numbers, glycoprotein and protein, respectively, followed by 2 numbers designating guishable by sensitive immunological and biochemical molecular weight in thousands (e.g., gp70, p27); gp69/71, glycoprotein with a molecular weight range of 69.000 to 71,000; RD114, feline endogenous virus; KC, human glioma; RHFS, rhesis monkey foreskin; RIA, radioimmuno- 1 This work was supported by the Virus Cancer Program, Contract N01- assay; FeLV, feline leukemia virus; cDNA, complementary DNA, SSV, woolly CO-75380, National Cancer Institute, NIH, Bethesda, Md. 20014. monkey virus; GALV, gibbon ape virus; BaLV, baboon leukemia virus; Received April 5, 1978; accepted June 16, 1978. F-MuLV, Friend leukemia virus; R-MuLV, Rauscher leukemia virus. OCTOBER 1978 3123 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1978 American Association for Cancer Research. D. Fine and G. Schochetman monkey (Macaca mulatta). This animal had developed a present in all HeLa cell stocks, as measured by nucleic acid spontaneous tumor (69) in the region of the left mammary hybridization, but are present in those cultures expressing gland after being in a state of continuous estrus for almost MPMV (25). Numerous isolations of MPMV-like viruses from 1 year. The animal was sacrificed approximately 2 months a variety of human cell cultures have been reported; Table after the discovery of the tumor, at which time virus was 1 lists the names and sources of the various isolates. observed in tumor samples by thin-section electron micros Recently, many of these cell lines were shown to possess copy (19, 23). At necropsy the tumor was found to have HeLa cell chromosomal and isoenzyme markers (65, 75). It metastasized into both breasts, the left axilla, flank, and rib is possible that these cell cultures are examples of cross- cage. Secondary tumors were also found that involved a contamination of the original cell cultures with HeLa cells, number of organs including an ovary, the adrenals, pan and it seems reasonable to assume that the virus isolates creas, kidney, liver, stomach, and lymph glands. The pri also represent laboratory contaminants.3 Interestingly, mary tumor histologically resembled a medullary carcinoma these virus isolations occurred in separate laboratories lacking lymphoid stroma (69). Because the tumor did not around the world and, supposedly, none of the research closely resemble conventional breast adenocarcinomas mi groups was conducting research on MPMV. These striking croscopically and because surrounding breast parenchyma observations indicate the widespread distribution of viruses did not present any evidence of developing in situ malignant indistinguishable from MPMV and demonstrate the propen changes, the possibility was raised that the tumor arose as sity of these viruses for infection of human cells. These an intramammary anaplastic lesion (M. Black, personal features dictate the need for extreme caution in studying communication). primate-derived retroviruses with regard to their role in the Since the tumor specimen grew poorly when placed into etiology of human cancers. culture, virus isolation was effected by cocultivation of PO-1-Lu. A new retrovirus resembling MPMV was isolated minced tumor tissues with primary or early-passage monkey from another Old World monkey, Presbytis obscurus, the embryo cell cultures (60). This led to the establishment of a spectacled langur (99). The virus, designated PO-1-Lu, was continuous cell culture system (CMMT) which served as a recovered from cultures of lung tissue cocultivated with bat producer of MPMV. Cultures of CMMT cells transferred for lung cells (TbILu) and could be distinguished from MPMV more than 95 passages consist of cells with distinct rhesus based on differences in host range, antigenic characteris monkey karyotype (74). Although CMMT cultures were tics, and nucleic acid sequence homology. Complete pro- originally maintained by adding nonirradiated rhesus em viral sequences of PO-1-Lu have been found in langur bryo cells to the MPMV-infected cells every 30 days, high monkeys, indicating that the virus is endogenous in this passages of the culture grew without further cocultivation species (12). (74). Virus from the original tumor was successfully trans SMRV. Another retrovirus,