PIP: Herpes-simplex virus 1 (HSV1) and 2 can cause recurrent infection in man and in nonhuman species localized on a specific area of the body, such as face, cornea, or genitals. The origin of the virus responsible for a recurrent infection is not usually apparent. Some possible sources of virus can be exogenous infection, endogenous infection from another site of the body, chronic, continuous viral multiplication around the site of involvement, and persistence of the virus at the site of the recurrent infection. No definite information is yet available regarding the mechanism by which HSV1 or HSV2 persists and it is triggered to multiply, or regarding the cells that harbor the virus. It is possible that frequent or constant antigenic stimulation occurs in at least some cases of recurrent herpetic infections. The role of antibodies and of interferon in host resistance to HSV remains to be elucidated. Several recent studies have shown the association of more than a dozen herpes viruses with cancer in man and various animals; for example with limphoma, and with squamous cell carcinoma of the lip and cancer of the cervix. Genital HSV infections and cervical cancer were first linked when it was noted that women with genital herpes had a high frequency of cervical dysplasia and cancer. The results of new seroepidemiologic studies on this subject are still difficult to evaluate. Inocculation of HSV2 in laboratory animals has resulted in sarcomas, but it has never been possible to prove that the virus caused the tumors, since no HSV antigens could be detected in the tumors. However, herpesvirus antigens have been demonstrated by immunofluorescent technics in exfoliated cervical cells obtained from women with dysplasia, carcinoma in situ, and invasive carcinoma. In the absence of other kinds of data, it is difficult to rule out the possibility that the presence of HSV2 or of antigens is not an independent event unrelated to the cancer.

Infection with herpes-simplex viruses 1 and 2. II.

A C-type virus (“M7”) has been isolated from a specimen of baboon placenta cocultivated with various mammalian host cell lines. Nucleic acid hybridisation with a 3H-DNA transcript of the viral genome demonstrates that this virus is genetically different from previously studied mammalian C-type viruses, and suggests that M7 is an endogenous baboon virus.

Infectious C-type virus isolated from a baboon placenta

The RD114/simian type D retroviruses, which include the feline endogenous retrovirus RD114, all strains of simian immunosuppressive type D retroviruses, the avian reticuloendotheliosis group including spleen necrosis virus, and baboon endogenous virus, use a common cell-surface receptor for cell entry We have used a retroviral cDNA library approach, involving transfer and expression of cDNAs from highly infectable HeLa cells to nonpermissive NIH 3T3 mouse cells, to clone and identify this receptor The cloned cDNA, denoted RDR, is an allele of the previously cloned neutral amino acid transporter ATB0 (SLC1A5) Both RDR and ATB0 serve as retrovirus receptors and both show specific transport of neutral amino acids We have localized the receptor by radiation hybrid mapping to a region of about 500-kb pairs on the long arm of human chromosome 19 at q133 Infection of cells with RD114/type D retroviruses results in impaired amino acid transport, suggesting a mechanism for virus toxicity and immunosuppression The identification and functional characterization of this retrovirus receptor provide insight into the retrovirus life cycle and pathogenesis and will be an important tool for optimization of gene therapy using vectors derived from RD114/type D retroviruses

https://www.pnas.org/content/pnas/96/5/2129.full.pdf

The RD114/simian type D retrovirus receptor is a neutral amino acid transporter

Retroviral diagnostics have become standard in human laboratory medicine. While current emphasis is placed on the human exogenous viruses (human immunodeficiency virus and human T-cell leukemia virus), evidence implicating human endogenous retroviruses (HERVs) in various human disease entities continues to mount. Literature on the occurrence of HERVs in human tissues and cells was analyzed. Substantial evidence documents that retrovirus particles were clearly demonstrable in various tissues and cells in both health and disease and were abundant in the placenta and that their occurrence could be implicated in some of the reproductive diseases. The characteristics of HERVs are summarized, mechanisms of replication and regulation are outlined, and the consistent hormonal responsiveness of HERVs is noted. Clear evidence implicating HERV gene products as participants in glomerulonephritis in some cases of systemic lupus erythematosus is adduced. Data implicating HERVs as etiologic factors in reproductive diseases, in some of the autoimmune diseases, in some forms of rheumatoid arthritis and connective tissue disease, in psoriasis, and in some of the inflammatory neurologic diseases are reviewed. The current major needs are to improve methods for HERV detection, to identify the most appropriate HERV prototypes, and to develop diagnostic reagents so that the putative biologic and pathologic roles of HERVs can be better evaluated.

Human endogenous retroviruses: nature, occurrence, and clinical implications in human disease.

Retroviral elements are found in abundance throughout the human genome but only rarely have alterations of endogenous genes by retroviral insertions been described. Herein we report that a human endogenous retrovirus (HERV) type C is inserted in the human growth factor gene pleiotrophin (PTN) between the 5' untranslated and the coding region. This insert in the human genome expands the region relative to the murine gene. Studies with promoter-reporter constructs show that the HERV insert in the human PTN gene generates an additional promoter with trophoblast-specific activity. Due to this promoter function, fusion transcripts between HERV and the open reading frame of PTN (HERV-PTN) were detected in all normal human trophoblast cell cultures as early as 9 weeks after gestation (n = 7) and in all term placenta tissues (n = 5) but not in other normal adult tissues. Furthermore, only trophoblast-derived choriocarcinoma cell lines expressed HERV-PTN mRNA whereas tumor cell lines derived from the embryoblast (teratocarcinoma) or from other lineages failed to do so. We investigated the significance of HERV-PTN mRNA in a choriocarcinoma model by targeting this transcript with ribozymes and found that the depletion of HERV-PTN mRNA prevents human choriocarcinoma growth, invasion, and angiogenesis in mice. This suggests that the tissue-specific expression of PTN due to the HERV insertion in the human genome supports the highly aggressive growth of human choriocarcinoma and possibly of the human trophoblast.

Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus

Ultrastructural investigations have revealed the presence of apparent endogenously derived C-type particles in the placental villi of each of 13 baboons studied. Both budding and mature forms were observed in the syncytiotrophoblast of these animals at various stages of pregnancy.

http://science.sciencemag.org/content/sci/179/4080/1332.full.pdf

Observations of apparent C-type particles in baboon (Papio cynocephalus) placentas.

Previous studies have shown that the baboon and squirrel monkey are resistant to certain herpesviruses that cause serious infection or induce tumours in the cebus monkey and marmoset. This study was undertaken to evaluate the immunological competence of the four species of nonhuman primates. A variety of clinical immunological techniques were employed to evaluate the bursal, thymicdependent and phagocytic systems of immunity in these species. No primate was found to demonstrate immune competence of the same magnitude observed in normal humans.

The baboon manifested immune responsiveness most closely resembling that of man. These animals displayed no abnormalities in circulating white blood cell populations, ability to form antibody, delayed skin response to mitogens or lymphocyte transformation in vitro. Rebuck skin window (RSW) findings closely resembled those observed in humans. While the squirrel monkey also appeared to be relatively competent, antibody formation, skin test reactivity and RSW responses were slightly less than those observed in the baboon. Cebus monkeys showed several abnormalities which included significant leukopenia, very low serum alpha-1 globulin levels, cutaneous anergy and a poor RSW response. The most marked abnormalities were found in the marmosets that had persistent leucocytosis, absent to poor antibody responses to immunogens, weak responses to phytohaemagglutinin in vivo and in vitro, with a uniquely greater response to pokeweed mitogen in vitro. The poor RSW response was similar to that observed in the squirrel monkey and cebus. While these studies suggest that baboons and squirrel monkeys are relatively intact immunologically, the marmoset and cebus monkey species appear to have significant manifestations of immunological incompetence in association with susceptibility to a variety of infectious and oncogenic agents.

Immunological competence in non-human primates: differences observed in four species.

SummaryA graded response of the baboon (P. cynocephalus), Cebus (C. apella) and marmoset (S. oedipus) monkeys to infection via the female genital tract with H. hominis type 2 was demonstrated. A subclinical disease with limited virus production and antibody response was noted in the baboons. All Cebus monkeys showed clinical evidence of genital infection, extensive virus excretion and antibody response. Whereas baboons and Cebus monkeys survived inoculation with H. hominis type 2, a generalized fatal infection was observed in the marmosets.This study was funded in part by U.S. Public Health Service grants RR05519, RR00278, RR00361, RR00451 and contract NIH 69–93 and WHO grant Z2/181/27. Dr. Nahmias is supported in part by grant T-521 from the American Cancer Society.

Experimental Herpesvirus hominis type 2 infection in nonhuman primates.

Experimental infection of the cebus monkey genital tract was demonstrated following the intravaginal inoculation of oral and genital strains ofHerpesvirus hominis. This was determined by the appearance of clinical lesions, isolation of virus and production of neutralizing antibody.

Experimental genital infection of cebus monkeys with oral and genital isolates of Herpesvirus hominis types 1 and 2.

Marmosets (S. oedipus and S. fuscicollis) inoculated intravaginally with Herpesvirus hominis type 2 developed severe genital lesions followed by death. At necropsy, extensive hemorrhagic and necrotic lesions were observed in the urogenital tract. Four animals tested had BUN values of 98–220 mg/100 ml. Pathological and clinical observations suggest that the animals developed a uremia as a secondary complication of the genital herpes infection.

P. J. Felsburg

Papers

Observations of apparent C-type particles in baboon (Papio cynocephalus) placentas.

Immunological competence in non-human primates: differences observed in four species.

Experimental Herpesvirus hominis type 2 infection in nonhuman primates.

Experimental genital infection of cebus monkeys with oral and genital isolates of Herpesvirus hominis types 1 and 2.

Experimental genital herpes infection of the marmoset.