Frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in Japanese macaques.

BACKGROUND: Simian T-cell leukemia virus type 1 (STLV-1) is disseminated among various non-human primate species and is closely related to human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Notably, the prevalence of STLV-1 infection in Japanese macaques (JMs) is estimated to be > 60%, much greater than that in other non-human primates; however, the mechanism and mode of STLV-1 transmission remain unknown. The aim of this study is to examine the epidemiological background by which STLV-1 infection is highly prevalent in JMs. RESULTS: The prevalence of STLV-1 in the JMs rearing in our free-range facility reached up to 64% (180/280 JMs) with variation from 55 to 77% among five independent troops. Anti-STLV-1 antibody titers (ABTs) and STLV-1 proviral loads (PVLs) were normally distributed with mean values of 4076 and 0.62%, respectively, which were mostly comparable to those of HTLV-1-infected humans. Our initial hypothesis that some of the macaques might contribute to frequent horizontal STLV-1 transmission as viral super-spreaders was unlikely because of the absence of the macaques exhibiting abnormally high PVLs but poor ABTs. Rather, ABTs and PVLs were statistically correlated (p < 0.0001), indicating that the increasing PVLs led to the greater humoral immune response. Further analyses demonstrated that the STLV-1 prevalence as determined by detection of the proviral DNA was dramatically increased with age; 11%, 31%, and 58% at 0, 1, and 2 years of age, respectively, which was generally consistent with the result of seroprevalence and suggested the frequent incidence of mother-to-child transmission. Moreover, our longitudinal follow-up study indicated that 24 of 28 seronegative JMs during the periods from 2011 to 2012 converted to seropositive (86%) 4 years later; among them, the seroconversion rates of sexually matured (4 years of age and older) macaques and immature macaques (3 years of age and younger) at the beginning of study were comparably high (80% and 89%, respectively), suggesting the frequent incidence of horizontal transmission. CONCLUSIONS: Together with the fact that almost all of the full-adult JMs older than 9 years old were infected with STLV-1, our results of this study demonstrated for the first time that frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in JMs.

Enzooty of non-Hodgkin's malignant lymphoma of Papio hamadryas in Sukhumi monkey colony. Clinical and morphological signs of pre-lymphoma.

Inoculation of hamadryas baboons with blood of leukemia ill people-induced malignant non-Hodgkin's lymphoma in experimental animals for a very considerable latency period. At close contact of inoculated baboons with healthy non-inoculated animals, the lymphoma spread between them. The epidemiological analysis, postmortem examination, histological analysis, tissue culturing, and PCR were used for the diagnostics of lymphoma and pre-lymphoma, purification, identification of STLV-1, and HVP viruses. Characteristic clinical and morphological signs designated by us as pre-lymphoma often precede the lymphoma development. In some cases, pre-lymphoma does not develop in lymphoma because animals die from various diseases and do not reach the point of the lymphoma development. The horizontal transmission of lymphoma arising with the participation of T-lymphotropic retrovirus STLV-1 is shown.

Modes of transmission of Simian T-lymphotropic Virus Type 1 in semi-captive mandrills (Mandrillus sphinx).

Non-human primates (NHPs) often live in inaccessible areas, have cryptic behaviors, and are difficult to follow in the wild. Here, we present a study on the spread of the simian T-lymphotropic Virus Type 1 (STLV-1), the simian counterpart of the human T-lymphotropic virus type 1 (HTLV-1) in a semi-captive mandrill colony. This study combines 28 years of longitudinal monitoring, including behavioral data, with a dynamic mathematical model and Bayesian inference. Three transmission modes were suspected: aggressive, sexual and familial. Our results show that among males, STLV-1 transmission occurs preferentially via aggression. Because of their impressive aggressive behavior male mandrills can easily transmit the virus during fights. On the contrary, sexual activity seems to have little effect. Thus transmission appears to occur primarily via male-male and female-female contact. In addition, for young mandrills, familial transmission appears to play an important role in virus spread.

Spontaneous and experimental malignancies in non-human primates.

Contrary to earlier established opinion that tumors in monkeys are found rarely, now the large material confirms that monkey tumors are frequent phenomenon. Tumor incidence clearly increases with age. Frequencies of benign and malignant tumors of various locations and histogenesis are slightly different. Tumors of hematopoietic system are the most frequent. Sporadic cases and enzootic outbreaks of lymphomas are described for different kinds of monkeys, including apes, and probably are caused by viruses. Two viruses were isolated by us from sick monkeys - the retrovirus C-type STLV-1 and the herpes virus papio HVP. Inoculation of virus cultures into monkeys and rabbits induces neoplasms. Monkey neoplasms can be induced by exposure to various chemical agents, and by oncogenic and non-oncogenic viruses. There is no strict species specificity of tumor viruses. The role of polyoma viruses in neoplasms etiology is discussed.

Simian T-cell lymphotropic virus type I alters the proviral load and biodistribution of simian retrovirus type 2 in co-infected macaques, supporting advancement of immunosuppressive pathology.

The infection dynamics and pathology of a retrovirus may be altered by one or more additional viruses. To investigate this further, this study characterized proviral load, biodistribution and the immune response in Macaca fascicularis naturally infected with combinations of simian retrovirus type 2 (SRV-2) and simian T-cell lymphotropic virus type I (STLV-I). As the mesenteric lymph node (MLN) and the spleen have been implicated previously in response to retroviral infection, the morphology and immunopathology of these tissues were assessed. The data revealed a significant change in SRV-2 biodistribution in macaques infected with STLV-I. Pathological changes were greater in the MLN and spleen of STLV-I-infected and co-infected macaques compared with the other groups. Immune-cell populations in co-infected macaque spleens were increased and there was an atypical distribution of B-cells. These findings suggest that the infection dynamics of each virus in a co-infected individual may be affected to a different extent and that STLV-I appears to be responsible for enhancing the biodistribution and associated pathological changes in SRV-2 in macaques.

High simian T-cell leukemia virus type 1 proviral loads combined with genetic stability as a result of cell-associated provirus replication in naturally infected, asymptomatic monkeys.

Simian T-cell leukemia virus type 1 (STLV-1) is a primate T cell leukemia virus of the group of oncogenic delta retroviruses. Sharing a high level of genetic homology with human T cell leukemia virus type 1 (HTLV-1), it is etiologically linked to the development of simian T cell malignancies that closely resemble HTLV-1 associated leukemias and lymphomas and might thus constitute an interesting model of study. The precise nature of STLV-1 replication in vivo remains unknown. The STLV-1 circulating proviral load of 14 naturally infected Celebes macaques (Macaca tonkeana) was measured by real-time quantitative PCR. The mean proportion of infected peripheral mononuclear cells was 7.9%, ranging from <0.4% to 38.9%. Values and distributions were closely reminiscent of those observed in symptomatic and asymptomatic HTLV-1 infected humans. Sequencing more than 32 kb of LTRs deriving from 2 animals with high proviral load showed an extremely low STLV-1 genetic variability (0.113%). This paradoxical combination of elevated proviral load and remarkable genetic stability was finally explained by the demonstration of a cell-associated dissemination of the virus in vivo. Inverse PCR (IPCR) amplification of STLV-1 integration sites evidenced clones of infected cells in all infected animals. The pattern of STLV-1 replication in these asymptomatic monkeys was indistinguishable from that of HTLV-1 in asymptomatic carriers or in patients with inflammatory diseases. We conclude that, as HTLV-1, STLV-1 mainly replicates by the clonal expansion of infected cells; accordingly, STLV-1 natural monkey infection constitutes an appropriate and promising model for the study of HTLV-1 associated leukemogenesis in vivo.

[HTLV-1 infection in time and space]. / HTLV-1 dans le temps et dans l'espace.

Human T-cell leukemia virus type 1 (HTLV-1) is a member of the Oncoretrovirinae family containing several viruses that have been associated with a low incidence of leukemia and sarcoma in mammals. Primates are susceptible to viruses of genera HTLV (humans) and STLV (other primates). The high degree of homology in genomic arrangement of HTLV and STLV is probably due to the existence of a common simian ancestor. Most infections are asymptomatic but a few cases exhibit blood diseases, e.g., T-lymphoma or T-cell leukemia, or neurologic disease, mainly, HTLV-1 associated myelopathy and tropical spastic paraparesia (HAM-TSP). The four major modes of viral transmission are vertical transmission from mother to child either in utero or, more commonly, during breastfeeding, sexual intercourse, blood transfusion, and intravenous drug use. Geographic distribution of HTLV-1 and its confinement to a few well-defined ecosystems have yet to be explained. Diagnosis is now easy and can reduce transmission by intravenous drugs use. Development of a vaccine seems possible given the low genetic variability of this virus.

Human and simian T-cell leukemia viruses type 2 (HTLV-2 and STLV-2(pan-p)) transform T cells independently of Jak/STAT activation.

Human T-lymphotropic virus type 1 (HTLV-1) and HTLV-2 differ in pathogenicity in vivo. HTLV-1 causes leukemia and neurologic and inflammatory diseases, whereas HTLV-2 is less clearly associated with human disease. Both retroviruses transform human T cells in vitro, and transformation by HTLV-1 was found to be associated with the constitutive activation of the Jak/STAT pathway. To assess whether HTLV-2 transformation may also result in constitutive activation of the Jak/STAT pathway, six interleukin-2-independent, HTLV-2-transformed T-cell lines were analyzed for the presence of activated Jak and STAT proteins by electrophoretic mobility shift assay. In addition, the phosphorylation status of Jak and STAT proteins was assessed directly by immunoprecipitation and immunoblotting with an antiphosphotyrosine antibody. Jak/STAT proteins were not found to be constitutively activated in any of the T-cell lines infected by the type 2 human and nonhuman primate viruses, suggesting that HTLV-2 and the cognate virus simian T-lymphotropic virus type 2 from Pan paniscus transform T cells in vitro by mechanisms at least partially different from those used by HTLV-1.

[Morpho-immunologic phenotypes of T-cell non-Hodgkin's malignant lymphoma in baboons and their connection with with T-lymphotropic retrovirus STLV-1]. / Morfoimmunologicheskie fenotipy T-kletochnykh nekhodzhinskikh zlokachestvennykh limfom pavianov i ikh sviaz' s T-limfotropnym retrovirusom STLV-1.

8 cytological types were detected among 58 cases of T-NHL of Papio hamadryas according to human updated Kiel classification (1988). 5 of them were of low grade (lymphocytic, prolymphocytic, T-zone, angioimmunoblastic, small cell pleomorphic) and 3-of high grade (medium and large cell pleomorphic, immunoblastic, large cell anaplastic CD30/Ki-1+). There are differences in a tumor structure and generalization in baboon and human lymphomas in spite of significant similarities. STLV-1 presence (antibodies in blood and virus genome fragments in the lymphoma cell DNA) detected by PCR-amplification in 7 investigated types of baboon T-NHL. CD4+ immune phenotypes were predominant in T-cell baboon lymphomas, while CD8+ phenotypes were rare. Abnormal phenotypes in some cases were also detected in the three-color FACS-analyses.

Constitutive cytokine release by simian T-cell lymphotrophic virus type I (STLV-I) and human T-cell lymphotrophic virus types I/II (HTLV-I/II) transformed cell lines.

Simian T-cell lymphotrophic virus type I (STLV-I) and human T-cell lymphotrophic virus types I/II (HTLV-I/II) contain the tax gene which can transactivate the transcription of viral and cellular genes including several cytokines. These investigations used two STLV-I and four different HTLV-I/II transformed cell lines to quantitate constitutive cytokine release, p24 antigen production, and to correlate gag p24 antigen and cytokine release. These investigations are the first to report 1) quantitative comparison of constitutive release of multiple cytokines by several STLV-I and HTLV-I/II transformed cell lines and to determine the cytokines constitutively released by STLV-I transformed cell lines as IL-6, b-FGF, and GM-CSF (and TNF-beta, and PDGF in a higher viral producing line); 2) statistically significant differences in levels of cytokines produced by STLV-I and HTLV-I/II transformed cell lines, dependent on the method of results quantification; and 3) a correlation between levels of STLV-I and HTLV-I/II and gag p24 antigen production and cytokine production.

The natural history and evolution of human and simian T cell leukemia/lymphotropic viruses.

The past five years have seen significant advances in understanding the origin and evolution of human T-cell leukemia/lymphotropic virus types I and II. The highlights include the identification of human T-cell leukemia/lymphotropic virus types I and II genotypic variants in remote human populations and the discovery of widely divergent simian T-cell leukemia virus in African and Asian non-human primates.

Human T-cell leukaemia virus.

HTLV-I has a complex and finely regulated mechanism of replication, which can be used as a model to study both cellular and viral regulation pathways in T-cells. Understanding of the underlying mechanisms involved in the pleiotropic effects of HTLV-I in the host represents a real challenge. Immunological regulation likely plays a central role in HTLV-I induced neurological disease, uveitis, and perhaps arthritis, implicating the importance of host factors as well. Viral proteins, including tax and p12' might play a role in T-cell proliferation, but the event(s) that result in the late leukaemic phase are unknown. The lack of effective therapy against HTLV-I-induced leukaemia renders prevention of viral infection the best means to eliminate HTLV-I associated diseases. Elimination or reduction of breast feeding from seropositive mothers in Japan has already produced encouraging results. In developing countries, probably only a vaccine will prevent the spread of HTLV-I infection. The molecular epidemiology of HTLV and STLV will help understand not only the phylogeny of these viruses but also the migration of human populations in the past. Episodes of horizontal transmission in the past and probably the present, indicates that nonhuman primates are the natural reservoir of HTLVs. New related viruses will likely be discovered in monkeys (and humans) in the future.

[Simian AIDS virus: review]. / Affen-Aidsviren: Ubersicht.

The review article on Simian AIDS viruses compiles the presently known facts of AIDS-related simian retroviruses causing immunodeficiencies or lymphomas in nonhuman primates. They are also compared to the situation in man. Simian acquired immunodeficiencies or lymphoproliferative diseases can be caused by infectious (exogenous) oncoviruses (C- or D-type) or by lentiviruses. Infectious D-type oncoviruses of simian origin are: Mason-Pfizer Monkey Virus (MPMV), Simian Retrovirus type 1 (SRV-1), Simian Retrovirus type 2 (SRV-2). The simian D-type oncoviruses do not have a counterpart in man. Infectious C-type oncovirus of monkeys is STLV, related to, but not identical with HTLV. Most serious to man might be simian lentivirus-infections (SIVs) due to the genetic instability of many lentiviruses. The properties of the different viruses, the clinical symptoms and morphological lesions caused by these agents are outlined and the possible dangers to man discussed. MPMV and the SRVs are considered as genetically stabilized and probably not infectious to man, at least no D-type virus infections of man are known. STLV should be treated with caution due to the close genetic relationship of man and nonhuman primates and of STLV and HTLV, although even in STLV-positive colonies no human infections were reported so far. Extreme caution seems advisable regarding the SIVs, not only because of the close phylogenetic and genetic relationships to HIVs. HIVs and SIVs, which are considered to have diverged only comparably recently from common ancestors and from each other possess a marked genetic plasticity (unstability). Therefore working with Old World monkeys, especially of African origin, with tissues of blood obtained from such animals requires certain protective action.