Divergent simian T-cell lymphotropic virus type 3 (STLV-3) in wild-caught Papio hamadryas papio from Senegal: widespread distribution of STLV-3 in Africa

Among eight samples obtained from a French primatology research center, six adult guinea baboons (Papio hamadryas papio), caught in the wild in Senegal, had a peculiar human T-cell leukemia virus type 2 (HTLV-2)-like Western blot seroreactivity (p24(+), GD21(+), K55(+/-)). Partial sequence analyses of the tax genes (433 bp) indicated that these baboons were infected by a novel divergent simian T-cell lymphotropic virus (STLV). Analyses of the complete proviral sequence (8,892 bp) for one of these strains (STLV-3/PPA-F3) indicate that this STLV was highly divergent from the HTLV-1 (61.6% of nucleotide similarity), HTLV-2 (61.2%), or STLV-2 (60.6%) prototype. It was, however, much more closely related to the few other known STLV-3 strains, exhibiting 87 and 89% of nucleotide similarity with STLV-3/PHA-PH969 (formerly PTLV-L/PH969) and STLV-3/CTO-604, respectively. The STLV-3/PPA-F3 sequence possesses the major HTLV or STLV open reading frames corresponding to the structural, enzymatic, and regulatory proteins. However, its long terminal repeat comprises only two 21-bp repeats. In all phylogenetic analyses, STLV-3/PPA-F3 clustered together in a highly supported single clade with the other known strains of STLV-3, indicating an independent evolution from primate T-cell lymphotropic virus type 1 (PTLV-1) and PTLV-2. The finding of a new strain of STLV-3 in a West African monkey (Guinea baboon) greatly enlarges the geographical distribution and the host range of species infected by this PTLV type in the African continent. The recent discovery of several different STLV-3 strains in many different African monkey species, often in contact with humans, strongly suggests potential interspecies transmission events, as it was described for STLV-1, between nonhuman primates but also to humans.     

Inbreeding,heterozygosity, and lymphoma risk among the baboons (Papio hamadryas) of Sukhumi,USSR

This paper describes the spread of lymphoma through a baboon (Papio hamadryas) colony in the Institute of Experimental Pathology and Therapy at Sukhumi, USSR. In the late 1960s, Soviet scientists inoculated 12 baboons with cells from hospitalized human leukemia patients, causing the death of a total of 135 animals between 1967 and 1978. The death rate from lymphoma averages almost 12 baboons per year in the Sukhumi colony. Genetic investigations of these baboons revealed the following: 1) Six blood protein markers out of 16 systems (38%) tested were polymorphic; 2) the average inbreeding coefficient for the entire colony (N = 1,226) was 0.027 (exclusion of baboons with F values equal to 0.0 raised the mean inbreeding coefficient to 0.096); 3) no relationship between inbreeding and risk of lymphoma was noted; and 4) there was an apparent association between both PGM loci and the incidence of lymphoma at the 0.005 levels of significance. This association was further supported by the significantly lower incidence of PGM2 (2-1) genotype in baboons with high anti-VCA-HVP titers.     

Molecular epidemiology of simian T-cell lymphotropic virus type 1 in wild and captive sooty mangabeys

A study was conducted to evaluate the prevalence and diversity of simian T-cell lymphotropic virus (STLV) isolates within the long-established Tulane National Primate Research Center (TNPRC) colony of sooty mangabeys (SMs; Cercocebus atys). Serological analysis determined that 22 of 39 animals (56%) were positive for STLV type 1 (STLV-1). A second group of thirteen SM bush meat samples from Sierra Leone in Africa was also included and tested only by PCR. Twenty-two of 39 captive animals (56%) and 3 of 13 bush meat samples (23%) were positive for STLV-1, as shown by testing with PCR. Nucleotide sequencing and phylogenetic analysis of viral strains obtained demonstrated that STLV-1 strains from SMs (STLV-1sm strains) from the TNPRC colony and Sierra Leone formed a single cluster together with the previously reported STLV-1sm strain from the Yerkes National Primate Research Center. These data confirm that Africa is the origin for TNPRC STLV-1sm and suggest that Sierra Leone is the origin for the SM colonies in the United States. The TNPRC STLV-1sm strains further divided into two subclusters, suggesting STLV-1sm infection of two original founder SMs at the time of their importation into the United States. STLV-1sm diversity in the TNPRC colony matches the high diversity of SIVsm in the already reported colony. The lack of correlation between the lineage of the simian immunodeficiency virus from SMs (SIVsm) and the STLV-1sm subcluster distribution of the TNPRC strains suggests that intracolony transmissions of both viruses were independent events.     

Genetics of primate lymphomas in a baboon (Papio hamadryas) colony of Sukhumi,USSR

A lymphoma outbreak occurred at the Sukhumi Center in the Late 1960's, when 12 baboons were inoculated with blood from human leukemia patients. Out of a total of 3219 animals, 218 contracted lymphoma and died. This outbreak appears to be primarily horizontal in transmission. Genetic investigations reveal that: (1) inbreeding does not increase risk of lymphoma; (2) there is a weak association between the PGM₂ locus and lymphoma; (3) based upon path analysis, there is evidence of a significant transmissible component (genetic predisposition) passed from the parental to the next generation.     

Subsets of T cells in healthy rhesus macaques (Macaca mulatta) infected with simian T-lymphotropic virus type 1

Simian T-lymphotropic virus type 1 (STLV-1) is a C-type retrovirus of nonhuman primates that is genetically and antigenically related to human T-lymphotropic virus type 1 (HTLV-1). Infection with STLV-1 has been reported in many species of Old World monkeys and apes, including rhesus macaques (Macaca mulatta). Similar to HTLV infection in humans, STLV infection has been associated with T-cell lymphoproliferative disease or lymphoma in a small proportion of infected animals, predominantly African species. There are conflicting reports of T-cell subset alterations in healthy HTLV-1 carriers. To the authors' knowledge, analysis of T-cell subsets in healthy STLV-1 carrier rhesus macaques has not been reported. Subsets of T cells in peripheral blood from healthy, STLV-1-seropositive rhesus macaques (n = 17) and seronegative controls matched for age and sex (n = 17) were determined by use of fluorescence-activated cell sorter analysis. Parameters measured included CD3, CD4, CD8, CD25, CD28, CD38, and HLA-DR cell sets. Significant differences in T-cell subsets or hematologic parameters were not observed between healthy STLV-seropositive and seronegative groups.     

High variety of different simian T-cell leukemia virus type 1 strains in chimpanzees (Pan troglodytes verus) of the Taï National Park, Côte d'Ivoire

We found human T-cell leukemia virus type 1- and simian T-cell leukemia virus type 1 (STLV-1)-related infections in 5 of 10 chimpanzees originating from three groups of wild chimpanzees. The new virus isolates showed a surprising heterogeneity not only in comparison to STLV-1 described previously in other primate species but also between the different chimpanzee groups, within a group, or even between strains isolated from an individual animal. The interdisciplinary combination of virology, molecular epidemiology, and long-term behavioral studies suggests that the primary route of infection might be interspecies transmission from other primates, such as red colobus monkeys, that are hunted and consumed by chimpanzees.     

Viruses detected in cells explanted into tissue culture from naturally occurring malignant lymphoma in rhesus monkeys

During a 4-year period 43 cases of spontaneous lymphoma occurred in macaques at the California Primate Research Center. In an attempt to determine if there might be a common viral etiology to the outbreak, lymphoma tissues from 10 rhesus monkeys were explanted into tissue culture and examined for the presence of virus. Electron microscopic studies of the cultured lymphoma cells revealed viruses morphologically characteristics of adenovirus, reovirus, foamy virus, and herpesvirus. Cell-free filtrates from tissue cultures possessing the latter three viruses produced cytopathology in virus-free indicator cells. Virus particles typical of the explant culture were demonstrable in the infected indicator cells. Type-C RNA tumor virus particles were not observed electron microscopically in any of the lymphoma tissues or lymphoma cell cultures examined.     

Isolation and characterization of a new simian T-cell leukemia virus type 1 from naturally infected celebes macaques (Macaca tonkeana): complete nucleotide sequence and phylogenetic relationship with the Australo-Melanesian human T-cell leukemia virus type 1.

A study of simian T-cell leukemia virus type 1 (STLV-1) infection in a captive colony of 23 Macaca tonkeana macaques indicated that 17 animals had high human T-cell leukemia virus type 1 (HTLV-1) antibody titers. Genealogical analysis suggested mainly a mother-to-offspring transmission of this STLV-1. Three long-term T-cell lines, established from peripheral blood mononuclear cell cultures from three STLV-1-seropositive monkeys, produced HTLV-1 Gag and Env antigens and retroviral particles. The first complete nucleotide sequence of an STLV-1 (9,025 bp), obtained for one of these isolates, indicated an overall genetic organization similar to that of HTLV-1 but with a nucleotide variability for the structural genes ranging from 7.8 to 13.1% compared with the HTLV-1 ATK and STLV-1 PTM3 Asian prototypes. The Tax and Rex regulatory proteins were well conserved, while the pX region, known to encode new proteins in HTLV-1 (open reading frames I and II), was more divergent than that in the ATK strain. Furthermore, a fragment of 522 bp of the gp21 env gene from uncultured peripheral blood mononuclear cell DNAs from five of the STLV-1-infected monkeys was sequenced. Phylogenetic trees constructed with the long terminal repeat and env (gp46 and gp21) regions demonstrated that this new STLV-1 occupies a unique position within the Asian STLV-1 and HTLV-1 isolates, being, by most analyses, related more to the Australo-Melanesian HTLV-1 topotype than to any other Asian STLV-1. These data raise new hypotheses on the possible interspecies viral transmission between monkeys carrying STLV-1 and early Australoid settlers, ancestors of the present day Australo-Melanesian inhabitants, during their migrations from the Southeast Asian land mass to the greater Australian continent.     

Virological studies of baboon (Papio hamadryas) lymphoma: isolation and characterization of foamyviruses.

In accordance with a memorandum of understanding in cancer research between scientists in the USSR and the USA, virological studies were performed on two baboons from the Russian colony at the Institute of Experimental Pathology and Therapy at Sukhumi where several cases of leukemia have been observed over the past few years. Foamyvirus isolations were made from lymphoid cells of both of these monkeys, one of which had a confirmed case of lymphoma. The isolates were similar to each other serologically and morphologically, possessed characteristics typical of foamyviruses, and cross-reacted to a low level with antibody to simian foamyvirus type 1.     

Simian T-Cell Lymphotropic Virus Type 1 from Mandrillus sphinx as a Simian Counterpart of Human T-Cell Lymphotropic Virus Type 1 Subtype D

A recent serological and molecular survey of a semifree-ranging colony of mandrills (Mandrillus sphinx) living in Gabon, central Africa, indicated that 6 of 102 animals, all males, were infected with simian T-cell lymphotropic virus type 1 (STLV-1). These animals naturally live in the same forest area as do human inhabitants (mostly Pygmies) who are infected by the recently described human T-cell lymphotropic virus type 1 (HTLV-1) subtype D. We therefore investigated whether these mandrills were infected with an STLV-1 related to HTLV-1 subtype D. Nucleotide and/or amino acid sequence analyses of complete or partial long terminal repeat (LTR), env, and rex regions showed that HTLV-1 subtype D-specific mutations were found in three of four STLV-1-infected mandrills, while the remaining monkey was infected by a different STLV-1 subtype. Phylogenetic studies conducted on the LTR as well as on the env gp21 region showed that these three new STLV-1 strains from mandrills fall in the same monophyletic clade, supported by high bootstrap values, as do the sequences of HTLV-1 subtype D. These data show, for the first time, the presence of the same subtype of primate T-cell lymphotropic virus type 1 in humans and wild-caught monkeys originating from the same geographical area. This strongly supports the hypothesis that mandrills are the natural reservoir of HTLV-1 subtype D, although the possibility that another monkey species living in the same area could be the original reservoir of both human and mandrill viruses cannot be excluded. Due to the quasi-identity of both human and monkey viruses, interspecies transmission episodes leading to such a clade may have occurred recently.     

The simian T-lymphotropic/leukemia virus from Pan paniscus belongs to the type 2 family and infects Asian macaques.

The proviral DNA of the simian T-leukemia/lymphotropic virus (STLV) isolate, originally obtained from a captive colony of pygmy chimpanzees (Pan paniscus) (STLV(pan-p)), was cloned from the DNA of the chronically infected human T-cell line L93-79B. The entire proviral DNA sequence was obtained and compared with sequences of the known genotypes of STLV and human T-leukemia/lymphotropic virus types 1 and 2 (HTLV-1 and -2). Phylogenetic analysis indicates that STLV-2(pan-p) is an early divergence within the type 2 lineage and should be referred to as STLV-2(pan-p). Since STLV-2(pan-p) has been found in African nonhuman primates, we investigated its infectiousness and pathogenicity in Asian monkeys. Pigtailed macaques were inoculated with human cells harboring STLV(pan-p), and infection was assessed by virus isolation, PCR analysis of peripheral blood mononuclear cells, and seroconversion against viral antigens in HTLV-1/HTLV-2 and Western blot assay. Pigtailed macaques became persistently infected by STLV-2(pan-p), and the virus could be transferred by blood transfusion from an infected pigtailed macaque to a rhesus macaque. In addition, like HTLV-1 and HTLV-2, STLV-2(pan-p) was infectious in rabbits. In summary, STLV-2(pan-p) is a novel retrovirus distantly related to HTLV-2 and displays a host range similar to that demonstrated for other HTLV and STLV strains.     

Simian T-cell leukemia virus (STLV) infection in wild primate populations in Cameroon: evidence for dual STLV type 1 and type 3 infection in agile mangabeys (Cercocebus agilis)

Three types of human T-cell leukemia virus (HTLV)-simian T-cell leukemia virus (STLV) (collectively called primate T-cell leukemia viruses [PTLVs]) have been characterized, with evidence for zoonotic origin from primates for HTLV type 1 (HTLV-1) and HTLV-2 in Africa. To assess human exposure to STLVs in western Central Africa, we screened for STLV infection in primates hunted in the rain forests of Cameroon. Blood was obtained from 524 animals representing 18 different species. All the animals were wild caught between 1999 and 2002; 328 animals were sampled as bush meat and 196 were pets. Overall, 59 (11.2%) of the primates had antibodies cross-reacting with HTLV-1 and/or HTLV-2 antigens; HTLV-1 infection was confirmed in 37 animals, HTLV-2 infection was confirmed in 9, dual HTLV-1 and HTLV-2 infection was confirmed in 10, and results for 3 animals were indeterminate. Prevalences of infection were significantly lower in pets than in bush meat, 1.5 versus 17.0%, respectively. Discriminatory PCRs identified STLV-1, STLV-3, and STLV-1 and STLV-3 in HTLV-1-, HTLV-2-, and HTLV-1- and HTLV-2-cross-reactive samples, respectively. We identified for the first time STLV-1 sequences in mustached monkeys (Cercopithecus cephus), talapoins (Miopithecus ogouensis), and gorillas (Gorilla gorilla) and confirmed STLV-1 infection in mandrills, African green monkeys, agile mangabeys, and crested mona and greater spot-nosed monkeys. STLV-1 long terminal repeat (LTR) and env sequences revealed that the strains belonged to different PTLV-1 subtypes. A high prevalence of PTLV infection was observed among agile mangabeys (Cercocebus agilis); 89% of bush meat was infected with STLV. Cocirculation of STLV-1 and STLV-3 and STLV-1-STLV-3 coinfections were identified among the agile mangabeys. Phylogenetic analyses of partial LTR sequences indicated that the agile mangabey STLV-3 strains were more related to the STLV-3 CTO604 strain isolated from a red-capped mangabey (Cercocebus torquatus) from Cameroon than to the STLV-3 PH969 strain from an Eritrean baboon or the PPA-F3 strain from a baboon in Senegal. Our study documents for the first time that (i) a substantial proportion of wild-living monkeys in Cameroon is STLV infected, (ii) STLV-1 and STLV-3 cocirculate in the same primate species, (iii) coinfection with STLV-1 and STLV-3 occurs in agile mangabeys, and (iv) humans are exposed to different STLV-1 and STLV-3 subtypes through handling primates as bush meat.     

Survival and reproduction in the first two years following a large-scale primate colony move and social reorganization

(Macaca nemestrina) and baboon (Papio cynocephalus, Papio anubis, and hybrids) breeding colonies from the Primate Field Station (PFS) (Medical Lake, WA) to the Tulane Regional Primate Research Center (Covington, LA). Colony records on all 598 pigtailed macaques (Macaca nemestrina) and 157 baboons (P. c. anubis) shipped to the Tulane Primate Center from the PFS breeding colony were used for analysis of species, sex, age, origin, current status, and the number of animals born at Tulane and their status. To provide comparative statistics, colony records on all 1,002 macaques and 258 baboons alive on 1 January 1991 at the Field Station were retrieved in the same manner as the Tulane data. Overall survival rates of macaques in the months following the move (71.7%) were similar to those associated with the Arashiyama West colony move from Japan to Texas. In our colony, significantly lower survival following the move was seen only in older (10 years+) macaques, while survival in other age groups was slightly lower than in the comparison year of 1991 at the Primate Field Station. Captive-bred macaques exhibited higher survival than wild-caught animals. Infant survival at Tulane was not significantly different than in pre-move years. Baboons fared well in the move, with no significant differences in mortality or reproduction when compared with the 1991 Medical Lake baboon colony.     

High Prevalence of Simian T-Lymphotropic Virus Type L in Wild Ethiopian Baboons

Simian T-cell leukemia viruses (STLVs) are the simian counterparts of human T-cell leukemia viruses (HTLVs). A novel, divergent type of STLV (STLV-L) from captive baboons was reported in 1994, but its natural prevalence remained unclear. We investigated the prevalence of STLV-L in 519 blood samples from wild-living nonhuman primates in Ethiopia. Seropositive monkeys having cross-reactive antibodies against HTLV were found among 22 out of 40 hamadryas baboons, 8 of 96 anubis baboons, 24 of 50 baboons that are hybrids between hamadryas and anubis baboons, and 41 of 177 grivet monkeys, but not in 156 gelada baboons. A Western blotting assay showed that sera obtained from seropositive hamadryas and hybrid baboons exhibited STLV-L-like reactivity. A PCR assay successfully amplified STLV sequences, which were subsequently sequenced and confirmed as being closely related to STLV-L. Surprisingly, further PCR showed that nearly half of the hamadryas (20 out of 40) and hybrid (19 out of 50) baboons had STLV-L DNA sequences. In contrast, most of the seropositive anubis baboons and grivet monkeys carried typical STLV-1 but not STLV-L. These observations demonstrate that STLV-L naturally prevails among hamadryas and hybrid baboons at significantly high rates. STLV-1 and -2, the close relative of STLV-L, are believed to have jumped across simian-human barriers, which resulted in widespread infection of HTLV-1 and -2. Further studies are required to know if STLV-L is spreading into human populations.     

Use of nonhuman primates in cancer research

A short historical review of the use of primates in cancer research is presented followed by a review of various forms of neoplasma observed in the oldest existing Primate Center. Special attention is paid to baboon lymphomas studied for the past two decades at the U.S.S.R. Primate Center at Sukhumi.     

Etiological aspects of leukemias in primates including man

Attempts have been made to induce viral leukemia in monkeys (Papio hamadryas and Macaca arctoides) by inoculating them with blood from humans with different types of leukemias. In hamadryas baboons, the disease spread horizontally. By today 218 P. hamadryas and 5 M. arctoides monkeys had died of malignant lymphoma. The following viruses have been isolated from sick monkeys: lymphotropic baboon herpes virus (HVP), endogenous baboon C type viruses--xenotropic (BILN), and ecotropic (EVPG). C type oncovirus called "plasmic", which differs immunologically from the endogenous one, was also detected in the blood of sick animals. Altogether 165 sera from baboons, different species of macacas and chimpanzee were examined by the immunofluorescent technique for antibodies to HTLV virus isolated recently from sick humans with T cell leukemia/lymphoma. Antibodies to HTLV virus were detected only in monkeys (P. hamadryas and M. arctoides) with malignant lymphomas or in those which had been in close contact with them. Possible origin of simian HTLV-like virus is discussed. It originates either from leukemic patients or there is a family of primate HTLV like viruses related to the occurrence of leukemia.     

Cytomorphological and immunocytochemical study of non-Hodgkin's lymphoma in pleural effusion and ascitic fluid

INTRODUCTION: Non-Hodgkin's lymphoma (NHL) is often complicated by pleural effusion and ascites. The present study is an attempt to categorize the lymphomatous effusions according to the WHO classification, using archival material. METHODS: May-Grünwald-Giemsa and Papanicolaou-stained smears of 31 lymphomatous effusion specimens were reviewed. Of these, detailed cytological assessment was done on 12 pleural effusions and ten ascitic fluid specimens from 22 patients using the WHO lymphoma classification system. Immunocytochemical studies were performed in 21 specimens. RESULTS: Based on cytomorphological features, the 22 lymphomatous effusion specimens were categorized into lymphoplasmacytoid lymphoma (1), follicle centre cell (FCC) grade-1 (centrocytic) lymphoma (3), FCC grade-2 (centrocytic-centroblastic) lymphoma (3), FCC grade-3 (centroblastic) lymphoma (4), large cell immunoblastic lymphoma (4), lymphoblastic lymphoma (2), anaplastic large cell lymphoma (3) and miscellaneous types (2). Immunocytochemically, the lymphoma cells were T-cell (positive for CD3) and B-cell type (CD20 positive) in five and six cases respectively. CONCLUSION: Cytological examination of pleural effusion and ascitic fluid samples, supported by immunocytochemical studies, may be useful for the classification of lymphomas under the WHO system.     

Passage of human T-cell leukemia virus type-1 during progression to cutaneous T-cell lymphoma results in myelopathic disease in an HTLV-1 infection model

Studies comparing functional differences in human T-cell leukemia virus type 1 (HTLV-1) clones that mediate distinct outcomes in experimentally infected rabbits, resulted in a dermatopathic smoldering adult T-cell leukemia/lymphoma following chronic infection with HTLV-1 strain RH/K34. During the 3.5 years' follow-up, HTLV-1 skin disease progressed to cutaneous T-cell lymphoma. When infection was passed to several naive rabbits, progressive paraparesis due to myelopathic neurodegeneration, analogous to HTLV-associated myelopathy, resulted in one of 4 transfusion recipients. Similar proviral loads were detected in the two diseases, regardless of stage of progression or tissue compartment of infection. Complete proviral sequences obtained from the donor and affected recipient aligned identically with each other and with the inoculated virus clone. Existence of disparate pathogenic outcomes following infectious transmission further extends the analogy of using rabbits to model human infection and disease. Although the experimental outcomes shown are limited by numbers of animals affected, they mimic the infrequency of HTLV-1 disease and authenticate epidemiological evidence of virus sequence stability regardless of disease phenotype. The findings suggest that further investigation of a possible role for HTLV-1 in some forms of cutaneous T-cell lymphoma is warranted.     

A field study of infection with human T-cell leukemia virus among African primates

African non-human primates were surveyed seroepidemiologically for natural infection of human T-cell leukemia virus type I (ATLV/HTLV-I) or its closely related virus(es). Materials from three genera (Cercopithecus, Papio, and Theropithecus), four species (grivet monkey, Anubis baboon, Hamadryas baboon, and gelada), totalling 983 animals under natural conditions, were obtained in a field study in Ethiopia. Virus infection was determined by the indirect immunofluorescence test using HTLV-I specific antigens. Animals seropositive for HTLV-I were found among grivet monkeys and Anubis baboons including the hybrid offspring between Anubis and Hamadryas baboons but not pure-Hamadryas baboons and geladas. From these results, the HTLV-I family was proved to be widespread on the African continent and was regarded as a common retrovirus among catarrhines.